Received: 28 June 2021 Revised: 9 October 2021 Accepted: 21 October 2021

DOI: 10.1111/bph.15797

RESEARCH ARTICLE

Linking drug and food addiction via compulsive appetite

Amanda Laque1 | Grant E. Wagner1 | Alessandra Matzeu2 |

Genna L. De Ness1 | Tony M. Kerr1,3 | Ayla M. Carroll1 |
Giordano de Guglielmo1,4 | Hermina Nedelescu1 | Matthew W. Buczynski1,5 |
Ann M. Gregus5 | Thomas C. Jhou6 | Eric P. Zorrilla2 |
Remi Martin-Fardon2 | Eisuke Koya7 | Robert C. Ritter8 | Friedbert Weiss1 |
Nobuyoshi Suto1

1
Department of Neuroscience, The Scripps
Research Institute, La Jolla, California, USA Background and Purpose: ‘Food addiction’ is the subject of intense public and
2
Department of Molecular Medicine, The research interest. However, this nosology based on neurobehavioural similarities
Scripps Research Institute, La Jolla, California,
USA among obese individuals, patients with eating disorders and those with substance
3
College of Pharmacy, University of Texas use disorders (drug addiction) remains controversial. We thus sought to determine
Austin, Austin, Texas, USA
which aspects of disordered eating are causally linked to preclinical models of drug
4
Department of Psychiatry, University of
California San Diego, San Diego, California,
addiction. We hypothesized that extensive drug histories, known to cause addiction-
USA like brain changes and drug motivation in rats, would also cause addiction-like food
5
School of Neuroscience, Virginia Polytechnic motivation.
Institute and State University, Blacksburg,
Virginia, USA Experimental Approach: Rats underwent extensive cocaine, alcohol, caffeine or
6
Department of Neurosciences, Medical obesogenic diet histories and were subsequently tested for punishment-resistant
University of South Carolina, Charleston,
food self-administration or ‘compulsive appetite’, as a measure of addiction-like food
South Carolina, USA
7
Sussex Neuroscience, School of Psychology, motivation.
University of Sussex, Falmer, UK Key Results: Extensive cocaine and alcohol (but not caffeine) histories caused com-
8
Department of Integrative Physiology and
pulsive appetite that persisted long after the last drug exposure. Extensive
Neuroscience, Washington State University,
Pullman, Washington, USA obesogenic diet histories also caused compulsive appetite, although neither cocaine
nor alcohol histories caused excess calorie intake and bodyweight during abstinence.
Correspondence
Nobuyoshi Suto and Friedbert Weiss, Hence, compulsive appetite and obesity appear to be dissociable, with the former
Department of Neuroscience, The Scripps
sharing common mechanisms with preclinical drug addiction models.
Research Institute, La Jolla, CA, USA.
Email: [email protected] and bweiss@scripps. Conclusion and Implications: Compulsive appetite, as seen in subsets of obese indi-
edu
viduals and patients with binge-eating disorder and bulimia nervosa (eating disorders
Funding information that do not necessarily result in obesity), appears to epitomize ‘food addiction’.
National Institute on Drug Abuse, Grant/
Because different drug and obesogenic diet histories caused compulsive appetite,
Award Numbers: K99/R00DA035865,
R01DA037294, R01DA08467; National overlapping dysregulations in the reward circuits, which control drug and food moti-
Institute on Alcohol Abuse and Alcoholism,
vation independently of energy homeostasis, may offer common therapeutic targets
Grant/Award Numbers: R01AA021549,
R01AA023183, T32AA007456 for treating addictive behaviours across drug addiction, eating disorders and obesity.

Abbreviations: LgA, long-access; SCM, sweetened condensed milk; ShA, short-access.

Amanda Laque, Grant E. Wagner and Alessandra Matzeu are co-first authors. These authors contributed equally to this project.

Friedbert Weiss and Nobuyoshi Suto are co-senior authors.

Br J Pharmacol. 2022;1–21. wileyonlinelibrary.com/journal/bph © 2022 The British Pharmacological Society 1

2 LAQUE ET AL.

KEYWORDS
eating disorders, food addiction, substance use disorders

1 | I N T RO DU CT I O N
What is already known
Obesity and some eating disorders, such as binge-eating disorder and
bulimia nervosa, are increasingly considered ‘food addiction’ (Avena • The validity of ‘food addiction’ is largely based on corre-
et al., 2011; Gearhardt et al., 2011). The putative validity of this nosol- lational evidence and remains controversial.
ogy relies largely on neurobehavioural similarities between these
forms of disordered eating and substance use disorders (drug addic-
tion) (Serafine et al., 2021; Volkow & Wise, 2005), the prototypical What does this study add
addictive disorder. However, the legitimacy of food addiction, based
on such correlational evidence, remains controversial (Fletcher & • Punishment-resistant ‘compulsive’ food intake is causally
Kenny, 2018). We have thus investigated which aspects of disordered linked to preclinical drug addiction models.
eating are causally linked to well-established preclinical models of
drug addiction.
Major characteristic of drug addiction is compulsive drug crav- What is the clinical significance
ing and use that persist despite adverse consequences (punish-
ments) (American Psychiatric Association, 2013). In animals, • Like drug addiction, ‘food addiction’ is better defined as a
extensive drug histories can cause punishment-resistant ‘compul- disorder of compulsive behaviour.
sive’ drug self-administration and brain changes resembling those
in patients with drug addiction (Vanderschuren & Ahmed, 2020).
Similarly, extensive obesogenic diet histories can cause addiction-
like food motivation and brain changes in animals (Wiss
et al., 2017). Because patients with drug addiction—as a universally 2 | METHODS
recognized form of addiction—and people with obesity and/or eat-
ing disorders—as putative ‘food addiction’—share similar brain pro- 2.1 | Animals
files (Serafine et al., 2021; Volkow & Wise, 2005), we
hypothesized that extensive drug histories would similarly cause All animal care and experimental procedures were conducted in accor-
punishment-resistant operant food self-administration or ‘compul- dance with the National Institutes of Health (USA) Guidelines for the
sive appetite’ in animals. Care and Use of Laboratory Animals and approved by the Institutional
We tested this hypothesis in male and female rats undergoing Animal Care and Use Committees at The Scripps Research Institute.
long-term abstinence from different drug (cocaine/alcohol/caffeine) Animal studies are reported in compliance with the ARRIVE guidelines
and obesogenic diet (high fat and high sugar/high fat [but not high (Percie du Sert et al., 2020) and with the recommendations made by
sugar]/high sugar [but not high fat]/high protein) histories. We the British Journal of Pharmacology (Lilley et al., 2020).
determined compulsive appetite based on established procedures A total of 552 Wistar rats (RRID:MGI:5657554) were used. Of
to test punishment-resistant 'compulsive' operant drug and food these, 409 were male and 143 were female. All rats were purchased
self-administration in rats (see Deroche-Gamonet et al., 2004; from Charles River, Inc. (Wilmington, MA, USA). Adult male and
Johnson & Kenny, 2010). For these procedures, along with caloric- female rats weighing 250–300 g and 150–175 g, respectively, at the
sweetened condensed milk (SCM), we used non-caloric saccharin start of experiments were used. Male and female rats were roughly
as a food reward to isolate ‘non-homeostatic’ (hedonic/incentive) the same age. All rats were housed in a temperature and humidity-
appetite regulation from ‘homeostatic’ (caloric/metabolic) regulation controlled room and maintained on a 12-h/12-h reverse light/dark
(Berthoud, 2006). We also used saccharin to isolate the hedonic/ cycle. At all times, water and food were available ad libitum. All rats
incentive impacts of food rewards arising from sensory processes were maintained on standard lab chow (Product #7012, Teklad Diets-
(e.g., taste) from those arising from enteric or metabolic feedback Envigo, Madison, WI, USA) and regular tap water, unless otherwise
signals from the gut (de Araujo et al., 2020). Additionally, we specified.
determined the long-term effects of past drug (cocaine/alcohol/caf- We used rats in the current study, because rats are known to rep-
feine) histories on ad libitum calorie intake and weight licate aspects of neurobehavioural profiles of human drug addiction
changes under unchallenged (no operant task/no punishment) and disordered eating (Serafine et al., 2021; Volkow & Wise, 2005).
conditions. For all cases, studies were designed to generate groups of equal size,
LAQUE ET AL. 3

FIGURE 1 Legend on next page.

