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 References R-39

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Boersma, L. E., et al. Nicotine Regional brain activity in Corder, G., et al. (2016). Struc- external sensory perception
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22 Meyer4e References.indd 39 12/15/21 12:56 PM

 The Opioids 361

FIGURE 11.21 PET scans of cerebral blood Amygdala Nature video Cocaine video
flow Blood flow in a cocaine-dependent individual
differed during exposure to a non–drug-related
video (nature video) and exposure to a cocaine-­
related video containing many cues. Areas with

From A. R. Childress et al. 1999. Am J Psychiatry 156: 11–18

the greatest activity are shown in red. Activity in
the amygdala and anterior cingulate is signifi- 2.5
cantly increased during the cocaine video.
1.5

2.0
Anterior cingulate
environmental stimuli in humans as well 1.0
(Childress et al., 1986). The high rate of re-
lapse among detoxified people may be due 0.5
to the conditioned abstinence syndrome in 0.0
the old environment. O’Brien (1993) and
others have presented reports of individu-
als who describe withdrawal symptoms
when they visit areas of prior drug use
even years after the withdrawal syndrome
has ended. These findings have convinced many re- symptoms on a fairly regular basis because they have
searchers that learning is a critical factor in opioid use difficulty securing more drug. Alternatively, detoxi-
disorder (WEB BOX 11.4). Under what circumstance fication may be assisted by the administration of a
individuals develop drug-enhancing associations or long-acting opioid drug, such as methadone, that reduc-
drug-opposing responses is not clear, but the meso- es the symptoms to a tolerable level. The dose of metha-
limbic DA pathway may be involved in both (Self and done is gradually reduced over a period of 5 to 7 days
Nestler, 1995). until it can be terminated with only mild symptoms.
Sometimes the α2-adrenergic agonist clonidine is used in
Treatment programs for opioid use disorder this stage. Clonidine acts on noradrenergic autoreceptors
Treating opioid use disorder requires understanding to reduce norepinephrine activity. Since the noradrener-
the multiple contributors to the problem. Treatment gic neurons in the locus coeruleus are inhibited by opi-
clearly depends on more than eliminating the drug oids and the cells increase firing during withdrawal (see
from the body (detoxification), since the relapse rate Nestler et al., 1994, described earlier), clonidine-induced
for detoxified people is very high. Ultimately, a host inhibition of firing reverses this hyperexcitable state.
Meyer 4e
of behavioral and social factors must be identified and The drug seems to relieve the chills, tearing, yawning,
Psychopharmacology
altered for a successful outcome. stomach
Dragonfly Media cramps, sweating, and muscle aches that are as-
Group
Most drug treatment programs utilize a biopsycho- sociated with the activity of the locus coeruleus but does
Sinauer Associates
social model as the basis for therapy. Models in this not reduce
Meyer4e_11.21 the remaining withdrawal symptoms nor the
10-21-21
category take into account the multidimensional nature subjective discomfort and craving (Gold, 1989; O’Brien,
of chronic drug use: 1993). Unfortunately, clonidine itself has side effects, in-
■ The physiological effects of the drug on nervous
cluding insomnia, dry mouth, sedation, joint pain, and
dizziness. For these reasons, it is not very popular with
system functioning, as when the opioids activate
opioid-dependent individuals, who much prefer detoxi-
the mesolimbic reward pathway
fication with an opioid.
■ The psychological status of the individual and the
An ultrarapid detoxification that is completed in
individual’s unique neurochemical makeup and a few hours or over several days requires that with-
history of drug use drawal be initiated with opioid antagonists while the
■ The environmental factors that provide salient patient is treated with clonidine, a benzodiazepine, or
cues for drug taking and powerful secondary general anesthesia. This method is considered by many
reinforcement. to be ineffective because it does not produce improved
abstinence rates and is associated with potentially
Detoxification is the first step in the life-threatening events.
therapeutic process Rather than pharmacological intervention to prevent
Detoxification, or the elimination of the abused drug withdrawal, it is possible to use electroacupuncture
from the body, can be assisted or unassisted. Unassisted (EA) instead. Using morphine-dependent rats, G. B.
detoxification is often referred to as going “cold tur- Wang and colleagues (2011) showed that 30 minutes of
key,” and many opioid abusers experience withdrawal 100-Hz EA delivered 12 hours after the last morphine

11_Meyer4e_CH11.indd 361 12/9/21 11:30 AM

 126 Chapter 4

The technique requires a specialized cannula made might sample extracellular materials at nerve termi-
of a fine, cylindrical semipermeable membrane that is nals following discrete electrical or chemical stimula-
implanted stereotaxically (FIGURE 4.14B). The mem- tion of neural pathways.
brane surface is sealed along its length except at the A second method used to measure neurotransmitter
tip, allowing investigators to sample material in the release is in vivo voltammetry. Whereas microdialysis
extracellular space at precise sites, even deep within collects samples of extracellular fluid for subsequent
the brain. Artificial cerebrospinal fluid (CSF) is con- analysis, in vivo voltammetry uses stereotaxically im-
tinuously pumped through the microdialysis cannula. planted microelectrodes to measure neurochemicals
The CSF in the cannula and in the extracellular fluid in the extracellular fluid of freely moving animals. In
are identical except for the material to be collected. On voltammetry, a very fine electrode is implanted, and
the basis of the difference in concentration, chemicals a small electrical potential is applied. Changes in the
in the extracellular space, including neurotransmitters, flow of current at the electrode tip reflect changes in
diffuse across the membrane from the synaptic space the concentration of electroactive substances such as
into the cannula. The CSF is pumped out of the cannula neurotransmitters or their metabolites. A major ad-
through an outlet tube where it is collected for sub- vantage of this method is that because measurements
sequent analysis by high-performance liquid chroma- are made continuously and require as little as 15 ms
tography (HPLC) or another method. HPLC, like other to complete, researchers can evaluate neurotransmitter
types of chromatography, serves two purposes. First, release as it is occurring in real time. For an historical
chromatography separates the sample into component overview of the techniques used for monitoring extra-
parts depending on characteristics of the sample, such cellular neurotransmitter concentrations, see Kehr and
as molecular size or ionic charge. Second, the concen- Yoshitake (2013).
tration of the molecules of interest can be determined
(FIGURE 4.15). ELECTROPH YSIOLOGICA L STIMUL ATION A ND
Microdialysis is important to neuropsychophar- RECORDING In a similar fashion, implanted macro-
macology because it can be used in several types of electrodes (FIGURE 4.16A) can be used to activate cells
experiments that combine biochemical and behavioral at the tip while the change in animal behavior during
analyses. For example, we might evaluate the released stimulation is evaluated. The minute amount of electri-
neurochemicals during ongoing behaviors, such as cal current applied changes the membrane potential
sleep and waking, feeding, or operant tasks, to obtain of those cells and generates action potentials. The ac-
a window into the functioning CNS. We might also tion potentials in turn cause the release of neurotrans-
investigate the effects of drugs on extracellular concen- mitter at the cell terminals to mimic normal synaptic
trations of neurotransmitters in selected brain areas. transmission. Hence the electrical stimulation should
Since multiple samples can be collected from freely produce biobehavioral effects that are similar to those
moving animals over time, correlated changes in be- seen upon injection of the natural neurotransmitter or
havior can be monitored simultaneously. Finally, we neurotransmitter agonists into the brain. In addition,

2 Microdialysis samples 3 The sample is forced through a

are injected here. column that separates the sample
into constituent molecules. The
type of column chosen determines
how the molecules are separated
1 Pump forces mobile (e.g., by size or ionic charge).
phase fluid through
the system to move the
sample through the
column and into the
detector. 4 The detector identifies and
measures the separated
Recorder
molecules as they are washed
from the column.

Pump

Mobile
Detector
phase 5 The chromatograph pictorially
fluid shows a peak for each compound
being measured and indicates
Drain to waste the quantity of the compound.
FIGURE 4.15 Components of an HPLC system

Meyer 4e
Psychopharmacology
Dragonfly
04_Meyer4e_CH04.indd 126Media Group 12/9/21 1:16 PM
 References R-49

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 404 Chapter 12

STUDY QUESTIONS
1. Why are drugs like cocaine, amphetamine, 13. Describe (a) the observed patterns of cocaine use
and other compounds that produce similar that most commonly lead to a progression from
psychological and behavioral effects called occasional use to development of cocaine depen-
“psychostimulants”? dence/cocaine use disorder, and (b) the phenom-
2. In what part of the world is the coca shrub cul- enon of a cocaine binge and the phases of the
tivated? How did coca and cocaine make their abstinence syndrome that have been observed
way to Europe and then to the United States? following a typical binge.
3. What are the different routes of administration 14. What is the role of craving in the development of
by which people take cocaine? How are the two cocaine dependence, and what is known about
forms of cocaine, namely cocaine HCl and co- the neurobiology of cocaine craving?
caine base, related to these different routes? 15. Brain imaging studies in regular cocaine users
4. Studies performed many years ago showed that have shown that several markers of striatal do-
in vitro, cocaine binds to the plasma membrane paminergic function are ________ (increased, de-
transporters for DA, NE, and 5-HT. What are the creased, or unaffected) compared to controls who
consequences of such binding when an animal are not cocaineusers. These changes are ________
is administered cocaine or when a person con- (consistent or inconsistent) with the dopamine
sumes the drug? depletion hypothesis of cocaine addiction.
5. Acute administration of cocaine causes an 16. How is it possible that repeated cocaine use can
increased frequency of transient DA release lead to tolerance in some cases but sensitization
events. Describe the hypothesized mechanism in others? What are the patterns of cocaine use
for this effect. that lead to one or the other change in drug sen-
6. Although DA plays the most important role in sitivity, and what is known about the underlying
mediating the behavioral effects of cocaine, ACh mechanisms of these changes?
and 5-HT additionally modulate these effects. 17. Discuss the evidence for cognitive deficits and
Provide experimental findings that support this brain abnormalities in regular users of cocaine.
statement. Are these deficits and abnormalities present be-
7. What is the mechanism of action of cocaine- fore drug use begins, or are they a consequence of
based local anesthetic drugs such as Novocaine? such use? Explain your answer.
8. Compare and contrast the effects of cocaine on 18. What are the major health consequences (other
mood and behavior when taken occasionally at than neurobiological) of chronic or high-dose
low to moderate doses versus when taken chron- cocaine use?
ically and/or at high doses. 19. The following true/false questions pertain to cur-
9. The acute physiological effects of cocaine (e.g., rent treatment approaches for cocaine use disorder.
on heart rate and blood pressure) can be an- (a) Several different drugs have been approved by
tagonized by administering adrenergic receptor the FDA to treat cocaine use disorder. True or false?
blockers. Explain this finding. (b) Maintenance therapy with other psychostimu-
lants such as amphetamine, methylphenidate, or
10. Discuss the varying lines of evidence from ani-
modafinil is being tested as a possible treatment
mal studies that indicate a role of DA, especially
approach. True or false? (c) If an effective cocaine
in the nucleus accumbens (shell and core) and
vaccine could be developed, it would protect
dorsal striatum, in the behaviorally activating
people against addiction to a wide range of differ-
and rewarding/reinforcing effects of cocaine and
ent psychostimulants. True or false? (d) One of the
other psychostimulants such as amphetamine.
most effective currently available treatments for
11. The text states that based on PET imaging stud- addiction to cocaine or amphetamine is a combina-
ies, “once a certain minimum level of DAT occu- tion of contingency management plus community
pancy (about 40% to 60%) is attained following reinforcement. True or false?
either cocaine or methylphenidate administra- 20. Amphetamine, methamphetamine, cathinone,
tion, the individual may experience a drug- and ephedrine are related structurally to the
induced high.” Note the use of the word “may.” neurotransmitter ________.
What are the two factors that are believed to de-
termine whether or not a high is likely to occur? 21. Describe the key historical events in the discov-
ery of amphetamine and its subsequent progres-
12. The ________ DA receptor subtype is necessary
sion to recreational use.
for cocaine’s behavioral effects to occur. What ex-
perimental evidence supports the critical role of 22. What are the typical routes of administration of
this subtype? What other DA receptor subtypes amphetamine and methamphetamine? What are
contribute to these effects and in what way? the features of binge use (i.e., a “speed run”) of
these drugs?