4 LAQUE ET AL.

F I G U R E 1 The effects of extensive cocaine histories on subsequent food motivated behaviour in male rats undergoing long-term abstinence.
(a) Effects of cocaine self-administration histories on punished SCM intake. Right panel depicts group averages (+SEM) of total numbers of
rewards obtained (30-min totals) during the last three training sessions as ‘baseline’. Left panel depicts group averages (±SEM) of numbers of
rewards obtained (30-min totals) during each test session as ‘% changes from baseline’ (normalized per rat). (b) Effects of cocaine self-
administration histories on high workload SCM intake. Right and left panels depict group averages (+SEM) of total numbers of rewards and active
lever-pressing under a progressive ratio (PR) schedule. (c) Effects of cocaine self-administration histories on ad libitum food intake (kcal). (d)
Effects of cocaine self-administration histories on ad libitum weight gain. (d) Effects of cocaine self-administration histories on punished saccharin
intake. (e) Effects of IP cocaine histories on punished SCM intake. (f) Effects of IP cocaine histories on punished saccharin intake. *P < 0.05,
significantly different from 0.0 mA (a,e–g) or Week 1 (c,d); #P < 0.05, significantly different from the drug-naïve control. IP, intraperitoneal; LgA,
long-access; SA, self-administration; SCM, sweetened condensed milk; ShA, short-access

using randomization and blinded analysis. However, equal group size 2.3.1 | Experiment 1: The effects of extensive
was not always achieved because of attrition of animals due to experi- cocaine histories on subsequent food-motivated
mental complications, including general health issues and failure to behaviour in male rats
meet training criteria. Below, we report the initial numbers of animals
used for each experiment as well as the final numbers retrained for Male rats were randomly assigned to a specific experimental condition
statistical analyses. defined first by drug history and then behavioural testing. We
describe each experimental condition below (experimental timelines
are shown in Figure 1).
2.2 | Surgery
I. Cocaine histories via operant self-administration (cocaine self-
Rats assigned to ‘cocaine histories via operant self-administration’ administration histories):
(see below) were implanted with intravenous catheters made of
Micro-Renathane (Braintree Science, Braintree, MA, USA) under Rats were randomly assigned to short-access (ShA) cocaine, long-
anaesthesia, as described previously (Laque et al., 2019). Rats were access (LgA) cocaine or saccharin history groups. LgA cocaine history
allowed to recover for at least 7 days. was based on procedures known to induce addiction-like escalation in
drug intake and brain changes in rats (Ahmed, 2012). ShA cocaine his-
tory was based on procedures known to induce addiction-like habitual
2.3 | Behavioural procedures and inflexible behaviour and brain changes (see Lucantonio
et al., 2014). Neither LgA nor ShA cocaine history is known to alter
For operant conditioning procedures, rats were trained and tested pain sensitivity in rats (Edwards et al., 2012). Because cocaine is non-
during the dark (active) phases in dedicated operant conditioning caloric, we used similarly non-caloric saccharin for the control self-
chambers (Med Associates, Saint Albans, VT, USA). Each chamber administration histories (drug naïve controls). Rats in LgA/ShA cocaine
was equipped with two retractable levers (one ‘active lever’ and and saccharin history groups were further randomly assigned to the
one ‘inactive lever’), a ‘light-cue’, a syringe pump and either a liquid following behavioural tests and trained accordingly:
swivel system for intravenous cocaine or a drinking well for SCM
and saccharin. At all times, insertion of active and inactive levers i. Compulsive appetite tests for SCM. Here, we determined the ani-
into an operant conditioning chamber signalled the start of a once- mals' willingness to work for caloric SCM despite adverse conse-
daily self-administration session conducted under a fixed ratio quences (punishments), as an indicator of addiction-like food
1 (FR1) schedule of reinforcement. Each press on the active lever motivation. Male (N = 54) rats were trained and tested according
resulted in a single delivery of either cocaine (1.0 mg/kg per infu- to the following three phases:
sion, intravenous) into the jugular vein or a non-drug reward (SCM
[33% dissolved in water, 0.2 ml, oral] or saccharin [0.125% dissolved 1. Drug histories (3–4 weeks): Rats in the ShA and LgA cocaine his-
in water, 0.2 ml, oral]) into the drinking well. Each cocaine delivery tory groups were trained to lever-press for cocaine for 2 and 6 h
was paired with 20-s illumination of a light cue, and each SCM or daily, respectively. Because cocaine is non-caloric, we used simi-
saccharin delivery was paired with 2-s illumination of a light cue; larly non-caloric saccharin for the control self-administration histo-
light-cue illumination signalled a timeout period during which pres- ries. Rats in the drug-naïve history group were trained to lever-
ses on the active lever were recorded but had no scheduled press for saccharin for 30 min daily. Rats were required to satisfy
consequences. the following training criteria or excluded: (1) a minimum of
Rats were randomly assigned to specific experimental conditions 21 days of training and (2) a minimum of 30 cocaine (ShA),
defined by drug/diet histories and behavioural tests. We describe 50 cocaine (LgA) and 50 saccharin (drug-naïve) deliveries for three
each experimental condition below. consecutive training sessions.
LAQUE ET AL. 5

2. SCM self-administration training (3 weeks): All rats were trained to session was terminated when 60 min had elapsed after the final
lever-press for SCM—instead of cocaine or saccharin—and were reinforced response.
required to satisfy the following training criteria or excluded: (1) a
minimum of 14 days of training and (2) a minimum of 50 SCM The final Ns retained for statistical analyses for the saccharin, ShA
deliveries daily for three consecutive training sessions. cocaine and LgA cocaine groups were 19/19/19.
3. Compulsive appetite tests for SCM (3 weeks): All rats were
tested to lever-press for SCM despite adverse consequences iii. Ad libitum calorie intake and weight gain tests. Here, we
during the fourth to sixth weeks after drug histories. Each SCM determined the animals' calorie intake and weight gain under
delivery was paired with an electric foot-shock punishment gen- unchallenged ‘ad libitum’ conditions (i.e., continuous access to
erated by a shocker/scrambler (Med Associates, Saint Albans, nutritionally balanced diet and then obesogenic diets, no operant
VT, USA), which was delivered contingent on a reinforced lever- conditioning and no punishment, etc.), as an indicator of homeo-
press, along with SCM. Each rat underwent a total of five test static appetite regulation. Male (N = 32) rats underwent the
sessions (30 min each) for the following five levels of foot- following three phases:
shock intensity: 0.0, 0.1, 0.15, 0.25 and 0.35 mA (0.5 s each).
The shock intensities were kept constant during each test ses- 1. Drug histories (3–4 weeks + 3 weeks for recovery): As described
sion (following a between-session design). Test sessions were for i. (Compulsive appetite tests for SCM). Six rats that died due to
separated by 2–4 days; on interim days, all rats were allowed to surgical complications were excluded. Six rats that did not satisfy
lever-press for SCM unpunished (0.0 mA) to re-stabilize lever- training criteria within 4 weeks of training were excluded. The rats
press responding (±20% of the average number of reward deliv- then remained in their home cages for 3 weeks; this was to match
eries during the last three sessions of SCM self-administration the period between addiction histories and current tests
retraining). These punished operant tests were based on (ad libitum calorie intake and weight gain tests) to that between
well-established procedures to determine punishment-resistant addiction histories and compulsive appetite tests.
‘compulsive’ drug and food motivation in rats (Ahmed, 2012; 2. Ad libitum access to nutritionally balanced diet (2 weeks): All rats
Clemens & Holmes, 2018; Deroche-Gamonet et al., 2004; were kept in their home cages and maintained on standard lab
Everitt et al., 2018; Johnson & Kenny, 2010; Pelloux et al., chow (Product #7012, Teklad Diets-Envigo, Madison, WI, USA)
2007; Spierling et al., 2020; Vanderschuren & Everitt, 2004). containing 17 kcal% fat, 58 kcal% carbohydrate (6.2 kcal%
sucrose), 25 kcal% protein, and vitamins and minerals. The animals'
The current operant punishment task was adapted from previ- consumption of this nutritionally balanced diet and their weights
ously published procedures to determine punishment-resistant ‘com- were measured weekly during the fourth to fifth weeks after drug
pulsive’ drug and food self-administration (see Deroche-Gamonet histories—roughly the same timeframe for compulsive appetite
et al., 2004; Johnson & Kenny, 2010; Laque et al., 2019; Spierling tests for SCM.
et al., 2020). 3. Ad libitum access to obesogenic diet (7 weeks): Instead of the
The final Ns retained for statistical analyses from the saccharine, standard lab chow, all rats were continuously maintained on a high
ShA cocaine and LgA cocaine groups were 14/18/14 for males. fat and high sugar (HFHS) diet (Product #D12451, Research Diets,
Inc., New Brunswick, NJ, USA) containing 45 kcal% fat, 35 kcal%
ii. Progressive ratio tests for SCM. As another indication of addiction- carbohydrate (17 kcal% sucrose) and 20 kcal% protein, as well as
like food motivation, we determined the animals' willingness to vitamins and minerals. The animals' consumption of this
work for caloric SCM under high workload requirements. Male rats obesogenic diet and their weights were measured weekly during
(N = 60) underwent the following three phases: the 6th–12th weeks after drug histories—roughly the same time-
frame for compulsive appetite tests for SCM.
1. Drug histories (3–4 weeks): As described in i. (Compulsive appetite
tests for SCM). The final Ns retained for statistical analyses from the saccharin,
2. SCM self-administration training (3 weeks): As described for ShA cocaine and LgA cocaine groups were 7/10/9 for males.
i. Compulsive appetite tests for SCM.
3. Progressive ratio tests for SCM (1 day): Rats lever-pressed for iv. Compulsive appetite tests for saccharin. Here, we determined the
SCM under a progressive ratio (PR) schedule of reinforcement dur- animals' willingness to work for non-caloric saccharin despite
ing the fourth week after drug histories—roughly the same time- adverse consequences (i.e., punishments), as an indicator of
frame as compulsive appetite tests for SCM. Under the current PR addiction-like food motivation. Male (N = 43) rats underwent the
schedule, the response requirements to obtain each SCM delivery following three experimental phases:
increased according to the following progression: 1, 2, 4, 6, 9, 12,
15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 145, 178, 219, 268 and so 1. Drug histories (3–4 weeks): As described in i. (Compulsive appetite
forth (adapted from Richardson & Roberts, 1996). Each test tests for SCM).
6 LAQUE ET AL.