12_Meyer4e_CH12.indd 404 12/22/21 2:03 PM

 I-4 Index

benzodiazepine-GABAA prevalence of use by depression, 116–117, 594–595 environmental cues and opi-
modulation of anxiety, 559 adolescent and adult men, effects of antidepressants on oid tolerance, 360
comorbidity of anxiety 531–532 serotonin, 599–601 functional abnormalities in
disorders and alcohol use side effects in women, 531 GHB reinforcement, 524, 525 schizophrenia, 624
disorder, 320 structural relationship to Huntington’s disease, 142–143 intravenous ketamine for
conditioned emotional re- testosterone, 530, 539 inhalant reinforcement, treatment of depression
sponse, 551 therapeutic applications, 517–518 and, 614
corticotropin-releasing factor 541–543 mania, 595–596 neurobiology of depression
and the anxiety response, Anacin, 440 nicotine dependence, 419 and, 602
553 Anadrol (oxymetholone), 529, nicotine reinforcement, 413 pain pathways and, 344, 345,
effects of early life stress on 530, 533, 536 obsessive-compulsive disor- 349
stress regulation, 564–565 Anafranil (clomipramine), 584, der, 116, 122, 574 PTSD and, 573
emotional memory, 551 611 opioid reinforcement, 353–354 serotonin-dependent develop-
generalized anxiety disorder, analeptics, 487 Parkinson’s disease, 658, 659 ment of the anxiety circuitry
568–569 analgesia quantification of pain, 344 and, 562
individual differences in the acupuncture, 349–350 schizophrenia, 122, 504, anterior hippocampus, 399
anxiety response, 563 animal measures of, 112 631–635 anterior nucleus of hypothala-
memory consolidation, 551 botulinum toxin A and, 206 toluene reinforcement, mus, 68, 539–540
modulation of anxiety by dual inhibition of enkephalin 517–518 anterior pituitary
dopamine, 562 peptidases, 350 animal studies/testing anxiety response and, 552
modulation of anxiety by gene therapy, 350–351 in alcohol research, 307–316 hormones secreted by, 100, 101
serotonin, 560–561, 562 opioids and, 347–351 drug reward studies, 266–267 hypothalamic–pituitary axis
morphological effects of periaqueductal gray and, 67 drug self-administration stud- and, 101
chronic stress, 567 analgesics ies, 264–267 hypothalamus and, 68
neurosteroid modulation of caffeine and, 440 effects of MDMA on forebrain neuroendocrine response to
GABA in anxiety, 560 difficulties in quantifying the serotonergic neurons, 185 stress and, 69
panic disorder, 569 effects of, 344 epigenetic mechanisms in anterograde amnesia, 579
PTSD, 573 dose–response curves, 29–30 drug addiction, 281–282 anteropulsion, 655
social anxiety disorder, ketamine, 509–510 firing patterns of serotonergic antianxiety drugs. See anxiolytics
570–571 overview, 27 dorsal raphe nuclei neurons antiasthma medications, 174–175
amyl nitrite, 514, 515 variations in interspecies in cats, 189 antibodies
β-amyloid (beta-amyloid), 663, responses to, 24 fragile X syndrome and trans- therapy for Alzheimer’s dis-
664, 665, 668 See also narcotic analgesics lational medicine, 231–233 ease and, 667
amyloid plaques Anamirta cocculus, 244 human and rat brains com- treatment of cocaine use disor-
description of, 663–664 anandamide, 79, 453, 454 pared, 71–72 der and, 387
PET visualization techniques, Anbesol, 56 methods to quantify and lo- using to identify and measure
665–666 Andriol (testosterone undecano- cate neurotransmitters and receptors, 130–132
treatment of, 667 ate), 529, 530 receptors, 127–134 anticholinergic drugs
amyloid precursor protein (APP), Androderm, 529 on negative reinforcement in cognitive effects of, 212
663–664, 665 AndroGel, 529 addiction, 267–268 treatment of Parkinson’s
β-amyloid protein, 663, 664, 665, androgen receptor, 534 stereotaxic surgery, 124–127 disease, 211
669 androgens, 99 on synaptic plasticity in drug anticholinergic syndrome, 63
amyotrophic lateral sclerosis See also anabolic–androgenic addiction, 282–283 anticipatory anxiety, 569
(ALS) steroids; testosterone on synthetic cathinones, 403 anticonvulsants
impaired glutamate uptake androstanediol, 247 See also baboons; behavioral benzodiazepines as, 579
and, 50 anesthetics pharmacology methods; CBD-based cannabinoid medi-
loss of motor neurons in, 672 arousal-promoting effects of knockout mice; mice; mon- cations, 458, 459
overview and description of, methylphenidate and, 397 keys; rats; rhesus monkeys; treatment of Huntington’s
672 defined, 331 rodents; transgenic animals; disease, 671
symptoms and disease pro- GABAA receptors and, 244, transgenic mice antidepressants
gression, 672, 675 245, 246 anomia, 662 animal testing methods,
treatments for, 673 as inhalants, 514, 515 anomic aphasia, 662 116–117
Amytal (amobarbital), 118, 575, local anesthetics, 56, 375 anorexia, 2 drugs for bipolar disorder,
577 presurgical anesthetics, 579 anorexigenic neurons, 197–198 615–617
Amyvid (florbetapir), 665 “angel dust,” 501 anosmia, 656 effect on norepinephrine activ-
Anabolic Steroids Control Act angina pectoris, 176 anosognosia, 671 ity, 601
(1990), 531 angiotensin-converting enzyme 2 ANS. See autonomic nervous effect on serotonin in animals,
anabolic–androgenic steroids (ACE2), 428 system 599–601
(AAS) anhedonia, 117, 662 Anslinger, Harry, 448 effect on transporters and
adverse side effects, 535–537, animal models Antabuse (disulfiram), 324 neurotransmitter inactiva-
538–540 AAS-induced aggression, antagonist medications tion, 88
background and history as a 539–540 for cocaine use disorder, 387 epigenetic histone modifica-
doping agent, 528–531, 532 AAS-related dependence and description of, 387 tions and, 605–606
chemical and trade names, 529 reward, 541, 542 antecubital vein, 372 glucocorticoid hypothesis of
defined, 529 affective disorders, 594–596 anterior, 57, 58 depression and, 604
dependence and withdrawal, alcohol use disorder, 307–316 anterior cingulate cortex (ACC) gut–brain axis and, 200
537, 540–541, 542 Alzheimer’s disease, 110, 666 anxiety response and, 549, hippocampus and, 70
introduction, 513 behavioral effects of cocaine, 550, 552 major classes and side effects,
mechanisms of action to en- 376, 377–378 cannabinoid tolerance and, 608
hance performance, 533–535 benzodiazepine reinforce- 469 mechanisms of action, 96
metabolic tolerance, 33 ment, 580–581 corticostriatal circuitry and monoamine hypothesis and,
patterns of use, polypharmacy, bipolar disorder, 595–596 drug addiction, 279 597–598
and masking strategies, brain areas in the opioid with- effects of cocaine dependence monoamine oxidase inhibi-
532–533 drawal syndrome, 358 on, 384 tors, 608–610
brain effects of chronic can- effects of THC and CBD on, neurogenesis and, 604, 607
nabis use, 473, 474 453

23 Meyer4e Index.indd 4 12/15/21 12:57 PM

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 Methods of Research in Psychopharmacology 109

animal subjects in ways not generally appropriate her infant will show signs of FAS. Although we know
for humans, for example over long periods of time to that infants of mothers who consume alcohol are more
determine toxic effects or the potential for addiction. likely to show fetal abnormalities, the type of study
Finally, the brains and behaviors of non-human mam- described shows only a correlational relationship; we
mals and humans are similar enough to allow gener- cannot conclude that alcohol causes FAS, because other
alization across species. For instance, lesions of the factors may be responsible for both. For example, pov-
central nucleus of the amygdala of rats produce pro- erty, poor diet, or other drug use may lead to increased
found changes in the conditioned emotional response alcohol consumption and cause developmental defects
of these animals. Likewise, tumors, strokes, and surgi- in the fetus. Therefore, to learn more about how alcohol
cal procedures that damage the human amygdaloid affects fetal development, we need to perform animal
complex produce profound changes in fearfulness, studies. Since animal testing remains an important
anxiety, and emotional memory. part of new drug development and evaluation, strict
The impact of animal testing in biomedical research animal care guidelines have been developed to ensure
on the quality of human life (FIGURE 4.1) is discussed proper treatment of subjects. The animal-testing stage
in a thought-provoking manner by Hollinger (2008), as provides an important step between basic science and
are its alternatives. The need for animal experimenta- the treatment of human conditions.
tion is best seen under conditions when research using The Health Research Extension Act of 1985 pro-
human participants is impossible, as when testing the vided strict guidelines for the care of animals used in
effects of alcohol on fetal development. Ethical con- biomedical and behavioral research. The goals of that
straints prohibit researchers from administering vary- legislation include humane animal maintenance and
ing doses of alcohol to groups of pregnant women to experimentation that limits both the use of animals and
evaluate the effects on their newborns. Instead, data animal distress. Each research institution must have
collected on alcohol consumption during pregnancy an animal care committee that reviews each scientific
and the occurrence of fetal alcohol syndrome (FAS) protocol with three considerations in mind:
suggest a relationship that tells us that the more alcohol 1. The research should be relevant to human or
a pregnant female consumes, the more likely it is that animal health, advancement of knowledge, or
the good of society.
2. Alternative methods such as computer simula-
tions that do not require animal subjects must
be considered.
3. Procedures must avoid or minimize discomfort,
distress, and pain.
Periodic inspection of living conditions ensures that
they are appropriate for the species and contribute to
health and comfort; cage size, temperature, lighting,
cleanliness, access to food and water, sanitation, and
medical care are ensured. Animal care and use com-
mittees have the authority to veto any studies that they
feel do not meet all predetermined criteria.
Some animal tests used to evaluate drug effects on
Courtesy of the Foundation for Biomedical Research

physiological measures such as blood pressure or body

temperature closely resemble tests used for humans.
These tests have high face validity. However, for many
psychiatric disorders, the symptoms are described in
typically human terms, such as feelings of guilt, delu-
sions, altered mood, or disordered thinking. In these
cases, a correlated, quantifiable measure in an animal
is substituted for a more cognitive human behavior
for testing purposes. When the correlation is strong,
a drug that modifies animal behavior in a specific
way can be expected to predictably alter a particular
human behavior, even though the two behaviors may
FIGURE 4.1 Poster used to counter the claims of animal seem unrelated. For instance, if a new drug were to re-
rights activists Scientists hope to increase public awareness duce apomorphine-induced hyperactivity in rats, tests
about the benefits of animal research. on humans might show it to be effective in treating

Meyer
04_Meyer4e_CH04.indd 109 4e 12/9/21 1:16 PM
 Catecholamines 157

■ A number of reuptake inhibitors are used clinically: substantia nigra,* and the A10 group, which is found
methylphenidate and amphetamine (both DA and NE) in a nearby area called the ventral tegmental area
for ADHD, atomoxetine (NE) for ADHD, reboxetine (NE) (VTA). Axons of dopaminergic neurons in the substan-
for depression, and tricyclic antidepressants (NE and tia nigra ascend to a forebrain structure known as the
5-HT) for depression.
caudate–putamen or dorsal striatum. Note that the
■ Catecholamine breakdown is catalyzed by MAO (mainly caudate and putamen are separate, though closely re-
MAO-A) and COMT. Both enzymes are located intra­ lated, structures in humans and non-human primates,
cellularly, which means that they are not positioned
whereas the two structures are fused in rodents (hence
to metabolize catecholamine molecules in the extra­
“caudate–putamen”). Nerve tracts in the central ner-
cellular fluid.
vous system are often named by combining the site of
■ The nonselective MAO inhibitors (inhibit both MAO-A
origin of the fibers with their termination site. Hence,
and MAO-B) phenelzine and tranylcypromine have a
the pathway from the substantia nigra to the dorsal
long history of use as antidepressants but have mostly
been replaced by safer medications. striatum is called the nigrostriatal tract (FIGURE 5.9A).
Two other important ascending dopaminergic sys-
■ Selective MAO inhibitors used clinically are moclo­
tems arise from cells of the VTA. Some of the axons
bemide (MAO-A) for depression and selegiline and
rasagiline (MAO-B) for Parkinson’s disease. from these neurons travel to various structures of the
limbic system, including the nucleus accumbens (the
■ The COMT inhibitors entacapone, opicapone, and tolca-
major component of the ventral striatum), septum,
pone are also prescribed for the treatment of Parkin-
son’s disease. amygdala, and hippocampus. These diverse projec-
tions constitute the mesolimbic dopamine pathway
■ The major catecholamine metabolites are HVA for
(meso represents mesencephalon, which is the site of
DA, and MHPG (mostly central metabolism) and VMA
(mostly peripheral metabolism) for NE. origin of the fibers; limbic stands for the termination
of fibers in structures of the limbic system) (FIGURE
5.9B). Other DA-containing fibers from the VTA go to
the cerebral cortex, particularly the PFC. This group
5.2 O
 rganization and Function of of fibers is termed the mesocortical dopamine pathway
the Dopaminergic System (FIGURE 5.9C). Together, the mesolimbic and mesocor-
tical pathways are very important to psychopharma-
The dopaminergic system originates in several cell cologists because they have been implicated in the neu-
groups located primarily in the midbrain. Ascending ral mechanisms underlying drug abuse (see Chapter 9)
fibers from these cells innervate a number of forebrain and also schizophrenia (see Chapter 19).
areas, where they regulate several important behav- A few other sites of dopaminergic neurons can be
ioral functions. mentioned briefly. For example, a small group of cells
in the hypothalamus gives rise to the tuberohypo­
Two important dopaminergic cell groups are physeal dopamine pathway. This pathway is important
found in the midbrain in controlling the secretion of the hormone prolactin
In the early 1960s, Swedish researchers first began to by the pituitary gland. There are also DA-containing
map the location of DA- and NE-containing nerve cells neurons within sensory structures such as the olfactory
and fibers in the brain using a fluorescence method bulbs and the retina.
(Dahlström and Fuxe, 1964). They developed a classifi-
cation system in which the catecholamine cell groups Ascending dopamine pathways have been
(clusters of neurons that stained for either DA or NE) implicated in several important behavioral
were designated with the letter A plus a number from functions
1 to 16. According to this system, cell groups A1 to One of the key functions of DA innervation of the dor-
A7 are noradrenergic, whereas groups A8 to A16 are sal striatum via the nigrostriatal tract is to facilitate vol-
dopaminergic. In this book, we will focus on only a untary movement. Loss of this function is illustrated
few catecholaminergic cell groups that are of particu- dramatically in the case of Parkinson’s disease, which
lar interest to psychopharmacologists. To identify the involves a massive loss of DA neurons in the substan-
various systems arising from these cells, we will use tia nigra and consequent DA denervation of the dor-
both the Swedish classification system and standard sal striatum. Parkinson’s disease is characterized by
anatomical names. progressive motor dysfunction, typically beginning
Several dense clusters of dopaminergic neuronal cell
bodies are located near the base of the mesencepha- * The term “substantia nigra” means “black substance.” It is so
named because the dopaminergic neurons contain the dark pigment
lon (midbrain). Particularly important is the A9 cell neuromelanin, which is related to the melanin pigment found in
group, which is associated with a structure called the skin and hair.

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 196 Chapter 6

but also indicate the importance of postsynaptic 5-HT1A projection to the BNST, and the outputs of these brain
receptors in reducing anxiety since there are no sero- areas are illustrated in FIGURE 6.13. We saw in the pre-
tonergic cell bodies and therefore no somatodendritic vious section that the amygdala and BNST have been
autoreceptors in the area of excitation or inhibition. The strongly associated with fear and anxiety; however, this
results additionally show that the BNST is an important circuitry has also been linked to the emotion of anger
site of serotonergic modulation of anxiety-like behaviors. (Blair, 2012). Thus, it appears that when an individual
Although the amygdala has received the most attention is faced with a provocative or threatening situation, the
as a brain region that mediates negative emotions such situation is evaluated in light of the current context and
as fear and anxiety, human imaging studies have begun past experiences to determine whether the response is
to show a role for the BNST in threat processing during defensive (elicitation of anxiety or fear along with defen-
anxiety-producing situations (Knight and Depue, 2019). sive behaviors) or aggressive (elicitation of anger along
with aggressive behaviors).
AGGRESSIVE BEHAVIOR What is aggression, and Historically, the first studies linking 5-HT to aggres-
how do we define and conceptualize aggressive be- sion appeared in the 1970s and 1980s (reviewed in Rosell
haviors? In the case of human aggression, the intent and Siever, 2015). Particularly noteworthy were reports
of the actor is important. Thus, a common definition that levels of 5-HIAA in the CSF, used as an indicator of
of aggression in human studies is “behavior that is brain serotonergic activity, were inversely related to ag-
intended to cause physical or psychological harm or gressiveness in people with personality disorders such
pain to the victim.” A few different categorical systems as borderline personality disorder. Combined with other
have been used to classify human aggression. One such findings, these results gave rise to the serotonin defi-
system is to classify aggressive acts as either reactive or ciency hypothesis of aggression, which proposes that
proactive (Rosell and Siever, 2015). Reactive aggression low CNS serotonergic activity is associated with hyper-
is a response to provocation, threat, or frustration; is aggressiveness (Umukoro et al., 2013). Animal studies
accompanied by strong negative emotions of anger or designed to test this hypothesis generally support the
rage; and functions to allay those emotions. In contrast, notion that relatively high serotonergic levels/activity
proactive aggression is planned rather than provoked; are associated with reduced aggressive behavior, where-
is not typically accompanied by a negative emotional as relatively low serotonergic levels/activity are associ-
state; and functions to achieve some tangible benefit, ated with increased aggressive behavior (Ferrari et al.,
such as monetary gain, social status, and so forth. The 2005; Siever, 2008; Carrillo et al., 2009; Lesch et al., 2012;
following discussion will focus on reactive aggression, Mosienko et al., 2015; Kästner et al., 2019; Liu et al., 2019).
since we know much more about the neurobiology of Studies on the link between 5-HT and aggression in
reactive compared to proactive aggression. humans have used three major approaches: (a) correlat-
Whereas studies of human aggression can benefit ing CSF 5-HIAA levels with aggressive mood or behav-
from self-reports of intentionality and emotional state, ior, (b) determining the effects of reducing central 5-HT
animal studies must operationalize the concept of ag- levels by means of the ATD procedure, and (c) manipu-
gression. This difference in approach has led to the de- lating the serotonergic system pharmacologically and
velopment of several formal typologies of aggressive assessing the resulting effects on aggressiveness. The
behavior. For example, the typology of Nelson and results showed no reliable relationship between CSF
Chiavegatto (2001) includes eight different categories 5-HIAA levels (an index of overall brain serotonergic
of aggression that can be observed in animals under activity) and aggressiveness, a small but statistically
naturalistic and/or specific experimental conditions: significant effect of ATD on aggressive mood or behav-
predatory, antipredator, dominance, sex-related, mater- ior, and a moderately strong relationship between 5-HT
nal, territorial, defensive, and irritable aggression. and aggression based on pharmacological challenge
The neural circuit underlying reactive aggression in studies (reviewed in Duke et al., 2013). Consistent with
humans has been elucidated using a combination of ap- the last point, several studies have found that admin-
proaches, including brain imaging studies and exami- istration of the SSRI sertraline can reduce anger and
nation of behavioral changes in patients with lesions of irritability in a variety of different psychiatric disor-
various brain areas (produced by stroke, tumor, head ders (reviewed in Romero-Martinez et al., 2019). On the
trauma, or other forms of brain injury). These approach- other hand, the weak findings using other methodolog-
es have implicated an extensive circuit that includes ical approaches suggest that the relationship between
several cortical areas, the striatum, amygdala, BNST, 5-HT and aggression in humans may be more complex
hippocampus, hypothalamus, and the periaqueductal than implied by the serotonin deficiency hypothesis.
gray in the brainstem (Siever, 2008; Rosell and Siever, In summary, although the serotonin deficiency
2015). Because of their involvement in processing threat- hypothesis appears to be too simplistic, there is still
ening stimuli, the amygdala and BNST have a central substantial evidence for a significant role of 5-HT in
role in this circuit. Relevant inputs to the amygdala, its aggressive mood and behavior both in animals and in

06_Meyer4e_CH06.indd 196 12/7/21 10:45 AM

 548 Chapter 17

17.1 Neurobiology of Anxiety response, enabling us to cope with impending emer-

gency. Unfortunately, many of the dangers we face in
We turn now to a class of maladaptive behaviors that the modern world do not involve fighting off or run-
produce an enormous amount of suffering, contribute ning from predators like the saber-toothed tiger, when
to low productivity, and generate a poor quality of life increased heart rate and blood pressure, elevated blood
for a large number of individuals. The fifth edition of glucose, and surges of adrenaline would be benefi-
the Diagnostic and Statistical Manual of Mental Disorders cial. Most of the anxiety-provoking situations that we
(DSM-5) has reclassified the anxiety disorders into face demand instead that we restrain our aggressive
three major categories: anxiety disorders; obsessive– impulses (wanting to attack our hostile boss), think
compulsive disorder (OCD) and related disorders; and clearly (during a difficult exam), and remain in the
trauma-related disorders, including post-traumatic anxiety-producing situation (giving a speech to a large
stress disorder (PTSD). Although specific symptoms group) until a resolution occurs. In these circumstanc-
vary, all three of the major categories have anxiety or es, the fight-or-flight response is not helpful and may
more severe stress response as a major component. Fur- impair our ability to perform at our best.
thermore, as you will see, there are a number of common Nevertheless, despite its unpleasantness, anxiety
neurobiological features, so we will continue to include in small doses is clearly a necessary stimulus for op-
OCD and PTSD in this chapter. Although the incidence timal performance in many everyday situations. If it
of each syndrome varies, it has been estimated that 10% is contextually appropriate, anxiety is a highly adap-
to 30% of Americans will suffer from debilitating anxi- tive response to threat. Anxiety before an exam en-
ety at some point in their lives. The ways in which that courages more study; anxiety before public speaking
anxiety is expressed vary greatly and include episodes forces us to practice our presentation one more time;
of panic, phobic avoidance of anxiety-eliciting stimuli, anxiety before a first date prompts us to recheck our
intrusive thoughts or compulsive behaviors, and dam- plans for the evening. Regardless of whether we are
aging negative thinking patterns. In addition, anxiety is students, factory workers, or business people, anxiety
a factor commonly associated with other psychopathol- boosts our energy level and pushes us to work harder
ogy, particularly clinical depression. The link between and longer. But sometimes we experience too much of
anxiety and depression is well documented: according a good thing. When anxiety increases beyond a certain
to the National Comorbidity Survey, 58% of patients level, performance deteriorates noticeably, particularly
with major depression also show signs of anxiety dis- on complex tasks. What begins as increasing alertness
order (Ninan, 1999). Furthermore, both neurobiologi- and focus becomes preoccupation with our own agita-
cal and pharmacological evidence support the idea of a tion that distracts us from our task. The ANS prepares
common link between the two. Before considering some our bodies for emergency; our muscles are tense, and
specific psychiatric disorders in the “Characteristics of we may suffer from digestive problems, sleep distur-
Anxiety Disorders” section, let’s look a little closer at the bances leading to fatigue, and psychosomatic illness.
neurobiology of anxiety itself. The final section of this Overanxious students often cannot focus on an im-
chapter will discuss the drugs that can be used to treat portant exam, because they are too preoccupied with
anxiety disorders—barbiturates, benzodiazepines, and thoughts of how awful it would be to fail. Worst of all,
second-generation anxiolytics*—as well as some of the because high anxiety has damaged our performance,
potential new approaches to treatment. our failures provide more reason to be anxious, creat-
ing an escalating circular pattern (FIGURE 17.1). Once
What is anxiety? we begin to have negative feelings about ourselves and
Most anxiety manifests as a subjectively unsettling feel- our lack of productivity, depression may develop or the
ing of concern or worry that is displayed by behaviors initial stages of substance abuse may begin.
such as having a worried facial expression, as well as Brief episodes of anxiety, even when rather intense,
by bodily responses such as increased muscle tension, are not likely to be harmful and may be quite rational
restlessness, impaired concentration, sleep disturbances, in many situations. Acute anxiety occurs in response
and irritability. In addition, activation of the sympathetic to real-life stressors, and symptoms occur only in re-
branch of the autonomic nervous system (ANS) produc- sponse to these events. Pharmacological treatment is
es increased heart rate, sweating, shortness of breath, very effective in providing relief from the anxiety asso-
and other signs of the “fight-or-flight” response (see ciated with major life changes such as death of a loved
Chapter 2). Anxiety can vary in intensity from feelings one, divorce, or permanent disability or with sudden
of vague discomfort to intense sensations of terror. stressors like major surgery that trigger intense anxi-
Evolutionarily, anxiety is important to survival since ety. The anxiolytics in the benzodiazepine class are
it warns us of danger and activates the fight-or-flight extremely effective for relieving this type of anxiety.
Although anxiety is related to the negative emo-
* An anxiolytic is a drug that reduces anxiety. tion fear, it is also somewhat different. Anxiety is

17_Meyer4e_CH17.indd 548 12/8/21 11:33 AM

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 Schizophrenia: Antipsychotic Drugs 639

Because the circuitry of the limbic structures and of 19.4 C

 lassic Neuroleptics and
the frontal cortex is complex, it is not surprising that
many other neurotransmitters modulate or interact
Atypical Antipsychotics
with DA transmission. ACh, GABA, norepinephrine, Drugs useful in treating schizophrenia are called an-
serotonin, and endorphins each may play a part in the tipsychotic drugs or neuroleptics, an older term that
presentation of individual symptoms of the disorder. refers to their ability to selectively reduce emotional-
ity and psychomotor activity. A large number of drugs
SECTION SUMMARY are included in this category, and they are commonly
divided into two classes: classic neuroleptics and the
■ The dopamine hypothesis suggests that positive symp-
newer second-generation (often called “atypical”) anti-
toms are caused by excessive mesolimbic DA activity.
psychotics. Although none of the drugs is consistently
Evidence includes the following: (1) amphetamine
more effective than the others, a particular individual
produces positive symptoms in healthy individuals and
makes symptoms worse in patients with schizophre- may respond better to one drug than to another. There-
nia; (2) a strong correlation exists between D2 receptor fore, treatment may require testing several antipsy-
blockade and antipsychotic efficacy; (3) schizophrenic chotic drugs to find the one that is most effective for
individuals show exaggerated DA release after amphet- a given patient. The classic antipsychotic drugs are the
amine challenge as well as in basal conditions; and phenothiazines, such as chlorpromazine (Thorazine),
(4) there is some evidence for increased D2 receptors and the butyrophenones, such as haloperidol (Haldol).
in schizophrenia. The second-generation antipsychotics, such as clozap-
■ Evidence that the negative and cognitive symptoms are ine (Clozaril), risperidone (Risperdal), and aripiprazole
due to reduced frontal lobe function includes the fol- (Abilify), are noteworthy because they appear to pro-
lowing: (1) the negative/cognitive symptoms resemble duce fewer side effects involving abnormal movements
characteristics after frontal lobotomy; (2) the sever- (e.g., tremors, rigidity). A review of classic and atypical
ity of negative symptoms is negatively correlated with antipsychotics is provided by Li and colleagues (2016).
prefrontal brain activity and decreased DA function; and
(3) prefrontal brain lesions or D1 receptor antagonists Phenothiazines and butyrophenones are
injected into PFC impair cognitive performance. classic neuroleptics
■ The neurodevelopmental model suggests that early
Chlorpromazine was the first phenothiazine used in
mesocortical deficits due to genetics or environmental
psychiatry, but many small changes in the shape of the
events that alter brain development are followed by loss
of inhibitory control of mesolimbic cells and the onset drug molecule produced a family of related compounds
of positive symptoms. that differ in potency, clinical effectiveness, and side ef-
fects. FIGURE 19.9 shows the three-ring phenothiazine
■ Poor glutamate signaling due to hypofunction of NMDA
receptors may be responsible for positive, negative, nucleus and the structural relationships of several other
and cognitive symptoms and corresponding changes drugs in this class. By changing the chemical groups
in DA activity. at the R1 and R2 positions, many new compounds can
■ Descending glutamate neurons from PFC activate me-
be created that vary in their effects. For example, chlor-
socortical neurons. Low glutamate signaling at NMDA promazine (which has a chlorine at R2) is much more
receptors (or NMDA receptor antagonist administra- potent than promazine (which has hydrogen at the R2
tion) reduces mesocortical function, causing negative/ position). By substituting at R1, an antipsychotic (thiorid-
cognitive symptoms. azine [Mellaril]) with fewer motor side effects is created.
■ Descending glutamate neurons from PFC activate mid- Further changes at R1 and R2 produce drugs (trifluopera-
brain inhibitory GABA cells that reduce mesolimbic DA zine [Stelazine], fluphenazine [Prolixene]) that further
cell firing. Low glutamate signaling at NMDA receptors vary in potency and side effects. This structure–activ-
(or NMDA receptor antagonist administration) prevents ity relationship provides clear evidence that molecular
the inhibition, leading to excessive mesolimbic firing modifications alter the ability of the drugs to bind to
and positive symptoms. specific receptor recognition sites in the cell membranes.
■ Accumulating evidence from challenge studies,
rodent studies, receptor subunit studies, and genet- EFFECTIVENESS The introduction of antipsychotic
ics suggests that NMDA hypofunction is central to drugs during the 1950s dramatically improved the
schizophrenia. treatment of patients with schizophrenia. The effective-
■ Low levels of glutamate are found in hippocampus and ness of these drugs has been demonstrated hundreds of
PFC of patients with schizophrenia post-mortem, and times in double-blind, placebo-controlled trials. After
low levels are correlated with greater brain atrophy. only a few doses, the hyperactive and manic symptoms
Glutamate release is lower in patients with schizophre-
usually disappear, whereas the positive symptoms of
nia than in controls, and glutamate receptor subunits
schizophrenia typically improve over several weeks.
are different.
Delusions, hallucinations, and disordered thinking

19_Meyer4e_CH19.indd 639 12/22/21 2:02 PM

 86 Chapter 3

may contain over 1000 vesicles. In the terminals with As with many different neurotransmitters, lipids and
the smaller number of vesicles, about 10 are in the read- gases have signaling functions outside of the central
ily releasable pool. Moreover, the release probability at nervous system (CNS). A well-known example of this
these synapses is much less than 1, meaning that a single pertains to nitric oxide (NO), the first gaseous transmit-
action potential often results in no vesicle fusion at all! ter to be discovered. The discovery of NO came about
The purpose of this discussion is to emphasize unexpectedly from the study of smooth muscle cells
that there is no universally applicable description of that surround the walls of arteries, regulating the rate
the synapse. As we have seen, synapses vary widely of arterial blood flow. A number of chemical substanc-
in their size, the number of vesicles participating in es, including the neurotransmitter ACh, were known
neuro­transmitter release, and even the
probability of vesicle exocytosis when
Classical synaptic signaling Signaling by gaseous and lipid transmitters
the cell generates an action potential.
Such diversity needs to be taken into Presynaptic Presynaptic
account when we think about how cell cell
neural circuits with different synaptic
properties respond to environmen-
tal stimuli, drugs, or other kinds of
challenges.