2. Saccharin self-administration training (3 weeks): Rats were trained the following behavioural tests and trained accordingly (experimental
to lever-press for saccharin and were required to satisfy the fol- timelines are schematized in Figure 1):
lowing training criteria: (1) a minimum of 14 days of training and
(2) a minimum of 100 saccharin deliveries daily for three consecu- i. Compulsive appetite tests for SCM. Male (N = 21) rats were sub-
tive training sessions. jected to the following four experimental phases:
3. Compulsive appetite tests for saccharin (3 weeks): Rats were
tested to lever-press for saccharin despite punishments during 1. SCM self-administration training (3 weeks): Rats were trained to
the fourth to sixth weeks after drug histories, as with compulsive lever-press for SCM under FR1 and required to satisfy the follow-
appetite tests for SCM. Each saccharin delivery was paired with ing training criteria or excluded: (1) a minimum of 21 days of train-
an electric foot-shock, which was delivered contingent on a ing and (2) a minimum of 50 SCM deliveries daily for three
reinforced lever-press along with saccharin. Each rat was sub- consecutive training sessions.
jected to a total of five test sessions (30 min each) for five levels 2. Drug histories (8 days): Rats were kept in their home cages and
of foot-shock intensity. Male rats were subjected to 0.0, 0.1, given once daily injections of IP cocaine (30 mg/kg per
0.15, 0.25 and 0.35 mA (0.5 s each). Each shock duration was injection dissolved in saline, 0.5 ml) or IP saline (0.5 ml) for
0.5 s, and shock intensities were kept constant during each test 8 days. Rats were then kept in their home cages for 1 week to
session. Test sessions were separated by 2–4 days. On interim recover.
days, rats were retrained (30 min, daily) to lever-press for saccha- 3. SCM self-administration retraining (2–3 weeks): Rats were
rin unpunished (0.0 mA) in order to re-stabilize responding retrained to lever-press for saccharin and required to satisfy the
(within 20% of the average number of reward deliveries during following training criteria or excluded: (1) a minimum of 14 days of
the last three sessions of saccharin operant self-administration training and (2) a minimum of 50 SCM deliveries daily for three
retraining). consecutive training sessions.
4. Compulsive appetite tests for SCM: As described in I. (Cocaine his-
The final Ns retained for statistical analyses from the saccharin, tory via operant self-administration). These tests were conducted
ShA cocaine and LgA cocaine groups were 11/11/11 for males. during the fourth to sixth weeks after drug histories, as after
ShA/LgA cocaine histories.
II. Cocaine histories via intraperitoneal administration (IP cocaine
histories): The final Ns retained for statistical analysis from the IP saline and
IP cocaine groups were 9/12 for males.
In Experiment I, rats were first trained to self-administer
cocaine (2 or 6 h daily) or saccharin (30 min daily) and then trained ii. Compulsive appetite tests for saccharin. Male (N = 25) rats were
and tested to self-administer caloric SCM or non-caloric saccharin subjected to the following four phases:
paired with food-shock punishments, as a measure of compulsive
appetite. This design did not permit to interpret the training effects 1. Saccharin self-administration training (3–4 weeks): Rats were
of the initial operant training with cocaine or saccharin compared trained to lever-press for saccharin under FR1 and required to sat-
with the pharmacological effects of cocaine on subsequent self- isfy the following training criteria or excluded: (1) a minimum of
administration tests. Moreover, the use of saccharin both as the 21 days of training and (2) a minimum of 50 saccharin deliveries
control stimulus and the stimulus representing compulsive appetite daily for three consecutive training sessions.
could have skewed the experimental results. We thus next deter- 2. Drug histories (8 days): Rats were kept in their home cages and
mined whether the pharmacological action of cocaine is sufficient given once daily injections of IP cocaine (30 mg/kg per injection
to induce punishment-resistant self-administration of SCM or dissolved in saline, 0.5 ml) or IP saline (0.5 ml) for 8 days. Rats
saccharin. remained in their home cages for 1 week to recover.
Rats were randomly assigned to one of the following addiction 3. Saccharin self-administration retraining (3 weeks): Rats were
history groups: IP cocaine or IP saline. The procedure for IP retrained to lever-press for saccharin and required to satisfy the
cocaine histories was based on procedures to induce locomotor following training criteria or excluded: (1) a minimum of 14 days of
sensitization (Schoenbaum et al., 2004)—thought to model drug training and (2) a minimum of 50 saccharin deliveries daily for
addiction (Robinson & Berridge, 2008)—and addiction-like brain three consecutive training sessions.
changes (e.g., Li et al., 2004) in rats. The current procedure is also 4. Compulsive appetite tests for saccharin: As described in I. (Cocaine
comparable with other IP cocaine regimens to induce addiction-like history via operant self-administration). These tests were con-
habitual/inflexible behaviour (e.g., Schoenbaum & Setlow, 2005) in ducted during the fourth to sixth weeks after drug histories, as
rats. Rats in the IP saline history group served as drug naïve after ShA/LgA cocaine histories.
controls.
Rats in IP cocaine and IP saline groups were then further ran- The final Ns retained for statistical analyses for the IP cocaine and
domly assigned to a specific experimental condition defined by one of IP saline groups were 11/14 for males.
LAQUE ET AL. 7

F I G U R E 2 The effects of extensive cocaine histories on subsequent food motivated behaviour in female rats undergoing long-term
abstinence. (a) Effects of cocaine self-administration histories on punished SCM intake. (b) Effects of cocaine self-administration histories on
punished saccharin intake. (c) Effects of cocaine self-administration histories on unpunished ad libitum calorie intake (kcal). (d) Effects of cocaine
self-administration on ad libitum weight gain. (e) Effects of IP cocaine histories on punished SCM intake. (f) Effects of IP cocaine histories on
punished saccharin intake. *P < 0.05, significantly different from 0.0 mA (a,b,e,f) or Week 1 (c,d); #P < 0.05, significantly different from the drug-
naïve control. IP, intraperitoneal; LgA, long-access; SA, self-administration; SCM, sweetened condensed milk; ShA, short-access
8 LAQUE ET AL.

2.3.2 | Experiment 2: The effects of extensive iii. Ad libitum calorie intake and weight gain tests. Female (N = 30)
cocaine histories on subsequent food-motivated rats underwent the following three phases:
behaviour in female rats
1. Drug histories (3–4 weeks + 3 weeks for recovery).
Female rats were randomly assigned to a specific experimental condi- 2. Ad libitum access to nutritionally balanced diet (2 weeks). These
tion defined first by drug history and then behavioural test. Experi- tests were conducted during the fourth to fifth weeks after drug
mental procedures mimicked those described for Experiment 1 (male histories, as after ShA/LgA/IP cocaine histories in male rats.
rats) unless noted otherwise. Experimental timelines are schematized 3. Ad libitum access to obesogenic diet (7 weeks). These tests were
in Figure 2. conducted during the 6th–12th weeks after drug histories, as after
ShA/LgA/IP cocaine histories in male rats.
I. Cocaine histories via operant self-administration:
The final Ns retained for statistical analyses from the saccharin,
i. Compulsive appetite tests for SCM. Female (N = 38) rats were ShA cocaine and LgA cocaine groups were 8/8/8 for females.
trained and tested according to the following three phases:
1. Drug histories (3–4 weeks). II. Cocaine histories via intraperitoneal administration:
2. SCM self-administration training (3 weeks).
3. Compulsive appetite tests for SCM (3 weeks). As described i. Compulsive appetite tests for SCM. Female (N = 20) rats were
for Experiment 1, except that female rats were subjected subjected to the following four experimental phases:
to 0.0, 0.15, 0.2, 0.25 and 0.35 mA of foot-shocks. This
was because a pilot experiment—where we tested 0.0, 0.1, 1. SCM self-administration training (3 weeks).
0.15, 0.2, 0.25 and 0.35 mA in drug-naïve rats—revealed 2. Drug histories (8 days).
that female rats were less sensitive to electric foot-shock 3. SCM self-administration retraining (2–3 weeks).
than male rats; 0.1 mA was sufficient to start reducing 4. Compulsive appetite tests for SCM: As described for Experiment
responding in male rats (Experiment 1) but not in female 1 (male rats), except that female rats were subjected to foot-
rats (pilot experiment). We thus used 0.15 mA as the second shocks at 0.0, 0.15, 0.2, 0.25 and 0.35 mA. These tests were con-
shock intensity (after 0.0 mA) to be tested in female ducted during the fourth to sixth weeks after drug histories, as
rats, rather than 0.1 mA for male rats. In the pilot study, after ShA/LgA/IP cocaine histories in male rats.
we also observed a pronounced reduction at 0.2 mA in
female rats, which was not tested in male rats (Experiment The final Ns retained for statistical analysis from the IP saline and
1), while both 0.25 and 0.35 mA were effective to reduce IP cocaine groups were 10/9 for females.
responding in female rats, as in male rats (Experiment 1).
Based on this, we decided to test 0.0, 0.15, 0.2, 0.25 and ii. Compulsive appetite tests for saccharin. Female (N = 23) rats were
0.35 mA in female rats, as opposed to 0.0, 0.1, 0.15, 0.25 subjected to the following four phases:
and 0.35 mA in male rats (Experiment 1) while keeping the
total number of tests for both male and female rats at five 1. Saccharin self-administration training (3–4 weeks).
tests per animal. 2. Drug histories (8 days).
3. Saccharin self-administration retraining (3 weeks).
The final Ns retained for statistical analyses from the saccharine, 4. Compulsive appetite tests for saccharin. As described for
ShA cocaine and LgA cocaine groups were 11/9/12 for females. Experiment 1 (male rats), except that female rats were subjected
to foot-shocks at 0.0, 0.15, 0.2, 0.25 and 0.35 mA. These tests
ii. Compulsive appetite tests for saccharin. Female (N = 32) rats were conducted during the fourth to sixth weeks after drug histo-
underwent the following three experimental phases: ries, as after ShA/LgA/IP cocaine histories in male rats.

1. Drug histories (3–4 weeks). The final Ns retained for statistical analyses for the IP cocaine and
2. Saccharin self-administration training (3 weeks). IP saline groups were 11/12 for females.
3. Compulsive appetite tests for saccharin (3 weeks): As described
for Experiment 1 (male rats), except that female rats were sub-
jected to foot-shocks at 0.0, 0.15, 0.2, 0.25 and 0.35 mA (as for 2.3.3 | Experiment 3: The effects of other histories
Compulsive appetite tests for SCM). on subsequent food motivated behaviour

The final Ns retained for statistical analyses from the We lastly determined the effects of extensive alcohol, caffeine and
saccharin, ShA cocaine and LgA cocaine groups were 11/8/6 for obesogenic diet histories in male rats. Rats (N = 174) were randomly
females. assigned to one of the following histories: 1. Alcohol history via
LAQUE ET AL. 9

FIGURE 3 Legend on next page.