Lipid and gaseous transmitters

are not released from
synaptic vesicles
We mentioned earlier that lipid and
gaseous transmitters break some of
the normal rules of neurotransmis-
sion. One of the reasons is that these
substances readily pass through mem-
branes. Consequently, these substanc-
es cannot be stored in synaptic vesicles
like classical and peptide transmitters,
so nerve cells must make these sub-
Postsynaptic
stances “on demand” when needed.
cell
Moreover, as lipid and gaseous trans-
mitters are not present in vesicles, they
are not released by exocytosis but sim- Presynaptic Presynaptic
ply diffuse out of the nerve cell through cell cell
the cell membrane. Once the transmit-
ter molecules reach the extracellular Neurotransmitter
fluid, they may not be confined to the
synapse but may travel far enough to
reach other cells in the vicinity of the
release point. This is particularly true
for the gaseous transmitters. Finally,
lipid and gaseous transmitters typi-
cally are released by the postsynaptic
Intracellular
rather than the presynaptic cell in the Postsynaptic signal Postsynaptic Retrograde
synapse. Molecules such as these that cell cell messenger
signal information from the postsyn-
aptic to the presynaptic cell are called FIGURE 3.9 Signaling by classical versus gaseous and lipid transmitters
retrograde messengers (Suvarna et In contrast to signaling by classical neurotransmitters (left), gaseous and lipid
al., 2016). In Chapter 14 we describe transmitters (right) are not released from synaptic vesicles. Gases and lipids can­
an example of retrograde signaling by not be stored within vesicles and therefore must be synthesized enzymatically
when needed. Synthesis of gaseous and lipid transmitters usually occurs in the
endogenous cannabinoids. FIGURE 3.9 postsynaptic cell following release of a classical transmitter from the presynaptic
illustrates how signaling by gaseous cell and postsynaptic receptor activation. The newly formed gas or lipid subse­
and lipid transmitters differs from quently diffuses across the membrane and acts as a retrograde messenger on
classical neurotransmitter signaling. the presynaptic cell as well as other neurons close enough to receive the signal.

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 676 Chapter 20

neurons and release pro-inflammatory cytokines. While Infectious processes can also increase the likelihood
the brain is generally considered immunoprivileged of developing MS. Infection with measles, human
(meaning that there is normally little interaction with herpes­virus 6, Epstein–Barr (EB) virus, and Chlamydia
the immune system), some immune cells enter the brain pneumoniae may increase one’s risk (about 90% of all
to surveil the environment. If they do not find a target, those with MS have also had an EB virus infection such
they die in the unwelcoming brain environment. If they as mononucleosis). These infections are more likely
do find their target, they recruit more cells to the area. (and spread more easily) in colder climates, where resi-
Some of the evidence for an environmental contribu- dents are likely to spend more time inside.
tor to the development of MS is the interesting trend Finally, MS is not a strictly hereditary disease. There
toward a geographical risk map (Simpson et al., 2011). has been no identified “MS gene,” as there is for HD.
Generally, the risk for MS is very much greater in those But indications suggest that some genes may increase a
who live above 40° latitude in the Northern Hemi- person’s risk for developing this disorder. This conclu-
sphere (FIGURE 20.17). The risk for development of MS sion comes from the fact that first-degree relatives of
seems to be determined by the location of residence those with MS are at greater risk for developing MS
up to about age 15. Those who move to a temperate than are those in the general population. It is likely that
climate from a tropical one before the age of 15 take on there are gene variants that make some people more
the increased risk of a temperate climate. Those who likely to react to certain environmental or immune trig-
make this move after age 15 keep the risk level from the gers with the development of autoimmunity.
tropical climate. There are several risk factors for MS
that might also be linked to this geographical anomaly. TREATMENTS FOR MS Treatments for MS may be
One is that vitamin D may be protective: those who live either (1) disease modifying or (2) intended to treat an
in more tropical climates tend to spend more time in acute exacerbation. Others may be used to treat specific
the sun and therefore produce more vitamin D. symptoms. In contrast to many of the other disorders
Interestingly, the warmer months in both the United discussed in this chapter, in MS there are several drugs
States and Italy tend to increase relapses of MS in diag- that can reduce the frequency and severity of relapses
nosed patients. The risk in the United States, particularly and the accumulation of lesions and that appear to slow
in Massachusetts, was found to be highest between May the accumulation of disability.
and August (Meier et al., 2010). In the study conducted in
Italy, the highest risk was between May and June, with Injectable medications The first class of drugs ap-
a smaller peak in November and December. Although proved for use in MS was the interferons. Interferon
these studies are small, they do indicate an interesting beta-1a and -1b likely work in MS by increasing
seasonal pattern that may invite further study. the function of suppressor T cells. These T cells
As with PD and ALS, there may be a role for envi- modulate the immune system and maintain toler-
ronmental toxins and metals in disease onset. There ance to self-antigens in contrast or opposition to the
are clusters, or areas, where the rate of MS is higher myelin-reactive T cells described previously. Thus,
than would normally be expected that are currently they decrease the self-attack in MS. Four interferon
being investigated for the presence of a toxin or toxins drugs are Avonex and Rebif (interferon beta-1a) and
that may influence the development of the disease. Betaseron and Extavia (interferon beta-1b). Each is

80°

60°
FIGURE 20.17 Geographical
45°
patterns to the distribution of 40°
multiple sclerosis (MS) cases
In general, colder climates bring
20°
increased risk for the develop-
ment of MS. (After J. W. Rose et 0°
al. 1996, updated 2000. Multiple
Sclerosis. Accessed December 29,
20°
2012 from library.med.utah.edu/kw/
ms/mml/ms_worldmap.html ; and
40° High risk Probable low risk
D. McAlpine 1965. Multiple Sclerosis: 45°
A Reappraisal by Douglas McAlpine. Probable high risk North-South gradient risk
Low risk Other risk
Livingstone: Edinburgh.)

20_Meyer4e_CH20.indd 676 12/8/21 4:32 PM

 9 Drug Misuse and Addiction
“CHRIS THRALL LEFT THE ROYAL MARINES [a unit of the Royal Navy of the
United Kingdom] to find fortune in Hong Kong but a year later was suffering from
drug-induced psychosis resulting from his crystal meth addiction. He became home-
less, lost his sanity and almost his life after becoming addicted to the deadly drug,
also known as ‘ice.’ Chris, from Plymouth, joined the Marines at 18 and served 7
years. He got an opportunity to get involved in a new business venture, left the Forces
and moved to Hong Kong. Unfortunately, the venture failed; he was in debt and job-
less. He found a job in marketing for a Hong Kong firm. A few months after starting
he walked in on a colleague in the toilets smoking meth. Chris accepted the offer
to try some, the next day he wanted more . . . His life went out of control and in an
attempt to get straight, he went from a day job to working as a nightclub doorman
with the intention that if he worked at night he wouldn’t be able to take drugs. But
his addiction was life consuming; he was on it constantly, hallucinating, and became
psychotic. He got sacked and several other jobs followed. He was living on the streets
and believed he was part of a global underground conspiracy. He put his life at risk
deciding to climb a huge construction crane ‘for a laugh.’ Thirteen months after
arriving in Hong Kong Chris booked a return flight to the UK paid for by his worried
family. He was ravaged, 4 stone [56 pounds] lighter, wild-eyed and gaunt. He returned
to Plymouth and even though he was ashamed of the addiction he continued to score
the drug and carried on using for another 18 months. Crystal meth wasn’t hard to
find. One day [he] looked in the mirror and didn’t know himself anymore; after a long
battle and several attempts, he slowly started his recovery. He has now been clean
for over 10 years.” ■
— From Love PR London Ltd. © BIOSPHOTO/Alamy Stock
© Photo
Paula /Alamy
Bronstein/Getty
Stock Photo

One of the most addicting routes of drug

administration is intravenous injection.
Images

09_Meyer4e_CH09.indd 252 12/10/21 10:17 AM

 Disorders of Anxiety and Impulsivity and the Drugs Used to Treat Them 555

BOX 17.1 ■ THE CUTTING EDGE (continued)

(A) Basolateral Locus coeruleus (B) (C)
amygdala projections
0.8 V

LED –0.5 V 1.5 V

–0.5 V

Carbon fiber
microelectrode

Baseline
20 µm
Local projections from the LC-NE activate BLA
neurons involved in anxiogenesis (A) The LC
(D) Photostimulation (E)
of mice was injected with a virus coding for en-
5 40 hanced yellow fluorescent protein (eYFP) that
Firing 5 Hz Firing rate was engineered to only express in LC neurons.
Fos+CTb+/Total Fos+ (%)

rate remains
Normalized firing rate (z)

Image shows an immunohistochemically stained

increases constant 30 BLA section with Nissl-stained cell bodies in
(n = 9) (n = 29) blue and eYFP-positive NE fibers from the LC in
yellow, demonstrating that LC-NE fibers directly
0 20 innervate the BLA. (B) A virus was used to ex-
press ChR2 exclusively in LC-NE neurons, and
Firing rate a light-emitting diode (LED) cyclic voltammetry
decreases 10
electrode was embedded in the BLA as depicted
(n = 4)
in the schematic. (C) Upon light stimulation,
–5 0 the electrode detected a voltage signature con-
0 180 360 540 vHPC CeA NAc sistent with NE release. Representative cyclic
Time (s) voltammograms are shown in the inset. (D) This
n = Number of neurons in each group experiment was repeated as in (B), but this time
embedding an LED electrophysiology electrode.
Light stimulation of LC-NE terminals in the BLA
resulted in a mix of neurons with increased (red),
resulting neural activity within the BLA, and Cholera decreased (light blue), or unchanged (dark blue)
toxin subunit B (CTb) retrograde tracing from either activity, with “n” denoting the relative numbers
of neurons that were measured in each category.
the ceA, vHIPP, or NAc (see above), the authors found
This demonstrated that LC-NE activation in the
that BLA neurons co-expressed both c-fos and the
BLA was sufficient to alter neuronal firing within
tracer more preferentially when projecting to the CeA
the BLA. (E) Mice were optogenetically stimu-
and vHIPP than the NAc (FIGURE E). This suggested lated to release LC-NE in the BLA as before to
that LC-NE projections to the BLA modulate neurons pinpoint activated neurons via c-fos staining,
that then drive the genesis of anxiety. after which one group of mice was injected with
To test this behavioral hypothesis more directly, a retro­grade tracer (CTb) in the vHPC, one in the
the researchers examined whether activating LC-NE CeA, and one in the NAc. Graph shows relative
terminals in the BLA could cause anxiety-like behav- percentages of neurons stained for both markers,
ior as measured by a conditioned place preference demonstrating that LC-NE-activated BLA neurons
test. Here, mice were placed in one of two distinct preferentially project to the vHPC and CeA rather
chambers within a box, after which optogenetic than the NAc, the former two projections involved
stimulation of LC-NE terminals in the BLA was paired in anxiogenesis, and the latter in reduction of anx-
with that chamber for 2 days. Control animals lack- iety. (After J. G. McCall et al. 2017. Elife 6: e18247.
ing the ChR2 protein but where the fiber-optic probe doi: 10.7554/eLife.18247. CC BY 4.0, creativecom-
was implanted and activated in the BLA underwent mons.org/licenses/by/4.0/.)
the same paradigm. On the third day, each mouse
was allowed to run freely between the two chambers (Continued)

Meyer 4e
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17_Meyer4e_CH17.indd 555 12/8/21 11:33 AM

 Schizophrenia: Antipsychotic Drugs 627

FIGURE 19.5 Lifetime risks of

developing schizophrenia among 50 48%
46%
relatives of an affected individual

Lifetime risk of developing schizophrenia (%)

Data are summarized from about
40 family and twin studies conducted 40
between 1920 and 1987. Compared
with a 1% risk of developing schizo-
phrenia in the general population,
second-degree relatives have an 30
average risk of 4%, first-degree
relatives have a 6% to 17% risk,
monozygotic twins have a 48% risk,
and children having two parents 20
17% 17%
with schizophrenia have an average
47% risk. (After I. I. Gottesman 13%
1991. Schizophrenia Genesis. 10 9%
W. H. Freeman: New York.) 6% 6%
4% 5%
1%
General 2% 2% 2%
population

First cousins

Uncles/
aunts
Nephews/
nieces

Grandchildren

Half-siblings

Children

Siblings

Siblings when 1
parent has schiz.