10 LAQUE ET AL.

F I G U R E 3 The effects of extensive alcohol, caffeine and obesogenic diet histories on subsequent food motivated behaviour in male rats
undergoing long-term abstinence. (a) Effects of alcohol vapour histories on punished saccharin intake. (b) Effects of alcohol liquid diet histories on
punished saccharin intake. (c) Effects of caffeine histories on punished saccharin intake. (d) Effects of obesogenic (high fat and high sugar [HFHS])
diet histories on punished saccharin intake. (e) Effects of obesogenic (high fat [HF]/high sugar [HS]/high protein [HP]) diet histories on punished
saccharin intake. (f) Effects of cocaine, alcohol (vapour) and caffeine histories on ad libitum calorie punished saccharin intake. (c) Effects of
caffeine histories on punished saccharin intake. (d) Effects of obesogenic (high fat and high sugar [HFHS]) diet histories on punished saccharin
intake. (e) Effects of obesogenic (high fat [HF]/high sugar [HS]/high protein [HP]) diet histories on punished saccharin intake. (f) Effects of
cocaine, alcohol (vapour) and caffeine histories on ad libitum calorie intake (kcal). (g) Cocaine, alcohol (vapour) and caffeine histories on ad libitum
weight gain. *P < 0.05, significantly different from 0.0 mA (a–e) or Week 1 (f,g); #P < 0.05, significantly different from the control group. IP,
intraperitoneal

vapour exposure, 2. Alcohol history via liquid diet, 3. Caffeine, procedures to induce alcohol dependence marked by somatic
4. Obesogenic diet I—high fat and high sugar (HFHS) diet and signs of withdrawal, addiction-like brain changes and excessive
5. Obesogenic diet II—high fat (HF), high sugar (HS) or high protein alcohol intake (McBride & Li, 1998). Rats in the control liquid diet
(HP) diet. Rats were trained and subjected to i. Compulsive appetite group were maintained on continuous non-alcohol liquid diet,
tests for saccharin or ii. Ad libitum calorie intake and weight gain tests. consisting of Boost® nutritional supplement fortified with a vita-
Experimental timelines are schematized in Figure 3. min and mineral mix, with a caloric content (kcal/ml) equal to that
of the alcohol liquid diet described above. Rats then were kept in
i. Compulsive appetite tests for saccharin. Male rats (N = 140) their home cages and maintained on standard lab chow for
underwent the following four experimental phases: 2 weeks to recover.
2.3 Caffeine histories (4 weeks). Rats were randomly assigned to caf-
1. Saccharin self-administration training: As described in II. (Cocaine feinated or non-caffeinated water groups and kept in their home
histories via intraperitoneal administration). cages. Instead of tap water, rats in the caffeinated water group
2. Drug/diet histories: Rats were randomly assigned to one of the were continuously (24 h; 7 days a week) maintained on caffeine
four histories (see below). For all cases, rats were randomly further (1.0 mg/ml) added to drinking water for 4 weeks. This caffeine
assigned to experimental or control groups. As described above, history was based on procedures to potentiate nicotine rewards
rats were maintained on standard lab chow (Product #7012, (e.g., Shoaib et al., 1999). Rats in the non-caffeinated water (con-
Teklad Diets-Envigo, Madison, WI, USA) and tap water, unless oth- trol) group were continuously maintained on regular tap water.
erwise specified. Rats were then kept in their home cages and maintained on regu-
2.1 Alcohol histories via vapour exposure (8 weeks). Rats were housed lar tap water for 2 weeks to recover.
in airtight plexiglass chambers, randomly assigned to alcohol 2.4 Obesogenic diet histories I—high fat and high sugar (HFHS) diet
vapour or control vapour groups and exposed to chronic intermit- (7 weeks). Rats were randomly assigned to obesogenic or control
tent alcohol vapour or continuous fresh air for 8 weeks. Rats in diet groups and kept in their home cages. Instead of standard lab
the alcohol vapour group underwent a daily cycle of alcohol chow, rats in the experimental group were continuously (24 h;
vapour (14 h) and fresh air (10 h). This alcohol history was based 7 days a week) maintained on an HFHS diet (Product #D12451,
on procedures to induce alcohol dependence in rats marked by Research Diets, Inc., New Brunswick, NJ, USA) containing 45 kcal
somatic signs of withdrawal, addiction-like brain changes and % fat, 35 kcal% carbohydrate (17 kcal% sucrose), 20 kcal% pro-
excessive alcohol intake (e.g., McBride & Li, 1998). Tail blood tein, and vitamins and minerals for 7 weeks. This procedure was
samples were collected daily at the 14th hour of alcohol vapour based on procedures to promote diet-induced obesity and obe-
exposure to determine blood alcohol levels (BALs); evaporated sity-related metabolic changes (e.g., Desai et al., 2007) and is
1
alcohol concentration (22–27 mg
L ) in the chamber was comparable with diet regimens known to induce compulsive eat-
adjusted as necessary to maintain BALs of 150 to 250 mg% ing (Johnson & Kenny, 2010; Spierling et al., 2020). Rats in the
1
(mg
dl ). Rats in the control group were exposed to continuous control group were maintained on standard lab chow (Product
fresh air (24 h). Rats were then kept in their home cages for #7012, Teklad Diets-Envigo, Madison, WI, USA). All rats com-
2 weeks to recover. pleted this phase. Rats were then kept in their home cages and
2.2 Alcohol histories via liquid diet (4 weeks). Rats were randomly maintained on standard lab chow for 2 weeks to recover.
assigned to alcohol or control liquid diet groups and kept in their 2.5 Obesogenic diet histories II—high fat (HF), high sugar (HS) or high
home cages. Instead of standard lab chow, rats in the alcohol liq- protein (HP) diets (7 weeks). Rats were randomly assigned to HF,
uid diet group were maintained on a continuous (24 h; 7 days a HS, HP or control diet groups and kept in their home cages.
week) liquid diet consisting of alcohol (10%, v/v) and Boost® Rats were maintained on their assigned diet type continuously
nutritional supplement (Nestle USA, Rosslyn, VA, USA) fortified (24 h; 7 days a week) for 7 weeks. Rats in the HF diet group
with a vitamin and mineral mix (adapted from Serrano were maintained on a high fat diet (Product #D12492, Research
et al., 2018) for 4 weeks. This alcohol history was based on Diets, Inc., New Brunswick, NJ, USA), containing 60 kcal% fat,
LAQUE ET AL. 11

20 kcal% carbohydrate (6.8 kcal% sucrose), 20 kcal% protein, described above—instead of standard lab chow—and regular tap
and vitamins and minerals. This diet has been used to induce water for 4 weeks.
an obese phenotype and non-alcoholic fatty liver in rodents 1-iii Caffeine histories (4 weeks). Rats were kept in their home cages
1
(e.g., Kirpich et al., 2011). Rats in the HS diet group were and maintained on standard lab chow and caffeine (1.0 mg
ml )
maintained on a high sugar diet (Product #D02022703, added to drinking water—instead of regular tap water—for
Research Diets, Inc., New Brunswick, NJ, USA) containing 4 weeks.
10 kcal% fat, 70 kcal% carbohydrate (60 kcal% sucrose) and 1-iv Control histories (4 weeks). Rats were kept in their home cages
20 kcal% protein, as well as vitamins and minerals. This diet has and maintained on standard lab chow and regular tap water for
been used to induce an obese phenotype and non-alcoholic 4 weeks.
fatty liver in rodents (e.g., Kirpich et al., 2011). Rats in the HP
diet group were maintained on a high protein diet (Product Rats were then kept in their home cages for 3 weeks to recover;
#D08091802, Research Diets, Inc., New Brunswick, NJ, USA) this was done to match the period between drug/diet histories and ad
containing 10 kcal% fat, 30 kcal% carbohydrate (6.7 kcal% libitum calorie intake and weight gain tests to that between drug/diet
sucrose) and 60 kcal% protein, as well as vitamins and minerals. histories and compulsive appetite tests.
This HP diet is not known to cause diet-induced obesity. Rats
in the control group were maintained on standard lab chow 2. Ad libitum access to nutritionally balanced diet (2 weeks): All rats
(Product #7012, Teklad Diets-Envigo, Madison, WI, USA). Rats were kept in their home cages and maintained on standard lab
were then kept in their home cages and maintained on standard chow. The animals' consumption of this nutritionally balanced diet
lab chow for 2 weeks to recover. and their weight gains were measured on a weekly basis during
3. Saccharin self-administration retraining (3 weeks): As described in the fourth to fifth weeks after drug/diet histories, as with ShA/LgA
II. (Cocaine histories via intraperitoneal administration). cocaine histories.
4. appetite tests for saccharin: As described in I. (Cocaine histories 3. Ad libitum access to obesogenic diet (7 weeks): Instead of standard
via operant self-administration). These tests were conducted dur- lab chow, all rats were maintained on an HFHS diet (Product
ing the fourth to sixth weeks after drug/diet histories, as after #D12451, Research Diets, Inc., New Brunswick, NJ, USA). The ani-
ShA/LgA/IP cocaine histories. mals' consumption of this obesogenic diet and their weight gains
were measured on a weekly basis during the 6th–12th weeks after
The final Ns retained for statistical analyses for alcohol and con- drug/diet histories, as with ShA/LgA cocaine histories.
trol vapour history groups were 11/11; alcohol and control liquid diet
history groups were 11/10; caffeinated and non-caffeinated water The final Ns retained for statistical analyses from the
history groups were 12/10; HFHS and control diet history groups cocaine, alcohol, caffeine and control history groups were 8/8/8/10.
were 12/10; and HF, HS, HP and control diet history groups were
12/12/14/12.
2.4 | Data analysis
ii. Ad libitum calorie intake and weight gain tests. Rats underwent
the following three experimental phases: The data and statistical analysis comply with the recommendations of
the British Journal of Pharmacology on experimental design and analy-
1. Drug/diet histories. Male rats (N = 34) were randomly assigned to sis in pharmacology (Curtis et al., 2018). Statistical analyses were
one of the following groups: i. Cocaine history via intraperitoneal undertaken only for studies where each group size was at least n = 5.
administration, ii. Alcohol history via liquid diet, iii. Caffeine history The declared group size is the number of independent values, and sta-
and iv. Control history. All groups were run simultaneously. For all tistical analysis was done using these independent values. Data were
cases, rats were maintained on standard lab chow (Product #7012, analysed by Student's t-test and parametric statistical analyses
Teklad Diets-Envigo, Madison, WI, USA) and regular tap water, (ANOVA). For all cases, differences were considered significant when
unless otherwise specified. P < 0.05 (two-tailed). In multigroup studies with parametric variables,
post hoc tests were conducted using Holm–Sidak tests only if F in
1-i. Cocaine histories via intraperitoneal administration (4 weeks). Rats ANOVA achieved P < 0.05 and there was no significant variance in
were kept in their home cages and maintained on standard lab homogeneity. For all cases, we did not observe statistical outliers and
chow and regular tap water for 4 weeks. During the initial thus no outlier was included in Section 3. We used GraphPad Prism
3 weeks, rats were left undisturbed. During the fourth week, rats 8.4.3 (GraphPad, San Diego, CA, USA; RRID:SCR_002798) and IBM
were given once daily injection of IP cocaine (30 mg/kg per SPSS Statistics 25 (IBM Corporation, Armonk, NY, USA; RRID:SCR_
injection dissolved in saline, 0.5 ml) for 8 days. 002865).
1-ii. Alcohol histories via liquid diet (4 weeks). Rats were kept in their We describe the statistical methods used for different experimen-
home cages and maintained on the alcohol (10% v/v) liquid diet tal conditions below.
12 LAQUE ET AL.

2.4.1 | Experiment 1: The effects of extensive (five levels) as within-subjects factor and history (three levels) as
cocaine histories on subsequent food motivated between-subjects factor.
behaviour in male rats
II. Cocaine histories via intraperitoneal administration (IP cocaine
I. Cocaine histories via operant self-administration: histories).

i. Compulsive appetite tests for SCM. We first calculated the aver- i. Compulsive appetite tests for SCM. As for cocaine histories via
age number of rewards obtained (30-min totals) during the last operant self-administration, we first calculated the average num-
three ‘SCM self-administration training’ sessions for each rat as a ber of rewards obtained (30-min totals) during the last three
measurement of basal SCM intake (baseline scores). These base- ‘SCM self-administration retraining’ sessions for each rat, as a
line scores were analysed using one-way ANOVA with history measurement of basal SCM intake (baseline scores). These base-
(three levels: drug naïve [saccharin], ShA and LgA) as between- line scores were analysed using one-way ANOVA with history
subjects factor. While this analysis revealed no significant (two levels: IP saline and IP cocaine) as between-subjects factor.
between-group effects (see Results), we observed large individual We used the baseline score of each rat to convert the number of
differences in these baseline scores. For example, the range of rewards obtained (30-min totals) during each test session as ‘%
baseline scores in the drug naïve control group was between changes from baseline’, a measurement of punishment resistance.
96.6 and 166.7. To control for this within-group variability, we These test scores were analysed using two-way repeated mea-
used the baseline score of each rat to convert the number of sures ANOVA with foot-shock intensity (five levels) as within-
rewards obtained (30-min totals) by the same animal during each subjects factor and history (two levels) as between-subjects
test session as ‘% changes from baseline’, a normalized measure- factor.
ment of punishment resistance. Based on this normalization, Ii. Compulsive appetite tests for saccharin. As for cocaine
50 rewards obtained by a rat with the baseline score of 100 are histories via operant self-administration, we first calculated the
expressed as ‘50% of baseline’, while the same 50 rewards average number of rewards obtained (30-min totals) during the
obtained by a rat with the baseline score of 150 are expressed as last three ‘saccharin self-administration retraining’ sessions for
‘33% of baseline’. The normalized test scores were analysed each rat, a measurement of basal SCM intake (baseline scores).
using two-way repeated measures ANOVA with foot-shock These baseline scores were analysed using one-way ANOVA
intensity (five levels) as within-subjects factor and history (three with history (two levels: IP saline and IP cocaine) as between-
levels) as between-subjects factor. subjects factor. We used the baseline score of each rat to con-
ii. Progressive ratio tests for SCM. Total numbers of active lever- vert the number of rewards obtained (30-min totals) during
presses and rewards obtained were separately analysed using each test session as ‘% changes from baseline’, a measurement
one-way ANOVA with history (three levels: saccharin, ShA and of punishment resistance. These test scores were analysed
LgA) as between-subjects factor. using two-way repeated measures ANOVA with foot-shock
iii. Ad libitum calorie intake and weight gain tests. Weekly calorie intensity (five levels) as within-subjects factor and history (two
intake and bodyweight gain were separately analysed using two- levels) as between-subjects factor.
way repeated measures ANOVA with week (nine levels: standard
lab chow for 2 weeks and then obesogenic diet for 7 weeks) as
within-subjects factor and history (three levels: drug naïve, ShA 2.4.2 | Experiment 2: The effects of extensive
and LgA) as between-subjects factor. cocaine histories on subsequent food motivated
iv. Compulsive appetite tests for saccharin. As for compulsive appe- behaviour in female rats
tite tests for SCM, we first calculated the average number of
rewards obtained (30-min totals) during the last three ‘saccharin Statistical procedures were as described for Experiment 1 (male rats).
self-administration retraining’ sessions for each rat as a measure-
ment of basal saccharin intake (baseline score). These baseline
scores were analysed using one-way ANOVA with history (three 2.4.3 | Experiment 3: The effects of other histories
levels: drug naïve, ShA and LgA) as between-subjects factor. As on subsequent food motivated behaviour
with basal SCM intake, we observed large individual differences
in these baseline scores. To control for this within-group variabil- i. Compulsive appetite tests for saccharin. As for cocaine histories,
ity, we used the baseline score of each rat to convert the number we used the average number of rewards obtained (30-min totals)
of rewards obtained (30-min totals) by the same animal during during the last three ‘saccharin self-administration retraining’
each test session as ‘% changes from baseline’, a measurement sessions as the ‘baseline’ score to calculate and depict the number
of punishment resistance. These test scores were analysed using of rewards obtained (30-min totals) during each test session as ‘%
two-way repeated measures ANOVA with foot-shock intensity changes from baseline’.
LAQUE ET AL. 13

i-1. Alcohol histories via vapour exposure. The baseline scores (St. Louis, MO, USA). Obesogenic diets were obtained from
were analysed using one-way ANOVA with addiction history Research Diets, Inc. (New Brunswick, NJ, USA). We used the follow-
(two levels: control vapour [air] and alcohol vapour) as ing diets from Research Diets: #D12451 (high fat and high sugar),
between-subjects factor. The test scores (% changes from #D12492 (high fat), #D02022703 (high sugar) and #D08091802
baseline) were analysed using two-way repeated measures (high protein).
ANOVA with foot-shock intensity (five levels) as within-sub-
jects factor and history (two levels) as between-subjects
factor. 2.6 | Nomenclature of targets and ligands
i-2. Alcohol histories via liquid diet. The baseline scores were analysed
using one-way ANOVA with history (two levels: control liquid Key protein targets and ligands in this article are hyperlinked to
diet and alcohol liquid diet) as between-subjects factor. The test corresponding entries in http://guidetopharmacology.org and are per-
scores (% changes from baseline) were analysed using two-way manently archived in the Concise Guide to PHARMACOLOGY
repeated measures ANOVA with foot-shock intensity (five levels) 2019/20 (Alexander et al., 2021).
as within-subjects factor and history (two levels) as between-sub-
jects factor.
i-3. Caffeine histories. The baseline scores were analysed using one- 3 | RE SU LT S
way ANOVA with addiction history (two levels: non-caffeinated
water [water] and caffeinated water [caffeine]) as between- For all cases, detailed statistical results are described in Tables 1, 2
subjects factor. The test scores (% changes from baseline) were or 3. Detailed justifications for each experiment are described in
analysed using two-way repeated measures ANOVA with foot- Section 4.
shock intensity (five levels) as within-subjects factor and history
(two levels) as between-subjects factor.
i-4. Obesogenic diet histories I—high fat and high sugar (HFHS) diet.
T A B L E 1 Statistical results for the effects of extensive cocaine
The baseline scores were analysed using one-way ANOVA
histories on subsequent food motivated behaviour in male rats
with addiction history (two levels: control diet and HFHS diet)
undergoing long-term abstinence (see Figure 1)
as between-subjects factor. The test scores (% changes from
Figure number Factor name F-value P-value
baseline) were analysed using two-way repeated measures
ANOVA with foot-shock intensity (five levels) as within-sub- 1a (left panel) History F(2,43) = 0.2640 NS