Parents

Dizygotic
twins
Monozygotic
twins
Children of 2
parents with schiz.
Spouses of
patients

3˚ Relatives 2˚ Relatives 1˚ Relatives

(12.5% shared (25% shared (50% shared genes)
genes) genes)

defects in proteins needed for synaptic vesicle recycling, compared with other, more common diseases such as
neurotransmitter release, and cytoskeleton organization diabetes, the size of the population sampled has been
and function. At present, 145 loci have been identified as much smaller for schizophrenia. It is also possible that
likely sites for genes that increase the risk for develop- the genetic variants identified are associated not with
ing schizophrenia (Pardiñas et al., 2018). the complex disorder of schizophrenia, but with spe-
The new technology has produced a huge number of cific symptom clusters. Indeed, recent GWAS evidence
studies and identified hundreds of genetic risk variants suggests a large genetic overlap for schizophrenia, au-
in an attempt to predict vulnerability to schizophrenia. tism, and bipolar disorder, as well as cardiovascular
The work has generated an enormous amount of en- risk factors and multiple sclerosis.
thusiasm among researchers because it holds such tre- Recent research reported that examination of a vast
mendous promise for understanding the neural basis array of independent GWAS using a powerful statisti-
for the disorder, developing better animal models for cal approach showed that many genes associated with
drug testing, and improving treatment options. The ex- schizophrenia involve the disruption of communica-
citement is in part due to refined statistical approaches tion between large numbers of ionotropic and metabo-
capable of handling very large amounts of data, along tropic families of receptors, as well as voltage-gated
with the establishment of the Schizophrenia Working calcium channels (Devor et al., 2017; Pardiñas et al.,
Group of the Psychiatric Genomics Consortium. The 2018). The failure of information processing based on
consortium provides the opportunity to pool data from abnormal synaptic regulation supports our earlier dis-
multiple large research projects to enhance the statisti- cussion of schizophrenia as a disorder of connectivity,
cal power of analysis (Devor at al., 2017). Nevertheless, since the integration of synaptic signaling is critical for
others are more pessimistic because despite the great all neurotransmitter systems and intracellular func-
effort and cost, success has been quite modest. Certain- tions. Devor and coworkers found genetic variations in
ly one reason is that there is little precision in diagnosis a large array of ionotropic and metabotropic receptors,
of schizophrenia (as is true for other psychiatric disor- including those for DA, glutamate, GABA, acetylcho-
ders) because there is no objective measure (as there is line (ACh), opioids, and serotonin (5-HT), all of which
for diabetes or cancer), and researchers cannot know impact symptoms of schizophrenia.
whether their sampling population isMeyer homogeneous
4e or It is clear that a single gene that makes a large contri-
whether it contains multiple subsetsMQ4E_19.05
of patients. Also, bution to the susceptibility to such a complex disorder
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Date 11/02/21

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 Marijuana and the Cannabinoids 455

endocannabinoids, particularly anandamide, target clear (reviewed in Marsicano and Lafenêtre, 2009;
more than one type of receptor. Finally, Figure 14.11C Kruk-Slomka et al., 2017). Using several different ex-
illustrates an unusual mode of signaling in which perimental approaches, researchers have found that
endocannabinoids activate cannabinoid receptors in in the Morris water maze spatial navigation task, the
the membranes of nearby astrocytes, which results in clearest role for the endocannabinoid system is to facili-
release of glutamate from the glial cells. tate extinction of the original platform location when
The retrograde signaling described above often the animals are required to learn a new location (Varvel
causes a type of short-term synaptic plasticity in the and Lichtman, 2002; Varvel et al., 2005, 2007).
presynaptic neuron in which neurotransmitter release When people consume cannabis at typical recre-
is suppressed for several seconds up to a minute (Au- ational doses, they commonly experience feelings of
gustin and Lovinger, 2018). When the presynaptic cell relaxation, reduced anxiety, elevated mood, and stress
is excitatory (e.g., glutamatergic), the effect is termed relief (see the section on acute behavioral and physi-
depolarization-induced suppression of excitation (DSE), ological effects of cannabinoids below). This pattern
since the endocannabinoid (2-AG) release that starts the of subjective responses led to the hypothesis that
process is triggered by depolarization of the postsyn- the endocannabinoid system helps regulate mood
aptic cell. When the presynaptic cell is inhibitory (e.g., states, anxiety and fear, and reactions to stress. In-
GABAergic), then the effect is called depolarization-­ deed, this hypothesis has been confirmed in a large
induced suppression of inhibition (DSI). DSE and DSI number of rodent studies (reviewed in McLaughlin
are produced by brief postsynaptic depolarization. In and Gobbi, 2012; Yin et al., 2019). For example, tests
contrast, longer-lasting postsynaptic stimulation can of depressive-like behaviors such as the forced-swim
give rise either to LTP or long-term synaptic depression and tail-suspension tests have shown that elevated
(LTD). This is one of the mechanisms by which endo- endocannabinoid activity exerts an antidepressant
cannabinoids participate in the processes of learning effect, whereas reduced endocannabinoid activ-
and memory (Kruk-Slomka et al., 2017). This topic is ity or deletion of the CB1 gene is associated with a
discussed further in the next section. depression-like phenotype (McLaughlin and Gobbi,
2012; Soriano et al., 2021). Other research found that
FUNCTIONAL EFFECTS OF THE ENDOCANNABINOID enhancement of endocannabinoid signaling by in-
SYSTEM FIGURE 14.12 provides an overview of the hibiting endocannabinoid metabolism or uptake has
major behavioral processes regulated by the endo- anxiolytic effects in the elevated plus-maze, elevated
cannabinoid system and the relevant brain areas in- zero-maze, light–dark test, and social interaction test.
volved in such regulation. We briefly discuss several In contrast, CB1-knockout mice that lack most CNS en-
of these processes. docannabinoid signaling show increased anxiety-like
As previously mentioned, it is well established that behaviors (McLaughlin and Gobbi, 2012; Soriano et
exogenous cannabinoids such as THC disrupt short- al., 2021). A different approach was taken by Gug-
and long-term memory of hippocampal-dependent genhuber and colleagues (2016), who used genetic
tasks. Surprisingly, the role of the endogenous can- methods to enhance 2-AG breakdown selectively in
nabinoid system in memory processes is not as hippocampal glutamatergic neurons. The result was

Spatial learning and memory Pavlovian

Sensory Emotional learning learning/
processing Pattern completion reflexes
Cerebral Seizures/epilepsy FIGURE 14.12 Brain regions
cortex associated with behavioral regula-
Goal-directed Visual tion by the endocannabinoid system
and habit sensory Research on the neural mecha-
Somato nisms of endocannabinoid action
learning Hippocampus Cerebellum
has largely been performed using
Dorsal laboratory mice and rats. Based
striatum on this research, the brain regions
where endocannabinoid activity
helps regulate particular behaviors
Ventral
striatum
are depicted on a sagittal section of
Amygdala a rodent brain. (Adapted with per-
mission from S. M. Augustin and
D. M. Lovinger. 2018. ACS Chem
Reward-driven/Pavlovian learning Neurosci 9: 2146–2161. © 2018
Addiction Fear consolidation/extinction American Chemical Society.)

14_Meyer4e_CH14.indd 455 12/7/21 1:16 PM

 206 Chapter 7

BOX 7.1 ■ PHARMACOLOGY IN ACTION

Botulinum Toxin—Deadly Poison, Therapeutic Remedy, and Cosmetic Aid
The bacterium Clostridium botulinum, which is respon­
Nerve
sible for botulism poisoning, produces what is perhaps
terminal Acetylcholine
the most potent toxin known to pharmacologists. The
estimated lethal dose of botulinum toxin in humans is
0.3 micrograms; in other words, 1 gram (equivalent
to the weight of three aspirin tablets) is enough to kill

–
more than 3 million individuals. Clostridium botulinum
does not grow in the presence of oxygen; however, it
Botulinum
can thrive in an anaerobic (oxygen-free) environment
toxin
such as a sealed food jar or can that has not been
properly heated to kill the bacteria.
Botulinum toxin actually consists of a mixture of
seven related proteins known as botulinum toxins A
through G. These proteins are taken up selectively by
ACh
peripheral cholinergic nerve terminals, including those Muscle receptors
located at the neuromuscular junction, autonomic gan­
glia, and postganglionic parasympathetic fibers (e.g.,
cholinergic fibers innervating smooth muscle and se­ Mechanism of action of botulinum toxin at the neuro­
cretory glands). The toxin molecules interfere with the muscular junction Botulinum toxin blocks ACh release
process of ACh release at the terminals, thereby block­ at the neuromuscular junction by preventing fusion of
synaptic vesicles with the nerve terminal membrane.
ing neurotransmission (see FIGURE). When cholinergic
motor neurons have been affected by botulinum toxin,
the result is muscle weakness and possible paralysis.
Other symptoms of botulism poisoning include blurred profession. Off-label drug use is frequently the topic
vision, difficulty speaking and swallowing, and gastroin­ of research studies as investigators explore the wider
testinal distress. Most victims recover, although a small clinical potential of a particular medication. However,
percentage die as the result of severe muscle paralysis care must be used, as adverse side effects can occur
and eventual asphyxiation. (for botulinum toxin, adverse reactions were recently
Once the mechanism of action of botulinum toxin reviewed by Witmanowski and Blochowiak, 2020).
became known, researchers began to consider that Interestingly, in addition to its action as a
this substance, if used carefully and at very low long-acting muscle relaxant, botulinum toxin A also
doses, might be helpful in treating clinical disorders exerts analgesic effects in certain kinds of chronic
characterized by involuntary muscle contractions pain disorders. This has led to its use as a treatment
(Ting and Freiman, 2004). After appropriate test­ for migraine headaches, trigeminal neuralgia (severe
ing, in 1989 the U.S. Food and Drug Administration chronic pain of the fifth cranial nerve), and chronic pel­
approved the use of purified botulinum toxin A for vic pain syndrome. The mechanisms underlying pain
the treatment of strabismus (crossed eyes), blepha­ relief from
Meyerbotulinum
4e toxin A have been investigated
rospasm (spasm of the eyelid), and hemifacial spasm but are not yet fully understood (Matak et al., 2019).
Psychopharmacology
(muscle spasms on just one side of the face). Since Even Dragonfly
if you’re not familiar
Media with the abovementioned
Group
that time, this substance has been administered for a medicalSinauer
applications of botulinum toxin, you may
Associates
variety of other disorders, including spastic cerebral have heard of its use (under9-21-21
Meyer4e_Bx7.01 the trade name Botox)
palsy, stroke-related spasticity, dystonias (prolonged by dermatologists for cosmetic purposes in patients
muscle contractions, sometimes seen as repeated with excessive frown lines, worry lines, or crow’s-feet
jerking movements), axillary hyperhidrosis (extreme around the eyes. Such “dynamic wrinkles,” as they are
underarm sweating), sialorrhea (excessive salivation called, result from chronic contraction of specific facial
leading to drooling), overactive bladder, achalasia muscles. When injected locally into a particular muscle
(failure of sphincter muscles to relax when appropri­ or surrounding area, Botox causes paralysis of that
ate), and bruxism (habitual teeth grinding) (Alster and muscle as the result of blockade of ACh release from
Harrison, 2020; Dressler, 2021). You should be able incoming motor nerve fibers. This leads to a reduction
to discern that some of these treatments are aimed in the offending lines or wrinkles, although each treat­
at relaxation of specific skeletal muscles, whereas ment remains effective for only a few months, after
others are aimed at reduction of smooth muscle or which it must be repeated. Despite this limitation, many
secretory activity. It’s also worth mentioning that dermatologists and their patients have chosen Botox
some of these are “off-label” uses, meaning that the treatment over plastic surgery for improving facial
drug is being administered for medical conditions that appearance (Satriyasa, 2019). It seems safe to say that
have not received prior FDA approval. This practice is both the medical and cosmetic uses of botulinum toxin
not illegal and is, in fact, not uncommon in the medical will continue to grow in the coming years.

07_Meyer4e_CH07.indd 206 12/7/21 10:51 AM

 Acetylcholine 221

STUDY QUESTIONS
1. What are the chemical reactions involved in ACh laboratory animals such as rats and mice? Dis-
synthesis and breakdown? Include the names of cuss experimental findings that support a role
the enzymes catalyzing each reaction. Why is the for ACh in facilitating sustained attention.
enzyme that catalyzes ACh synthesis the appro- 10. Nicotinic cholinergic receptors belong to the fam-
priate marker for cholinergic neurons rather than ily of __________ (ionotropic or metabotropic)
the enzyme that catalyzes ACh breakdown? receptors. Each receptor is composed of ________
2. How does AChE at the neuromuscular junction subunits. Which of these subunits is required
differ from AChE in the brain? for a nicotinic receptor to be formed, and why?
3. Among the various AChE inhibitors, some block Which nicotinic receptor subunit structures have
the enzyme both centrally and peripherally, been implicated in cognitive function?
whereas others are preferential inhibitors at the 11. A nicotinic receptor complex can be in one of
neuromuscular junction. Another differentiat- three different states: open, closed, and desen-
ing feature is that some AChE inhibitors are sitized. Describe the properties of each state, in-
reversible whereas others are irreversible. List cluding whether agonist is bound or not as well
the chemicals discussed in the chapter that have as the state of the receptor channel.
these various characteristics, and then describe 12. The text discusses three different drugs that act
whether each specific chemical is characterized on nicotinic receptors: succinylcholine, mecamyl-
as a toxin or as a medicinal compound. Explain amine, and d-tubocurarine. For each compound,
the underlying reasons for this categorization. indicate whether it is an agonist or an antagonist,
4. ________ is the name of a drug that blocks ve- and briefly discuss the effects of administering
sicular uptake of ACh. True or false: When this the drug (including any current medical use).
drug has been applied, the lack of ACh in the 13. How many subtypes of muscarinic receptors have
vesicles prevents the cholinergic neuron from been identified? Based on their signaling mecha-
undergoing exocytosis when it generates an nisms and postsynaptic effects (i.e., excitatory
action potential. or inhibitory), the receptors can be divided into
5. List and discuss the effects of toxins that either two families. Identify the members of each fam-
stimulate or inhibit ACh release. Include in your ily, their signaling mechanisms, and whether that
answer the therapeutic applications of toxins family of receptors is excitatory or inhibitory.
that inhibit the release of this neurotransmitter. 14. Discuss the role of M5 muscarinic receptors in
6. Unlike the monoamine transmitters discussed in the control of dopaminergic cell firing and the
previous chapters, there is no reuptake system for rewarding and reinforcing effects of abused
ACh itself. Describe the alternative mechanism drugs. Include relevant experimental findings
that has evolved to help cholinergic neurons re- in your answer.
cycle/reutilize the transmitter. How do we know 15. Describe the locations and functional roles of
that this recycling process plays an important role muscarinic receptors expressed by peripheral
in normal functioning of the nervous system? organs and glands. What is the “dry mouth
7. Name and describe the causes of disorders of effect,” and what is its cause?
cholinergic transmission at the neuromuscular 16. Explain the underlying rationale for the idea of
junction that lead to weakness, fatigue, and other using nicotinic or muscarinic allosteric modula-
motor symptoms. tors in the treatment of Alzheimer’s disease or
8. A cluster of cholinergic neurons called the other neuropsychiatric disorders involving
____________ gives rise to ascending projections deficits in cognitive functioning.
to the cortex and hippocampus that help regu- 17. What is meant by the terms parasympathomimetic
late cognitive function. The cell bodies of these and parasympatholytic? List examples of drugs
neurons are located in ____________ (list several belonging to these categories along with their
brain regions). physiological effects and medicinal or other uses.
9. What is meant by “sustained attention”? How
is sustained attention studied experimentally in