jects factor and history (two levels) as between-subjects 1a (right panel) History F(2,43) = 25.47 <0.05
factor. Shock F(4,43) = 127.3 <0.05
i-5. Obesogenic diet histories II—high fat (HF), high sugar (HS) or high History  Shock F(8,172) = 9.279 <0.05
protein (HP) diet. The baseline scores were analysed using one- 1b (left panel) History F(2,54) = 7.641 <0.05
way ANOVA with addiction history (four levels: HF, HS, HP and 1b (right panel) History F(2,54) = 6.819 <0.05
control diet) as between-subjects factor. The test scores (% 1c History F(2,23) = 0.747 NS
changes from baseline) were analysed using two-way repeated
Week F(8,23) = 54.435 <0.05
measures ANOVA with foot-shock intensity (five levels) as
History  Week F(16,184) = 1.625 NS
within-subjects factor and history (four levels) as between-sub-
1d History F(2,23) = 0.761 NS
jects factor.
Week F(8,23) = 530.44 <0.05
History  Week F(16,184) = 0.44 NS
ii. Ad libitum calorie intake and weight gain tests. Weekly calorie
intake and bodyweight gain were separately analysed using two- 1e (left panel) History F(2,30) = 0.2197 NS

way repeated measures ANOVA with week (nine levels: standard 1e (right panel) History F(2,30) = 25.11 <0.05

lab chow for 2 weeks and then obesogenic diet for 7 weeks) as Shock F(4,30) = 143.5 <0.05
within-subjects factor and history (four levels: lab chow [control], History  Shock F(8,120) = 12.09 <0.05
IP cocaine [cocaine], alcohol liquid diet [alcohol] and caffeinated 1f (left panel) History t(19) = 0.214 NS
water [caffeine]) as between-subjects factor. 1f (right panel) History F(1,19) = 6.804 <0.05
Shock F(4,19) = 70.67 <0.05
History  Shock F(4,76) = 2.789 <0.05
2.5 | Materials 1g (left panel) History t(23) = 0.168 NS
1g (right panel) History F(1,23) = 13.15 <0.05
Cocaine hydrochloride was obtained from the National Institute on
Shock F(4,23) = 37.06 <0.05
Drug Abuse (NIDA) Drug Supply Program (Bethesda, MD, USA).
History  Shock F(4,92) = 1.293 NS
Alcohol, caffeine and saccharin were obtained from Sigma-Aldrich
14 LAQUE ET AL.

T A B L E 2 Statistical results for the effects of extensive cocaine T A B L E 3 Statistical results for the effects of extensive alcohol,
histories on subsequent food motivated behaviour in female rats caffeine and obesogenic diet histories on subsequent food motivated
undergoing long-term abstinence (see Figure 2) behaviour in male rats undergoing long-term abstinence (see Figure 3)

Figure number Factor name t-value and F-value P-value Figure number Factor name t-value and F-value P-value
2a (left panel) History F(2,29) = 0.759 NS 3a (left panel) History t(20) = 0.214 NS
2a (right panel) History F(2,29) = 4.297 <0.05 3a (right panel) History F(1,20) = 6.489 <0.05
Shock F(4,29) = 105.9 <0.05 Shock F(4,20) = 112.7 <0.05
History  Shock F(8,116) = 3.065 <0.05 History  Shock F(4,80) = 4.375 <0.05
2b (left panel) History F(2,22) = 0.690 NS 3b (left panel) History t(19) = 0.601 NS
2b (right panel) History F(2,22) = 1.903 NS 3b (right panel) History F(1,19) = 3.121 NS
Shock F(4,22) = 81.45 <0.05 Shock F(4,76) = 110.3 <0.05
History  Shock F(8,88) = 3.321 <0.05 History  Shock F(4,76) = 3.820 <0.05
2c History F(2,21) = 0.402 NS 3c (left panel) History t(20) = 0.6677 NS
Week F(8,21) = 32.133 <0.05 3c (right panel) History F(1,20) = 0.307 NS
History  Week F(16,168) = 1.137 NS Shock F(4,20) = 41.68 <0.05
2d History F(2,21) = 0.508 NS History  Shock F(4,80) = 0.116 NS
Week F(8,21) = 325.831 <0.05 3d (left panel) History t(20) = 0.459 NS
History  Week F(16,168) = 0.067 NS 3d (right panel) History F(1,20) = 9.599 <0.05
2e (left panel) History t(17) = 0.558 NS Shock F(4,20) = 24.06 <0.05
2e (right panel) History F(1,17) = 18.51 <0.05 History  Shock F(4,80) = 1.863 NS
Shock F(4,17) = 89.40 <0.05 3e (left panel) History F(3,46) = 1.509 NS
History  Shock F(4,68) = 3.440 <0.05 3e (right panel) History F(3,46) = 3.149 <0.05
2f (left panel) History t(21) = 0.8620 NS Shock F(4,46) = 216.7 <0.05
2f (right panel) History F(1,21) = 7.183 <0.05 History  Shock F(12,184) = 1.98 <0.05
Shock F(4,21) = 87.94 <0.05 3f History F(3,30) = 1.027 NS
History  Shock F(4,84) = 2.577 <0.05 Week F(8,30) = 89.31 <0.05
History  Week F(30,240) = 1.527 NS
3g History F(3,30) = 0.116 NS
3.1 | Experiment 1: The effects of extensive Week F(8,30) = 514.3 <0.05
cocaine histories on subsequent food motivated History  Week F(30,240) = 1.335 NS
behaviour in male rats

Detailed statistical results are described in Table 1.

ii. Progressive ratio tests for SCM.
I. Cocaine histories via operant self-administration:
Compared with the control (saccharin) histories, ShA and LgA cocaine
i. Compulsive appetite tests for SCM. histories significantly increased the number of rewards obtained
(Figure 1b, left) and lever-presses (Figure 1b, right) under a high work
Compared with the control (saccharin) histories, neither ShA nor load condition. One-way ANOVA on SCM rewards obtained revealed
LgA cocaine histories significantly altered the average number of significant effects of History. Similarly, one-way ANOVA on lever-
rewards obtained during the last three SCM self-administration train- pressing revealed significant effects of History.
ing sessions, as a measure of unpunished ‘baseline’ SCM intake
(Figure 1a, left panel). One-way ANOVA on SCM rewards obtained iii. Ad libitum calorie intake and bodyweight tests.
revealed no significant effect of History. In contrast, ShA and LgA his-
tories significantly increased rats' punishment resistance to obtain Compared with the control (saccharin) histories, ShA and LgA
SCM (Figure 1a, right panel). Two-way ANOVA for repeated measures cocaine histories did not significantly alter weekly kcal intake
on active lever-pressing revealed significant effects of History, Shock (Figure 1c) and bodyweights (Figure 1d). Two-way ANOVA for
and History  Shock interaction. Post hoc Holm–Sidak tests further repeated measures on weekly kcal intake revealed only significant
revealed that LgA histories produced greater effects than ShA effects of Week. Similarly, two-way ANOVA for repeated measures
histories. on bodyweights revealed only significant effects of Week.
LAQUE ET AL. 15

iv. Compulsive appetite tests for non-caloric saccharin. ll. Cocaine histories via intraperitoneal administration:

Compared with the control (saccharin) histories, neither ShA nor Compared with the control (IP saline) histories, IP cocaine his-
LgA cocaine histories significantly altered unpunished ‘baseline’ sac- tories did not significantly alter ‘baseline’ SCM and saccharin
charin intake (Figure 1e, left panel). One-way ANOVA on rewards intake (Figure 2e/f, left panels). However, IP cocaine histories sig-
obtained revealed no significant effects of History. In contrast, ShA nificantly increased rats' punishment resistance to obtain SCM and
and LgA histories significantly increased rats' punishment resistance saccharin (Figure 2e/f, right panels). Two-way ANOVA for repeated
to obtain saccharin (Figure 1e, right panel). Two-way ANOVA for measures on active lever-pressing for SCM revealed significant
repeated measures on active lever-pressing revealed significant effects of History, Shock and History  Shock interaction. Two-
effects of History, Shock and History  Shock interaction. Post hoc way ANOVA for repeated measures on active lever-pressing for
Holm–Sidak tests revealed that LgA histories produced greater effects saccharin revealed significant effects of History, Shock and
than ShA cocaine histories. History  Shock interaction.