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 I-34 Index

techniques in behavioral phar- CB1 cannabinoid receptors head-twitch response to Schedule of Controlled
macology, 108–123 (see also and, 452 psychedelics, 493, 494 Substances, 262, 263
behavioral pharmacology inhalants, 517–518 model of inhalant reinforce- schedule of reinforcement,
methods) neuroadaptation and the ment, 517–518 111–112
resensitization, of nicotinic recep- down-regulation of, 277 models of alcohol use, 308–309 schizophrenia
tors, 216 pathways in and characteris- models of schizophrenia, 504, allosteric modulation of
reserpine tics of, 274–276 631–635 metabotropic receptors
animal models of Parkinson’s See also drug reward neurobiology of inhalants, and, 94
disease and, 659 reward-prediction error, 277 518–519 animal models, 122, 504,
blocking of VMAT, 151, 183 Rexulti (brexpiprazole), 646 reward circuit, 274–276 631–635
catecholamines and the seda- Reyvow (lasmiditan), 191, 193 See also knockout mice; mice; antipsychotics and, 27
tive effects of, 151, 152 rhesus monkeys rats; transgenic mice brain abnormalities in,
effect on neurotransmitter astrocytes, 49 Rohypnol (flunitrazepam), 506, 622–626
storage, 96 drug reinforcement studies, 577, 579 characteristics of, 620–622
effect on the dopaminergic 265 “roid rage,” 537, 538–540 dendritic spines and, 44
system, 167 effects of prenatal stress, 566 Rolfe, John, 407 dopamine supersensitivity
effect on the noradrenergic prenatal inflammation model rolipram, 316, 607 and, 163
system, 175 of schizophrenia, 633 Romazicon, 580 etiology of, 622–635
effect on the serotonergic reinforcer drugs, 118 See also flumazenil genetics and, 626–628, 635
system, 193 reinforcing effects of PCP and Romilar, 507 glutamate hypothesis of, 504
monoamine hypothesis of ketamine, 504 “Room Odorizer,” 401 interaction of genetic, environ-
mood disorders, 597 stimulus generalization task, ropinirole (Requip), 163, 167, 660 mental, and developmental
source of, 151 269 rostral, 57, 58 factors in, 626–631
reserve pool, of synaptic vesicles, studies of negative reinforce- rotarod, 142, 143 introduction, 619
81 ment in addiction, 267–268 rotenone, 659 LSD model of, 503–504
resident–intruder paradigm/test, rheumatoid arthritis, risk for rotigotine (Neupro), 163, 167, 660 mesocortical dopamine path-
194, 539 schizophrenia and, 625 RRMS. See relapsing–remitting way and, 157, 160, 636
respiratory system RIA. See radioimmunoassay multiple sclerosis neurochemical models of,
alcohol poisoning and, 299 ribosomes, 45 RTI-55, 371 635–639
effects of chronic cannabis use rifampicin, 33 rTMS. See repetitive transcranial PCP/ketamine models of,
on, 475 rigidity, in Parkinson’s disease, magnetic stimulation 503–504
effects of smoking on, 427 655 rum, 290 preclinical models of, 631–635
effects of vaping on, 429, 430 Rilutek (riluzole), 673 Rush, Benjamin, 254, 280 receptor antagonists and, 97
TPH2 knockout mice and, riluzole (Rilutek), 673 treatment of cognitive symp-
194–195 rimonabant (SR 141716A; S toms, 649–652
resting membrane potential, Accomplia), 451, 456, 463, Sabina, María, 485, 486 treatment with antipsy-
51–52 465, 470–471 Sabril (vigabatrin), 241 chotics, 639–649 (see also
resting-state fMRI, 137, 550, 623 risk genes, Alzheimer’s disease saclofen, 249 antipsychotics)
restless leg syndrome, 163 and, 664–665 SAD. See social anxiety disorder treatment with D2 receptor
Restoril (temazepam), 578, 579 risk-taking behavior, alcohol use safinamide (Xadago), 660 antagonists, 163
reticular formation and, 298 sagittal plane, 57, 58 schizophrenia spectrum and
brainstem and, 65 Risperdal, 103, 639 salicylic acid, 20 other psychotic disorders,
cholinergic system and, 211, See also risperidone saltatory conduction, 55, 56 620
213–214 risperidone (Risperdal) Salvia divinorum, 483, 489–490, Schultes, Richard, 485
description of, 66–67 5-HT2 receptor binding, 648 500 Schwann cells, 44, 48, 49, 65, 673
pain pathways and, 345 affinities for neurotransmitter See also salvinorin A scopolamine, 62, 212, 214, 219
retinal amacrine cells, 40 receptors, 646 salvinorin A sebum, 661
retinal bipolar cells, 40 benefits and risks of, 645 adverse reactions, 500 secobarbital (Seconal), 27, 577
retinal ganglion cells, 40 a broad-spectrum antipsy- background and effects of, Seconal (secobarbital), 27, 577
retrograde messengers, 86 chotic, 647 489–490 second pain, 344
retrograde signaling, endocan- clinical trials of antipsychotics chemical structure, 493 secondary cortex, 71
nabinoids and, 454, 455 and, 649 neurochemical actions of, 495 secondary hypogonadism, 542,
retropulsion, 655 a second-generation antipsy- potency and time course, 491 543
retroviruses, as viral vectors, 42 chotic, 639 a psychedelic drug, 484 secondary motor cortex, 71
reuptake treatment of symptoms SAMP8 transgenic mice, 666 secondary progressive multiple
of catecholamines, 153–155 comorbid with autism Sandoz pharmaceutical com- sclerosis (SPMS), 673, 674,
of neurotransmitters, 88 spectrum disorder, 103 pany, 487, 488 677
reverse anorexia, 537 Ritalin. See methylphenidate Sanofi Recherche pharmaceutical secondary sex characteristics,
reverse gateway theory, 467 ritanserin, 190, 193 company, 451 effects of anabolic–andro-
reverse pharmacology, 450 rivastigmine (Exelon), 207, 214, Sanofi-Aventis pharmaceutical genic steroids on, 536
reverse tolerance, 35, 383 667 company, 456 secondary somatosensory cortex,
See also sensitization RNA sequencing, 134 Santo Daime, 486 pain perception, 344, 345,
reversible AChE inhibitors, “Ro” drugs, 577 SAPAP3 knockout mice, 574 347
207–208 Robitussin DM cough syrup, 507 sarcopenia, 542, 543 second-generation antidepres-
reversible inhibitors, 151 “Robo,” 507 sarcosine, 651 sants, 610–611
Revex (nalmefene), 325, 365 “Robotripping,” 507 sarin, 208, 214 second-generation antipsy-
Revia, 324 Roche pharmaceutical company, SARS-CoV-2 virus, 428 chotics. See atypical
See also naltrexone 233, 670 Sativex (nabiximols), 458, 471 antipsychotics
Revised ALS Functional Rating rodents Savant, Marilyn vos, 222 second-generation anxiolytics,
Scale, 673 alcohol-preferring, 308–309, saxitoxin, 56 583–584
reward circuit 313, 315, 316 SB-612,111, 342 second-messenger systems
anabolic–androgenic steroids characteristics of hippocampal SCH 23390, 163, 167 adrenergic receptors and, 169
and, 541, 542 synapses, 85–86 Schaffer collaterals, long-term assays of enzyme activity and,
antireward system and, drug-taking behavior and the potentiation and, 234 130
278–279 Rat Park studies, 285 Schaler, Jeffrey, 284 calcium ions and, 92, 95
cannabinoids and, 465–466 defined, 90

23 Meyer4e Index.indd 34 12/15/21 12:57 PM

 426 Chapter 13

found evidence that some of these endogenous or added of the most widely used flavorings in both tobacco ciga-
chemicals either have their own reinforcing properties rettes and e-cigarettes is menthol, a chemical extracted
or alter nicotine uptake, bioavailability, or neurophysi- from the mint plant (Mentha arvensis). Most cigarettes
ological effects (Brennan et al., 2014; van de Nobelen et contain at least some menthol, although only certain
al., 2016). Below we discuss two major lines of research: brands contain high enough levels to be marketed as
(1) inhibition of monoamine oxidase (MAO) enzymes mentholated cigarettes. Such brands represent about
by cigarette smoke and e-cigarette vapor and (2) the 25% of cigarette sales overall but are especially ap-
influence of flavor additives on smoking and vaping. pealing to adolescents and to new smokers generally.
Researchers discovered some years ago that smokers Menthol is used in cigarettes to provide a pleasant
have substantially lower levels of MAO-A and MAO-B sensory experience that combats the harsh, irritating
activity in the brain as well as in several peripheral or- qualities of tobacco smoke. This effect is mediated by
gans that express one or both of these enzymes. FIGURE menthol-induced activation of TRPM8 receptors, a class
13.17 shows PET scans demonstrating MAO-B inhibi- of ion channels expressed by sensory neurons, that elic-
tion in various organs of a smoker compared with a non- its a sensation of cooling (Wickham, 2015). Menthol has
smoker. MAO inhibition in smokers has been attributed also been found to be a negative allosteric modulator
to non-nicotine constituents of cigarette smoke, although of both high- and low-affinity nAChRs in vitro, which
it’s not yet clear which of these substances is most im- results in reduced nicotine-mediated activation of these
portant for this effect (Hogg, 2016). Because MAO is im- receptors (Kabbani, 2013; Wickham, 2015). This inter-
portant in the breakdown of DA, it is plausible that MAO action might require the user to smoke or vape more
inhibition might contribute to the reinforcing effects of frequently or more intensively (in terms of puff rate
smoking. This hypothesis is supported by experiments and/or volume) in order to experience the same effects
demonstrating that pharmacological inhibition of of the nicotine. Flavorings are particularly important
MAO-A, the MAO subtype important for DA metabo- for e-cigarette use (Zare et al., 2018; Patten and De Biasi,
lism, enhances IV self-administration of low nicotine 2020). The availability of different flavors, especially
doses (Smith et al., 2016). The interaction between MAO sweet or fruity ones, is an important factor in the initia-
and nicotine reinforcement indicates that inhibition of tion of e-cigarette use by adolescents. The same flavors
the enzyme is probably only important for people smok- are often perceived as being less harmful than tobacco
ing low-nicotine cigarettes. E-cigarette vaping does not flavor, even though there is no evidence to support this
seem to contain the MAO-inhibiting substance(s) found assumption. Moreover, the addition of sweet or fruity
in cigarette smoke. However, recent research found that flavorings enhanced the subjective rewarding effects
certain flavored e-liquid brands, including several con- of e-cigarettes when the nicotine content was relatively
taining vanilla flavor, also possess varying degrees of low but not in the case of e-cigarettes containing more
MAO inhibitory activity (Truman et al., 2019). nicotine (Patten and De Biasi, 2020). These findings in-
A second line of research has focused on flavorings, dicate that beyond the delivery of nicotine, flavor addi-
which have been associated with tobacco products as tives play a key role in the initiation and maintenance
early as the seventeenth century (Klus et al., 2012). One of e-cigarette use.

Nonsmoker Smoker
Smoking is a major health hazard and
a cause of premature death
Brain The World Health Organization (WHO) collects
From J. S. Fowler et al. 2003. Proc Natl Acad Sci USA 100: 11600–11605.

global information on the prevalence of tobacco

use and the consequent health effects. According
to estimates provided by WHO, over 7 million peo-
ple worldwide die each year from the direct conse-
Lungs
quences of tobacco use, and an additional 1.2 mil-
lion nonsmokers are killed because of exposure to
Heart
second-hand smoke (World Health Organization,
2020). In 1964, the Surgeon General of the United
© 2003 National Academy of Sciences

States released the first federally authorized report

Liver on the health consequences of tobacco smoking.

Kidneys
FIGURE 13.17 Whole-body PET scans illustrating
reduced MAO-B activity The organs of a smoker are
compared with those of a nonsmoker. Warmer colors
indicate higher MAO-B activity.

Meyer 4e
Psychopharmacology
Dragonfly Media
13_Meyer4e_CH13.indd 426 Group 12/7/21 12:08 PM
 Psychomotor Stimulants: Cocaine, Amphetamine, and Related Drugs 383

Non-using controls Psychostimulant Users

Vesicular
monoamine
Dopamine transporter Dopamine
transporter (VMAT2) – transporter –

D3
Postsynaptic D1 Postsynaptic
D1 D3
receptors receptors

FIGURE 12.11 Summary of altered striatal dopaminergic (illustrated by fewer DA molecules in the synaptic cleft), less
markers in chronic psychostimulant users compared to non- DAT binding, and less D2/D3 receptor binding. Note that because
using controls Brain imaging methods such as PET were used the drug used to label the DA receptors did not differentiate
to quantify several markers of striatal dopaminergic activity between D2 and D3 receptors, this uncertainty is reflected in a
including DA synthesis, DA release, VMAT2 binding, DAT binding, decrease in both receptor subtypes. Not shown are the VMAT2
and D2/D3 receptor binding. Relative levels of each marker are binding results, which varied depending on the period of absti-
shown for non-using controls (A) versus chronic psychostimu- nence from psychostimulant use. Elevated VMAT2 binding was
lant (cocaine, amphetamine, or methamphetamine) users (B). observed in users who were recently abstinent at the time of the
The figure illustrates that the psychostimulant users showed study, whereas decreased binding was found after prolonged
decreased DA synthesis (illustrated by fewer DA molecules drug abstinence. (Adapted from A. H. Ashok et al. 2017. JAMA
per synaptic vesicle and fewer vesicles), decreased DA release Psychiatry 74: 511–519. doi:10.1001/jamapsychiatry.2017.0135.)