II. Cocaine histories via intraperitoneal administration:

3.3 | Experiment 3: The effects of other histories
Compared with the control (IP saline) histories, IP cocaine histories on subsequent food motivated behaviour in male rats
did not significantly alter ‘baseline’ SCM and saccharin intake
(Figure 1f/g, left panels). Student's t-test on SCM rewards obtained Detailed statistical results are described in Table 3.
revealed no significant effect of History. Student's t-test on saccharin
rewards obtained revealed no significant effect of History. In contrast, i. Compulsive appetite tests for saccharin.
IP cocaine histories significantly increased rats' punishment resistance
to obtain SCM and saccharin (Figure 1f/g, right panels). Two-way For all cases, no significant group difference was found in baseline
ANOVA for repeated measures on active lever-pressing for SCM rev- saccharin intake (Figure 3a-e, left panels). Compared with the control
ealed significant effects of History, Shock and History  Shock interac- vapour (air) histories, alcohol vapour histories significantly increased
tion. Two-way ANOVA for repeated measures on active lever-pressing rats' punishment resistance to obtain saccharin (Figure 3a, right panel).
for saccharin revealed significant effects of History and Shock. Two-way ANOVA for repeated measures on active lever-pressing rev-
ealed significant effects of History, Shock and History  Shock inter-
action. Compared with the control diet histories, alcohol liquid diet
3.2 | Experiment 2: The effects of extensive histories significantly increased rats' punishment resistance to obtain
cocaine histories on subsequent food motivated saccharin (Figure 3b, right panel). Two-way ANOVA for repeated mea-
behaviour in female rats sures on active lever-pressing revealed significant effects of Shock
and History  Shock interaction. Compared with the control histories,
Detailed statistical results are described in Table 2. caffeine histories did not significantly alter rats' punishment resistance
to obtain saccharin (Figure 3c, right panel). Two-way ANOVA for
I. Cocaine histories via operant self-administration: repeated measures on active lever-pressing revealed only the signifi-
cant effects of Shock. Compared with the control diet histories, HFHS
Compared with the control (saccharin) histories, neither ShA nor diet histories significantly increased rats' punishment resistance to
LgA cocaine histories significantly altered ‘baseline’ SCM and saccha- obtain saccharin (Figure 3d, right panel). Two-way ANOVA for
rin intake (Figure 2a/b, left panels). However, compared with the con- repeated measures on active lever-pressing revealed significant
trol histories, LgA, but not ShA, histories significantly increased rats' effects of History and Shock. Compared with the control diet histo-
punishment resistance to obtain SCM and saccharin (Figure 2a/b, ries, HFHS, but not high protein, diet histories, significantly increased
right panels). Two-way ANOVA for repeated measures on active rats' punishment resistance to obtain saccharin (Figure 3e, right panel).
lever-pressing for SCM revealed significant effects of History, Shock Two-way ANOVA for repeated measures on active lever-pressing rev-
and History  Shock interaction. Two-way ANOVA for repeated mea- ealed significant effects of History, Shock and History  Shock
sures on active lever-pressing for saccharin revealed significant interaction
effects of Shock and History  Shock interaction. Compared with the
control histories, ShA and LgA cocaine histories did not significantly ii. Ad libitum calorie intake and bodyweight tests
alter weekly calorie intake (Figure 2c) and bodyweights (Figure 2d).
Two-way ANOVA for repeated measures on weekly kcal intake rev- Compared with the control histories, IP cocaine, alcohol liquid
ealed only significant effect of Week but not History or diet and caffeine histories did not significantly alter weekly calorie
History  Week interaction. Similarly, two-way ANOVA for repeated intake (Figure 3f) and bodyweights (Figure 3g). Two-way ANOVA for
measures on weekly kcal intake revealed only significant effect of repeated measures on weekly kcal intake revealed only the significant
Week but not History or History  Week interaction. effect of Week but not History or History  Week interaction.
16 LAQUE ET AL.

Similarly, two-way ANOVA for repeated measures on weekly In the current study, punishment-resistant SCM self-
bodyweights revealed only the significant effect of Week but not administration (Figure 1a, right panel) was evident during long-term
History or History  Week interaction. (3–5 weeks) abstinence from cocaine self-administration, suggesting
prolonged changes in appetite regulation. However, when
unpunished, rats with (LgA/ShA) or without (drug-naïve) cocaine self-
4 | DISCUSSION administration histories all responded similarly for SCM (Figure 1a, left
panel). We thus next investigated the long-term effects of past
We hypothesized that extensive drug histories, which cause cocaine histories on unpunished ‘basal’ calorie intake and bodyweight
addiction-like brain changes and punishment-resistant ‘compulsive’ change. When male rats with (LgA/ShA) or without (drug-naïve)
drug self-administration in rats (Vanderschuren & Ahmed, 2020), cocaine self-administration histories were given unchallenged ad
would similarly cause punishment-resistant, self-administration of libitum access to nutritionally balanced diet and then obesogenic diets
food or ‘compulsive appetite’. We first tested this hypothesis in male high in fat and sugar during long-term (3–11 weeks) abstinence, all
rats with 6-h daily (LgA) cocaine self-administration histories known showed similar patterns of calorie intake and bodyweight change
to cause addiction-like neurobehavioural profiles (Ahmed, 2012). (Figure 1c/d).
Male rats with LgA cocaine histories endured greater shock intensi- Current cocaine users are known to exhibit altered fat metabo-
ties to obtain SCM than drug-naïve rats (Figure 1a, right panel). Rats lism and storage—physiological changes thought to prevent them from
with less extensive 2-h daily (ShA) cocaine self-administration histories, becoming overweight and obese (Billing & Ersche, 2015; Ersche
also known to cause addiction-like neurobehavioural profiles et al., 2013). Thus, similar metabolic alterations may explain why rats
(e.g., Lucantonio et al., 2014), showed smaller but significant resistance with past cocaine histories failed to show altered bodyweights beyond
(Figure 1a, right panel). In contrast, no significant group difference was drug-naïve rats during abstinence (Figure 1d). However, this interpre-
found in unpunished ‘baseline’ SCM intake (Figure 1a, left panel). tation is challenged by the fact that, unlike current stimulant users
Because LgA and ShA cocaine histories do not alter pain sensitivity who report increased preference for fatty foods and increased calorie
(Edwards et al., 2012), this punishment resistance is likely to reflect intake (Billing & Ersche, 2015; Ersche et al., 2013), rats with past
enhanced motivation (Singer et al., 2018) or craving (Chao cocaine histories did not consume extra calories beyond drug-naïve
et al., 2016)—rather than reduced pain or aversion sensitivity (Jean- controls even when given unchallenged ad libitum access to diets high
Richard-Dit-Bressel et al., 2019). Accordingly, when tested under a PR in fat and sugar (Figure 1c). Because calorie intake was not altered
schedule (an increasing workload paradigm not involving pain), rats with (beyond control rats), metabolic alterations due to past cocaine histo-
LgA and ShA histories worked more to obtain SCM (Figure 1b). Because ries are not likely to account for the ‘unaltered’ bodyweight of rats
the enhanced responding for SCM was apparent against at least two with LgA/ShA cocaine histories. Indeed, current stimulant users with
‘cost’ measures (foot-shock and increasing workload), these effects active metabolic alterations are known to maintain reduced weights
could also reflect insensitivity to punishment contingency (Jean-Rich- despite their increased calorie intake (Billing & Ersche, 2015; Ersche
ard-Dit-Bressel et al., 2019; Jean-Richard-Dit-Bressel et al., 2021) et al., 2013). Nevertheless, future studies should determine the long-
and/or the development of habitual behaviour (Everitt et al., 2018). term effects of past cocaine histories on energy metabolism and stor-
In the current study, rats with ShA/LgA cocaine histories—as a age in rats.
group—developed punishment-resistant SCM self-administration Food motivation is thought to operate under both ‘homeostatic’
(Figure 1a, right panel). However, only a minority of rats with exten- (caloric/metabolic) and ‘non-homeostatic’ (hedonic/incentive) control
sive cocaine histories developed punishment-resistant cocaine self- (Berthoud, 2006). Via visceral afferent and endocrine connections,
administration in previous studies (see Deroche-Gamonet et al., 2004; adipose tissue and gastrointestinal signals engage hypothalamic and
Pelloux et al., 2007). This apparent contradiction is likely due to differ- hindbrain circuits that control calorie intake to maintain energy bal-
ences in the experimental design: While these studies used a single ance (homeostatic control). We found that neither ShA nor LgA
strong shock intensity (e.g., 0.8 mA, 2 s, two shocks per reinforcer in cocaine histories significantly altered this homeostatic regulation
Deroche-Gamonet et al., 2004) to detect ‘individual differences’ (as reflected in unaltered basal calorie intake and bodyweight beyond
within rats with the same drug histories, we used multiple milder control histories). In contrast, the reward circuits, including the ventral
intensities (0.1–0.35 mA, 0.5 s, one shock per reinforcer) to detect tegmental area and the nucleus accumbens, regulate food and drug
‘group differences’ among rats with different drug histories. Consis- motivation independently of caloric needs (non-homeostatic control).
tent with this view, using a single strong shock intensity (0.8 mA) with Extensive cocaine histories cause aberrant neuroadaptations in the
a shorter duration (1 s) and only one shock per reinforcer, we previ- reward circuits, thereby dysregulating motivation for this non-caloric
ously found that rats with extensive cocaine histories—as a group— reward and ultimately manifesting as compulsive drug craving and use
could develop punishment-resistant cocaine self-administration (Volkow et al., 2016). We thus hypothesized that extensive cocaine
(Laque et al., 2019). Using a different procedure (conditioned suppres- histories would similarly cause compulsive appetite via non-
sion), another study has also found that rats with extensive cocaine homeostatic dysregulation.
histories—as a group—develop compulsive cocaine self-administration We tested this hypothesis by determining male rats' willingness
(Vanderschuren & Everitt, 2004). to lever-press for saccharin, a metabolically and gastrointestinally inert
LAQUE ET AL. 17