cocaine addiction proposed many years ago by Dackis kind of change one observes depends on the pattern
and Gold (1985). Down-regulation of dopamine synthe- of drug exposure, the response that’s being measured,
sis, DA release, and DA transporter and receptor levels and the time interval that has elapsed since the last
may result from repeated psychostimulant-induced in- dose. For example, continuous cocaine infusion into rats
creases in extracellular DA levels. Such down-regulation causes tolerance to the drug’s locomotor-stimulating
would be expected to result in a tolerance to subsequent effect (Inada et al., 1992), whereas once-daily cocaine
psycho­stimulant use, a topic taken up in the next section. injections lead to behavioral sensitization, as shown
by enhanced stereotyped behaviors (Post and Contel,
TOLERANCE AND SENSITIZATION As is the case 1983). Several studies have examined tolerance or sen-
with many potentially addictive drugs, chronic ex- sitization to self-administered cocaine rather than co-
posure to cocaine or other psychostimulants causes caine given by the experimenter. Once again, different
either tolerance (reduced drug responsiveness) or results were obtained depending on the pattern of drug
sensitization (increased responsiveness), sometimes exposure. Cocaine self-administered daily by IV injec-
called reverse tolerance. One of the amazing aspects tion for 6 hours per day (long-access model; see Web
of sensitization is that just a few exposures to cocaine Box 12.1 for details) caused a reduction in the stimula-
or amphetamine can produce an increased respon- tory effects (both locomotor activity and stereotypies)
siveness that lasts for weeks, months, or even longer of a 5 mg/kg intraperitoneal (IP) cocaine challenge
(Paulson et al., 1991). Although this kind of long-lasting given on the day after the last self-administration ses-
sensitization has usually been studied in experimental sion (Calipari et al., 2014a). In contrast, intermittent ac-
animals, a laboratory study by Boileau and colleagues cess to self-administered cocaine led to a sensitization
(2006) demonstrated sensitized behavioral and neu- of the drug’s behavioral effects (Calipari et al., 2014b;
Meyer 4e
rochemical responses to amphetamine at 1 year after 2015). Earlier studies of psychostimulant sensitization
MQ4E_12.11
aDragonfly
mere fourMedia
dosesGroup
of the drug given orally to human showed that this phenomenon can be divided into two
participants
Sinauer Associates 2-week period.
over a phases: induction (the process by which sensitization is
How
Date can psychostimulants produce both tolerance
10/12/21 established) and expression (the process by which the
and sensitization? Various studies have shown that the sensitized response is manifested). Between these two

12_Meyer4e_CH12.indd 383 12/22/21 2:03 PM

 Glossary G-5

C cathinone Psychostimulant that is the primary active

ingredient in khat. [12]
c-fos Transcription factor that rises rapidly within cells
during increased neural activity. [4] caudal The tail end of the nervous system is caudal
or posterior. [2]
cachexia Syndrome involving extreme loss of muscle mass
and body weight. [16] CBD See cannabidiol. [14]
caffeine Stimulant drug found naturally in coffee and tea. CBT See cognitive behavioral therapy. [12]
It is also consumed in tablet form and in various beverages central Of, or relating to, the central nervous system
such as such drinks and energy drinks. [13] (brain and spinal cord). [1]
caffeine dependence syndrome Disorder produced by central canal Channel within the center of the spinal cord
chronic high-dose caffeine use and characterized by caffeine filled with CSF. [2]
craving, difficulty controlling caffeine consumption, caffeine cerebellar peduncles Large bundles of axons that connect
tolerance, and withdrawal symptoms that occur following the cerebellum to the pons. [2]
abstinence. It is a recognized disorder within ICD-10 but not
cerebellum Large structure of the metencephalon that
within DSM-5. [13]
is located on the dorsal surface of the brain and that is
caffeine intoxication Disorder produced by recent connected to the pons by the cerebellar peduncles. It is
high-dose caffeine use and characterized by symptoms an important sensorimotor control center of the brain. [2]
of restlessness, nervousness, insomnia, and physiological
cerebral ventricles Cavities within the brain filled with
disturbances including tachycardia (increased heart rate),
muscle twitching, and gastrointestinal upset. [13] CSF. [2]
cerebrospinal fluid (CSF) Fluid that surrounds the brain
caffeine use disorder DSM-5 category with features
similar to those of caffeine dependence syndrome. It is not a and spinal cord, providing cushioning that protects against
recognized disorder but has been designated for additional trauma. It also fills the cerebral ventricles and the central
research. [13] canal of the spinal cord. [1]
Cesamet See nabilone. [14]
calcium/calmodulin kinase II (CaMKII) Enzyme stimulated
by calcium and calmodulin that phosphorylates specific cGMP See cyclic guanosine monophosphate. [3]
proteins in a signaling pathway. [3] Chantix See varenicline. [13]
cAMP See cyclic adenosine monophosphate. [3] ChAT See choline acetyltransferase. [7]
Campral See acamprosate. [10] chemogenetics The activation or suppression of a
cannabidiol (CBD) Phytocannabinoid that lacks the genetically engineered receptor with a designer ligand
intoxicating and dependence-producing effects of THC. [14] in order to study behavioral effects of longer duration
cannabinoid receptor Class of metabotropic receptors
compared to optogenetic manipulation. Sometimes referred
responsive to both endocannabinoids like anandamide to as DREADD. [4]
and phytocannabinoids such as THC. In the CNS, they are choline Precursor necessary for ACh synthesis. [7]
concentrated in the basal ganglia, cerebellum, hippocampus, choline acetyltransferase (ChAT) Enzyme that catalyzes
and cerebral cortex. [14] the synthesis of ACh from acetyl CoA and choline. [7]
Carbamazepine (Tegretol) An anticonvulsant drug used to choline transporter Protein in the membrane of the
treat bipolar disorder. [18] cholinergic nerve terminal responsible for the uptake of
carbidopa A decarboxylase inhibitor that cannot cross the choline from the synaptic cleft. [7]
blood–brain barrier. Increases the availability of l-DOPA to cholinergic Adjectival form of ACh. [7]
the brain. [6, 20]
cholinesterase inhibitors Drugs that improve cognitive
carcinoid syndrome Cluster of symptoms produced by the symptoms by increasing the presence of acetylcholine in
secretory products (including serotonin) of carcinoid tumors. the synapse by lessening breakdown of ACh. One of two
[6] categories of treatment for AD. [20]
case–control method Technique used to identify genes chromaffin cells The cells of the adrenal medulla. [3]
associated with a disorder by comparing the genes of
chromatin remodeling One type of environmentally
unrelated affected and unaffected people to determine
induced epigenetic modification that increases or decreases
if those who are affected are more likely to possess a
gene transcription.[2]
particular allele. [10]
chromosomes Double helical strands of DNA that
catalepsy State characterized by a lack of spontaneous
carry genes. [2]
movement. It is usually associated with D2 receptor blockers
(a DA receptor subtype), but can also be induced with chronic mild unpredictable stress Rodent model of
a D1 blocker. [5] depression created by exposing animals to a series of
stressful events in an unpredictable fashion. [4]
Catapres See clonidine. [5]
chronic social defeat stress Rodent model of depression
catechol-O-methyltransferase (COMT) One of the
created by the intense stress of being repeatedly placed as
enzymes responsible for metabolic breakdown of
an intruder in a cage with a resident animal. [4]
catecholamines. [5, 20]
classical conditioning Repeated pairing of a neutral
catecholamines Group of neurotransmitters and hormones
stimulus with an unconditioned stimulus. Eventually the
characterized by two chemical similarities: a core structure of
neutral stimulus becomes a conditioned stimulus and
catechol and a nitrogen-containing amine. They belong to a
elicits a (conditioned) response that is similar to the original
wider group of transmitters called monoamines or biogenic
unconditioned response. This type of learning has a role in
amines. [5]
drug use and tolerance. [1]

21 Meyer4e Glossary.indd 5 12/15/21 12:54 PM

 422 Chapter 13

of tobacco product users revealed that e-cigarettes were had much higher scores than intermittent smokers on a
most popular among people 18 to 44 years of age, where- standard test of nicotine dependence. As a result, daily
as tobacco cigarettes were most popular among people smokers exhibit a more compulsive smoking habit that
45 years of age or older. Moreover, among all surveyed is accompanied by strong cravings for tobacco and is
e-cigarette users, 36.9% were also current tobacco ciga- difficult to stop. Why intermittent smokers fail to de-
rette smokers (i.e., dual tobacco product users), 39.5% velop strong nicotine dependence despite years of ex-
were former tobacco cigarette smokers, and 23.6% had posure is not yet well understood.
never smoked tobacco cigarettes. Finally, for the young- A group of Canadian researchers determined the
est surveyed group of e-cigarette users, namely those rate of progression through predetermined “mile-
who were 18 to 24 years of age, over 50% indicated that stones” from the first cigarette to clinically defined nic-
they had never smoked tobacco cigarettes (Cornelius et otine dependence by following over 1000 students pro-
al., 2020). Taken together, these findings depict an overall spectively for 5 years beginning at the seventh grade
trend of e-cigarettes gradually replacing tobacco ciga- (Gervais et al., 2006). The researchers found that the
rettes as the nicotine vehicle of choice. first signs of craving, tolerance, and withdrawal symp-
toms often occurred before the smoker had smoked
a total of 100 cigarettes (just five packs!) in their life.
Nicotine users progress through a series of These results are consistent with other findings sug-
stages in their pattern and frequency of use gesting an early onset of nicotine dependence (DiFran-
INITIATION AND SUBSEQUENT TRA JECTORY OF za et al., 2011, 2015). On the other hand, the researchers
TOBACCO CIGARETTE SMOKING Most smokers pick also found that the time from first puff to the milestone
up the habit during adolescence. Looked at another way, of daily smoking ranged from 20 months to almost 40
early smoking greatly increases the chances that one months for the study participants who reached that
will smoke as an adult. For this reason, smoking and, milestone (Gervais et al., 2006). Therefore, the progres-
more recently, vaping by teenagers have received a lot of sion of smoking frequency can be fairly slow despite
attention from researchers as well as from policy mak- earlier signs of nicotine tolerance and dependence.
ers whose goal is to reduce the use of tobacco products
in our society. There are many theories about why teen- INITIATION AND SUBSEQUENT TRA JECTORY OF
agers take up smoking. Some of the hypothesized rea- E-CIGARETTE USE We have previously noted that
sons include establishing feelings of independence and more adolescents now use e-cigarettes than tobacco ciga-
maturity (by defying parental wishes or societal norms), rettes. This raises three important questions. First, what
improving self-image and enhancing social acceptance are the self-reported reasons for initiating vaping and
(assuming that one’s friends are already smokers), coun- the risk factors that are associated with e-cigarette use
teracting stress and/or boredom, and simple curiosity. compared to non-use? Second, what are the factors that
Moreover, young people tend to emphasize the positive lead young people to choose e-cigarettes over tobacco
elements of smoking and vaping while disregarding cigarettes for their initial exposure to tobacco products?
or denying the negative aspects, including the health Finally, does e-cigarette use by adolescents increase the
consequences. Longitudinal surveys have gone beyond likelihood of a later onset of tobacco cigarette smoking?
self-reported reasons for smoking to examine empiri- In self-report studies, young people typically cite
cally the various factors that predict smoking onset. A curiosity, taste (flavor), relief from boredom, having a
review of this research found that poor academic per- good time with friends, and alleviation of tension as
formance, rebelliousness, sensation seeking, receptiv- major reasons for beginning to vape (e.g., see Patrick
ity to cigarette advertising/marketing, and smoking by et al., 2016). Furthermore, e-cigarette users compared
family and/or friends were all significant predictors of to non-users were found to have less parental support
smoking onset (Wellman et al., 2016). and monitoring, more parental conflict, less academic
Early adolescent experimentation with cigarettes involvement, and poorer behavioral and emotional
can lead to a variety of outcomes. Some individuals, self-control and regulation (Wills et al., 2015). The
called intermittent smokers, develop a stable habit of users were characterized as being more rebellious and
non-daily smoking. In one study, for example, the in- sensation-seeking, and they were greater users of alco-
termittent smoking group smoked a mean of 4.45 ciga- hol and marijuana. These findings are hardly unique
rettes per smoking day, with smoking days averaging to e-cigarettes, since many of the same risk factors have
4.5 per week (Shiffman et al., 2014). This group had previously been reported for adolescent users of other
been smoking an average of 19.25 years, indicating that substances. Additional risk factors for e-cigarette use
their intermittent smoking pattern was not a temporary include having friends or family members who smoke
phenomenon on the way to greater cigarette consump- tobacco cigarettes (Wang et al., 2018) and having in-
tion. A comparison group that smoked daily averaged ternalizing and/or externalizing problems (Buu et
15.0 cigarettes per day. Not surprisingly, daily smokers al., 2020). Once e-cigarette use has begun, many users

13_Meyer4e_CH13.indd 422 12/7/21 12:08 PM

 68 Chapter 2

cortex, cingulate cortex, and entorhinal areas and are Additionally, other axons descend farther into the spinal
considered the mesocortical tract. All three of these do- cord to influence sympathetic nervous system function.
pamine pathways are of significance in our discussions Other hypothalamic nuclei communicate with the con-
of Parkinson’s disease (see Chapter 20), drug addiction tiguous pituitary gland by two methods: neural control
(see Chapter 9), and schizophrenia (see Chapter 19). of the posterior pituitary and hormonal control of the an-
terior pituitary. By regulating the endocrine hormones,
DIENCEPHALON The two major structures in the di- the hypothalamus has widespread and prolonged ef-
encephalon are the thalamus and the hypothalamus. fects on body physiology. Of particular significance to
The thalamus is a cluster of nuclei that first process and psychopharmacology is the role of the paraventricular
then distribute sensory and motor information to the nucleus in regulating the hormonal response to stress,
appropriate portion of the cerebral cortex. For example, because stress has a major impact on our behavior and
the lateral geniculate nucleus of the thalamus receives vulnerability to psychiatric disorders. BOX 2.5 describes
visual information from the eyes before projecting it to the neuroendocrine response to stress and previews its
the primary visual cortex. Most incoming signals are significance for psychiatric ills and their treatment.
integrated and modified before they are sent on to the
cortex. The functioning of the thalamus helps the cortex TELENCEPHALON The cerebral hemispheres make up
to direct its attention to selectively important sensory the largest region of the brain and include the external
messages while diminishing the significance of others; cerebral cortex, the underlying white matter, and subcor-
hence the thalamus helps to regulate levels of awareness. tical structures belonging to the basal ganglia and limbic
The second diencephalic structure, the hypothalamus, system. The basal ganglia include the caudate, putamen,
lies ventral to the thalamus at the base of the brain. Al- and globus pallidus and, along with the substantia nigra
though it is much smaller than the thalamus, it is made in the midbrain, make up a system for motor control (see
up of many small nuclei that perform functions critical Figure 2.22). Drugs administered to control symptoms
for survival (FIGURE 2.23). The hypothalamus receives of Parkinson’s disease act on this group of structures.
a wide variety of information about the
internal environment and, in coordina-
tion with closely related structures in
the limbic system (see the section on the
telencephalon below), initiates various
mechanisms important for limiting the
variability of the body’s internal states Tuberal
region
(i.e., they are responsible for homeostasis).
Several nuclei are involved in maintaining Anterior Lateral–posterior
region region
body temperature and salt–water balance.
Other nuclei modulate hunger, thirst, en- Fornix Thalamus
ergy metabolism, reproductive behaviors,
and emotional responses such as aggres-
sion. The hypothalamus directs behaviors
for adjusting to these changing needs by Paraventricular
controlling both the autonomic nervous nucleus
system and the endocrine system and or- Dorsomedial
Lateral and medial nucleus
ganizing behaviors in coordination with preoptic nuclei
other brain areas. Axons from nuclei in Posterior area
the hypothalamus descend into the brain- Anterior nucleus
stem to the nuclei of the cranial nerves
Mammillary
that provide parasympathetic control. Suprachiasmatic
body
nucleus

Supraoptic nucleus
FIGURE 2.23 Hypothalamus The hypo­ Arcuate nucleus
thalamus is a cluster of nuclei at the base
of the forebrain that is often subdivided into Ventromedial
three groups based on region: anterior, nucleus
tuberal, and lateral–posterior. Each of the Infundibular stalk
nuclei has its own complex pattern of neural
connections and regulates one or several
components of homeostatic function and Anterior pituitary Posterior
motivated behavior. pituitary

02_Meyer4e_CH02.indd 68 12/9/21 2:31 PM

 R-48 References

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 Alcohol 321

are working to identify gene polymorphisms that are Novelty seeking by individuals may also increase
involved in the differences, with the hope of developing the risk for using alcohol and other drugs of abuse
targeted drug treatment plans for selected individuals. because exposure to novel events activates the dopa-
Alcohol misuse has long been known to be associated minergic mesolimbic pathway in a manner similar to
with high levels of lifetime anxiety. Consistent with the that seen with most misused substances (Bardo, 1996).
findings of rodent studies, stress early in life is a signifi- Individual differences in the need for novelty and
cant environmental risk factor for alcohol misuse in the drug-seeking behavior are under genetic control and
adult, just as it predicts adult depression (see Chapter may explain why some individuals experiment with
18) and anxiety disorders (see Chapter 17). However, drugs initially and why some more readily become
in agreement with several other studies, Schmid and compulsive users. Differences in the need for stimula-
colleagues (2010) found that the number of early stress- tion have been applied to drug and alcohol prevention
ful life events could predict early onset of drinking and programs that use fast-paced, physiologically arousing,
higher levels of alcohol consumption at age 19, but only and unconventional message delivery to appeal to the
for those individuals with a particular polymorphism target audience.
of the corticotropin-releasing factor receptor 1 (CRF1) gene, In replicating and expanding on earlier studies, Nees
clearly indicating a gene × stress × alcohol interaction. and colleagues (2012) found that behavior (risk taking
The fact that gene polymorphisms of CRF1 are associ- and aversion for delayed reward), neural response in
ated with risky drinking behavior suggests a potential the brain reward circuitry in response to large versus
screening method for identifying future problem be- small rewards, and personality (extraversion, impulsiv-
haviors and perhaps indicates the optimal treatment ity, sensation seeking, and novelty seeking) interacted
approach for these individuals should such behaviors and were predictive of early alcohol use and subse-
develop. Differences in individuals’ stress response quent alcohol addiction. Personality traits represented
systems and in their perception and appraisal of stress the strongest predictor. Since genetics contributes to
may help to explain some of the differential vulnerabil- these phenotypic characteristics, future research may
ity to alcohol misuse. These and other pivotal studies be directed toward evaluating genetic factors in early
are summarized in two excellent reviews (Clarke and adolescent drinking models.
Schumann, 2009; Spanagel et al., 2014).
In an earlier section, we mentioned that alcohol NEUROBIOLOGICAL FACTORS One significant neu-
increases DA transmission in the mesolimbic tract, robiological factor in AUD is genetic vulnerability.
thereby mediating reinforcement. It is significant that Close relatives of alcohol-dependent individuals have
cortisol seems to sensitize this circuitry, which means a three to seven times greater risk for AUD than the
that alcohol-induced increases in the HPA axis function general population. Both twin and adoption studies
and subsequent elevations in cortisol may contribute show that genetics is correlated with vulnerability,
to its reinforcing properties. It is intriguing to find that particularly for the more severe type of AUD. In adop-
corticosterone (the rodent version of cortisol) itself is tion studies, the risk of AUD is higher in children of
self-administered by laboratory animals, apparently alcohol-dependent parents even when they are adopted
because its binding to glucocorticoid receptors in NAcc into nonalcoholic families. AUD concordance rates are
activates a feedback loop to VTA that enhances meso- higher in monozygotic (54%) than in dizygotic (28%)
limbic cell firing. This idea is supported by rodent stud- twins, demonstrating the influence of genes but leav-
ies showing that glucocorticoids enhance mesolimbic ing significant variability to be explained by other fac-
DA and increase drug-seeking behaviors. A striking tors. Overall, genetics explains 50% to 60% of the vari-
relationship exists: even among individuals without ance of risk for dependence in both men and women,
substance misuse problems, those who secreted more although the percentage may be higher for some types
cortisol in response to stress also released more meso- of AUD than others. The heritability of alcohol misuse
limbic DA and experienced greater subjective effects of is less, at about 38%.
psychostimulants. It is suspected that this relationship Although the importance of heritability is clear,
may cause some individuals to increase consumption identifying specific genes is much more difficult be-
beyond casual use. In contrast, as was mentioned in cause of the complexity of the disorder. To help with ge-
the section on DA, withdrawal reduces the mesolim- netic analysis, researchers utilize subgroups of people
bic neuron firing rate and is associated with a negative with AUD on the basis of various characteristics such
affective state that acts as an internal stressor. Hence, as severity, craving, occurrence of withdrawal, gender,
although mild stress enhances mesolimbic function, and so forth. Many genes have been identified as po-
chronic stress further reduces the function of this path- tential vulnerability factors, but each of them contrib-
way and increases craving—a state that would make ute only a small amount to the risk of developing AUD.
relapse to alcohol consumption more likely (Uhart and To find genetic patterns in humans with AUD, sev-
Wand, 2009; Spangel et al., 2014). eral methods may be used. Rietschel and Treutlein

10_Meyer4e_CH10.indd 321 12/8/21 11:16 AM

 Glossary G-21

parasympathomimetic agents Drugs that stimulate PCP See phencyclidine. [8, 15]
muscarinic receptors, thereby mimicking the effects of PCPA See para-chlorophenylalanine. [6]
parasympathetic system activation. [7]
PD See Parkinson’s disease. [20]
paraventricular nucleus (PVN) Hypothalamic nucleus
located adjacent to the 3rd ventricle that contains PDD See Parkinson’s disease dementia. [20]
vasopressin- and oxytocin-secreting neurons. Other neurons peak experience Intense psychedelic state experienced
with this nucleus participate in the neural circuit that during a hallucinogenic drug-assisted therapeutic session
regulates hunger and eating behavior. [3, 6] that is hypothesized to be an important contributor to the
paraxanthine Biologically active caffeine metabolite that therapeutic benefit. [15]
exerts CNS stimulant activity like the parent compound. [13] pedunculopontine tegmental nuclei (PPTg) Structure
parenteral Methods of drug administration that do not use within the dorsal lateral pons containing cholinergic neurons
the gastrointestinal system, such as intravenous, inhalation, that project to the substantia nigra (important for stimulating
intramuscular, transdermal, etc. [1] nigral dopamine neurons) and others that project to the brain-
stem and thalamus (important for behavioral arousal, sensory
parietal lobe One of four lobes of the cerebral cortex. processing, and initiation of rapid-eye-movement sleep). [7]
It contains the somatosensory cortex and helps integrate
information about body senses. [2] penetrance Frequency with which a particular gene
produces its main effect. [20]
Parkinson’s disease (PD) Chronic, progressive,
neurodegenerative disorder characterized by tremor, rigidity, pentylenetetrazol (Metrazol) Convulsant drug that acts by
difficulty in initiating movement, slowing of movement, and blocking the function of GABAA receptors. [8]
postural instability. [20] periaqueductal gray (PAG) Structure of the tegmentum
Parkinson’s disease dementia (PDD) Condition in which located around the cerebral aqueduct that connects the third
one or more cognitive functions are impaired to the point and fourth ventricles. It is important for regulating pain;
of interfering with the ability of the individual to navigate stimulation produces an analgesic effect. [2]
everyday life. [20] PET See positron emission tomography. [4]
parkinsonian symptoms Undesired response to anti- peyote button Crown of the peyote cactus, Lophophora
psychotic drugs that resembles Parkinson’s disease, williamsii, that can be dried and ingested to obtain the
including tremors, akinesia, muscle rigidity, akathesia, and psychedelic/hallucinogenic drug mescaline. [15]
lack of facial expression. [19] peyote cactus Species of cactus, Lophophora williamsii, that
Parlodel See bromocriptine. [5] produces mescaline. [15]
Parnate See tranylcypromine. [5] pharmacodynamic tolerance Type of tolerance formed by
partial agonists Drugs that bind to a receptor but have changes in nerve cell functions in response to the continued
low efficacy, producing weaker biological effects than a presence of a drug. [1, 10]
full agonist. Hence, they act as agonists at some receptors pharmacodynamics Study of physiological and
and antagonists at others, depending on the regional biochemical interactions of a drug with the target tissue
concentration of full agonist. These were previously called responsible for the drug’s effects. [1]
mixed agonist-antagonists. [1, 11] pharmacoepigenetics Study of the role of epigenetic
parts per million (ppm) Number of molecules of a gaseous modifications in individual variation in response to drug
substance per million molecules of air. When applied to effects. [1]
an inhaled substance, it is used to describe the amount of pharmacogenetics Study of the genetic basis for variability
exposure to the substance (i.e., dose). [16] in drug response among individuals (sometimes called
parvocellular neurons General term for neurons with pharmacogenomics). [1, 4]
small cell bodies. Included within this category are neurons pharmacokinetic Factors that contribute to bioavailability:
located in the paraventricular nucleus of the hypothalamus the administration, absorption, distribution, binding,
that project their axons to several different brain areas inactivation, and excretion of a drug. [1]
where they release vasopressin and oxytocin to act as
pharmacological MRI (phMRI) Spin-off of functional MRI
neurotransmitters/neuromodulators. [3]
(fMRI), it is a technique used to investigate the mechanism
passive avoidance learning Type of learning task in of drug action by visualizing changes in brain function
rats and mice in which the animal is trained to avoid a following drug administration. [4]
location that it would normally enter (e.g., going into a dark
pharmacology Study of the actions of drugs and their
compartment from one that is brightly lit) by administration
effects on living organisms. [1]
of a brief electric footshock when it enters the location. The
word “passive” in the name of the task reflects the fact that pharmacotherapeutic treatment Method of disease
the animal must withhold its usual response of moving into treatment that uses drugs to modify a clinical condition. [10]
the dark compartment. [5] phasic release Irregularly timed and larger amounts of
passive diffusion Movement of lipid-soluble materials neurotransmitter release than occurs in the case of tonic
across a biological barrier without assistance based on its release. It is typically associated with the burst mode of
concentration gradient, from higher to lower concentration. [1] cell firing and produces surges in extracellular levels of the
transmitter. [5]
patch clamp electrophysiology Technique used to measure
the function of a single ion channel by using a micropipette phencyclidine (PCP) Uncompetitive antagonist of the
to isolate the ion channel and obtain an electrical recording. NMDA receptor that binds to a site within the receptor
[4] channel. It is a dissociative anesthetic that was once used
medicinally but is now only taken recreationally. [8, 15]
Pavlovian conditioning See classical conditioning. [1]

21 Meyer4e Glossary.indd 21 12/15/21 12:54 PM

 Methods of Research in Psychopharmacology 145

optogenetically. Hence, while optogenetics (A) (B)

is optimal for controlling changes over mil-
ChR2 viral ChR2
liseconds, providing the finest level of tem- gene
vector
poral control over the behavior investigated,
chemogenetics may be chosen for studying
behavioral effects of longer duration, such

© John B. Carnett/Popular
as anxiety or feeding, because the designer

Science/Getty Images
ligands last longer than pulses of light. The
longer duration and the fact that designer li-
gands can be administered orally suggest the Packaging
potential for translation to therapeutic appli- cell line
cations such as treatment of obesity, epilepsy,
and addiction disorders. For further details FIGURE 4.31 Behavioral control
of the method and discussion of therapeutic using optogenetics (A) The steps
potential, refer to Urban and Roth (2015). required for an in vivo ChR2 opto-
genetic study include packaging the
Behavioral and ChR2 ChR2 gene along with an additional
neuropharmacological methods virus cell-targeting DNA sequence into
complement one another a viral vector, growing many copies
of the engineered virus, implanting
Bear in mind that under normal circum- the virus into a selected brain area,
stances, several of these techniques are used and stimulating the target neurons
in tandem to approach a problem in neu- that have incorporated the ChR2
roscience from several directions (see WEB gene with a blue light. (B) Mouse
BOX 4.3). The power of these experimental implanted with a fiber-optic probe
connected to a laser chosen to
tools is that when they are used together, a deliver light of the appropriate
more reasonable picture emerges, and con- wavelength. (A from K. Deisseroth.
flicting results can be incorporated into the 2015. Nat Neurosci 18: 1213–1225.
larger picture. Only in this way can we un- doi.org/10.1038/nn.4091)
cover the neurobiological substrates of cog-
nitive function and dysfunction. In every
case, interpretation of these sophisticated Illumination
approaches is subject to the same scrutiny Fiber-
optic
required by the earliest lesion experiments. Skull cable
Remember, healthy skepticism is central to
Cortex
the scientific method.

SECTION SUMMARY
■ Using a stereotaxic device, lesioning destroys
brain cells in selected areas with high-fre-
quency radio current. More selective lesions Blue light
are made by injecting an excitatory neurotoxin
that destroys cell bodies in the region with- Target neuron
out damaging axons passing through, or by
injecting a neurotoxin selective for a given
neurotransmitter.
■ Using a specialized cannula, microdialysis
allows researchers to collect material from
extracellular fluid from deep within the brain
in a freely moving animal, so correspond-
ing changes in behavior can be monitored
simultaneously. The material is analyzed and
quantified by high-pressure liquid chroma-
tography. In vivo voltammetry is a second way
to measure the neurotransmitter released
into the synapse.

Meyer 4e
Psychopharmacology
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Sinauer Associates
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