reward, paired with foot-shock punishment during long-term (3– excess alcohol intake in rats, McBride & Li, 1998), caffeine (thought to
5 weeks) abstinence. Rats with LgA cocaine histories exhibited greater provide anti-obesity action, Heckman et al., 2010) and obesogenic
punishment resistance for saccharin than drug-naïve controls diets (known to cause physiological changes resembling obese individ-
(Figure 1e, right panel). Rats with ShA cocaine histories exhibited uals and punishment-resistant food self-administration in rats; see
smaller but significant resistance (Figure 1e, right panel). As with base- Johnson & Kenny, 2010). Like rats with extensive cocaine histories,
line SCM intake, no significant group difference was found in baseline rats given alcohol via vapour or liquid diet endured greater foot-
saccharin intake (Figure 1e, left panel). Because saccharin is non-calo- shocks for saccharin during long-term abstinence (Figure 3a,b).
ric, its intake in well-trained animals is presumably not under homeo- Because alcohol exposures increase—rather than decrease—pain sen-
static control. Hence, like compulsive drug craving and use, sitivity (Edwards et al., 2012), this punishment resistance is likely to
compulsive appetite is likely to reflect non-homeostatic hedonic/ reflect enhanced motivation, rather than reduced pain sensitivity.
incentive dysregulation. Accordingly, a recent study has shown that rats, undergoing acute
We originally observed punishment-resistant SCM and saccharin (6 h) withdrawal from alcohol, work more to obtain sucrose under a
self-administration in rats trained to lever-press for cocaine before PR schedule (Alaux-Cantin et al., 2021). As with compulsive appetite
being tested to press the same lever for food rewards. We thus deter- after cocaine histories, these effects could also reflect punishment
mined whether extensive operant training—rather than cocaine insensitivity (Jean-Richard-Dit-Bressel et al., 2019; Jean-Richard-Dit-
itself—caused punishment-resistant self-administration. We here Bressel et al., 2021) and/or habitual behaviour (Everitt et al., 2018).
tested IP cocaine histories based on procedures to induce addiction- Unlike rats with cocaine and alcohol histories, rats with caffeine
like neurobehavioural profiles in rats (see Li et al., 2004; Schoenbaum histories did not show increased punishment resistance to obtain sac-
& Setlow, 2005). Like rats with cocaine self-administration histories, charin (Figure 3c). In contrast, extending previous reports (e.g., John-
rats with IP cocaine histories endured greater foot-shocks to obtain son & Kenny, 2010; Rossetti et al., 2014; Spierling et al., 2020), rats
SCM and saccharin (Figure 1f/g, left panels), while no significant given obesogenic diets high in both fat and sugar endured greater
group difference was found in baseline SCM and saccharin intake foot-shocks to obtain saccharin (Figure 3f). Similar punishment resis-
(Figure 1f/g, right panels). These results parallel previous findings that tance was observed in rats given diets high in either fat or sugar but
similar IP cocaine histories facilitate operant responding for sucrose not diets high in protein (Figure 3g). These results are consistent with
under a high workload condition (FR30) (Klein et al., 2007) and indi- previous findings that highly processed diets high in refined fat and
cate that the pharmacological action of cocaine is sufficient to induce carbohydrates—but not those high in protein—are most strongly asso-
compulsive appetite. These results also indicate that the development ciated with addictive behaviours (Gearhardt & Hebebrand, 2021b;
of punishment resistance is independent from the shift from initial Small & DiFeliceantonio, 2019).
cocaine to subsequent SCM or saccharin self-administration or the As with cocaine histories, punishment-resistant self-
‘negative/positive contrast’ effects which can result in compulsive administration of saccharin was evident during long-term abstinence
appetite (Heyne et al., 2009). Finally, the use of saccharin both as the from alcohol and obesogenic diets. Previous studies have shown that
control stimulus and the stimulus representing compulsive appetite rats with past opioid (morphine) histories endure greater foot-shock
does not appear to have skewed the experimental results. punishments to obtain sucrose (Li et al., 2017), while rats with past
Drug addiction is more common among men, but eating disorders nicotine histories work more to obtain sucrose under a PR schedule
disproportionately affect women (Whiteford et al., 2013). We thus (LeSage et al., 2006). Thus, both drug and obesogenic diet histories
investigated whether sex plays a role in the long-term effects of appear to produce prolonged changes in appetite regulation.
cocaine on food motivation. Like male rats, female rats showed However, when given unchallenged ad libitum food access, male
increased punishment resistance to obtain SCM or saccharin during rats with IP cocaine, alcohol vapour or caffeine histories showed no
long-term abstinence from voluntary (LgA) or passive (IP) cocaine excess calorie intake or bodyweight gain while undergoing long-term
administration (Figure 2a,b,d,e, right panels). In contrast, female rats abstinence (Figure 3h/i). Cocaine and alcohol histories thus appear to
with ShA cocaine histories failed to show such resistance, suggesting cause compulsive appetite via non-homeostatic dysregulation. In con-
sex differences in drug sensitivity. Like male rats, no significant group trast, previous studies have found that rats with obesogenic diet his-
difference was found in baseline SCM and saccharin intake (Figure 2a, tories maintain significantly higher bodyweights after being placed on
b,d,e, left panels). Like male rats, female rats with ShA/LgA cocaine nutritionally balanced diets for 5–10 weeks and exhibit altered calorie
histories also showed neither excess calorie intake nor weight gain intake (in some cases reducing calorie intake) (Holtrup et al., 2017;
when given ad libitum food access (Figure 2c/d). Thus, extensive Uriarte et al., 2013). Taken together with our findings (Figure 3d,e),
cocaine histories appear to induce compulsive appetite via non- obesogenic diet histories, unlike drug histories, may cause compulsive
homeostatic dysregulation, irrespective of sex. appetite via homeostatic as well as non-homeostatic appetite dys-
Extensive exposures to different drugs and obesogenic diets regulation. Further studies should determine this possibility.
cause similar brain changes (Serafine et al., 2021; Volkow & Given that current drug users often prefer meals high in fat (Billing
Wise, 2005). We thus investigated the generalizability of compulsive & Ersche, 2015; Ersche et al., 2013), the effects of simultaneous or
appetite in male rats with different drug and diet histories: alcohol (via sequential drug and obesogenic diet histories on subsequent food
‘vapour’ or ‘liquid diet’ known to cause physical dependence and motivated behaviours in rats should also be determined. Further
18 LAQUE ET AL.

studies should also explore the relevance of the current results to on Alcohol Abuse and Alcoholism, National Institutes of Health,
‘cross-addiction transfer’ where individuals with drug use histories are USA: R01DA037294 (N.S.), R01AA023183 (N.S.), R01DA08467 (F.
more prone to gain weight, develop binge eating and prefer more W.), R01AA021549 (F.W.) and K99/R00DA035865 (M.W.B.). A.L.
intensely sweet foods during abstinence, despite often reporting signif- and H.N. were supported by Ruth L. Kirschstein Institutional
icant weight concerns (e.g., Cowan & Devine, 2008; Hodgkins National Research Service Award from National Institute on Alco-
et al., 2007). However, when given unchallenged ad libitum access to hol Abuse and Alcoholism, National Institutes of Health, USA:
diets high in fat and sugar, drug naïve rats consumed as many calories T32AA007456 (PIs, Drs Loren ‘Larry’ Parsons, Michael Taffe and
(Figures 1c,2c,3f) and gained as much weight (Figures 1d,2d,3g) as rats Marisa Roberto). This is the manuscript #30130 published by The
with drug histories. Another aspect worth studying is the effect of drug Scripps Research Institute.
histories on subsequent diet preference under a challenged condition.
Future studies should further explore the differences in food motivated AUTHOR CONTRIBU TIONS
behaviour between humans and rats with past drug histories. NS and FW conceived the research. NS, AL, RCR, TMK and RM-F
In summary, extensive drug histories known to cause addiction- designed the research. AL, GEW, GLDN, AMC, AM, GdG, HN, TMK,
like neurobehavioural changes in rats also caused compulsive appetite, MWB and TCJ performed the experimental procedures. NS, AL and
without causing excess calorie intake and bodyweight gain. Compul- GEW analysed the results. NS and GEW created figures. NS, AL, AM,
sive appetite and obesity thus appear to be dissociable (Boswell AMC, EK, TCJ, EPZ, RCR and FW wrote the manuscript. NS coordi-
et al., 2021; Gearhardt & Hebebrand, 2021a). Indeed, binge-eating dis- nated this work. All authors helped with data interpretation and man-
order and bulimia nervosa are marked by compulsive appetite but not uscript editing.
necessarily obesity (Udo & Grilo, 2018), and obesity is not part of the
diagnostic criteria for these disorders (American Psychiatric Associa- CONFLIC T OF INT ER E ST
tion, 2013). However, mechanisms leading to obesity may also mani- The authors declare no competing interests.
fest as compulsive appetite, as subsets (30%) of obese individuals
exhibit compulsive eating (Gearhardt et al., 2016; Minhas et al., 2021). DECLARATION OF T RANSPARENCY AND SCI ENTIFIC
Taken together, like drug addiction, ‘food addiction’ is perhaps better RE GOUR
defined as a disorder of compulsive appetite, as seen in subsets of eat- This Declaration acknowledges that this paper adheres to the prin-
ing disorder patients and obese individuals, than as a disorder of obe- ciples for transparent reporting and scientific rigour of preclinical
sity in general, which is a heterogeneous, multifaceted condition. research as stated in the BJP guidelines for Design & Analysis and
Beyond similar behavioural profiles, drug addiction, binge-eating Animal Experimentation and as recommended by funding agencies,
disorder and bulimia nervosa share similar brain profiles (Boswell publishers and other organizations engaged with supporting
et al., 2021; Serafine et al., 2021) as well as genetic risk factors research.
(Munn-Chernoff et al., 2020) and higher-than-expected comorbidities
(e.g., the rates of drug addiction in patients with binge-eating disorder DATA AVAILABILITY STAT EMEN T
[20%–40%] are higher than those in the general population [10%]) The data that support the findings of this study are available from the
(e.g., Udo & Grilo, 2018). Similarly, ‘food addiction’ as defined by the corresponding author upon reasonable request. Some data may not
Yale Food Addiction Scale is characterized by addiction-like compul- be made available because of privacy or ethical restrictions.
sive eating but not necessary obesity and shares higher-than-
expected comorbidities with binge-eating disorder, bulimia nervosa OR CID
and drug addiction (e.g., Horsager et al., 2021; Jiménez-Murcia Amanda Laque https://orcid.org/0000-0002-3650-0459
et al., 2019). These findings suggest common aetiologies for compul- Grant E. Wagner https://orcid.org/0000-0001-8659-1187
sive behaviours in drug addiction, eating disorders, obesity and puta- Alessandra Matzeu https://orcid.org/0000-0002-7654-4149
tive ‘food addiction’. Genna L. De Ness https://orcid.org/0000-0003-0194-943X
The current results provide an animal model to investigate the Tony M. Kerr https://orcid.org/0000-0002-8962-6215
common neurobiological mechanisms that mediate compulsive behav- Ayla M. Carroll https://orcid.org/0000-0001-8068-9693
iours motivated by drugs and obesogenic diets. Overlapping Giordano de Guglielmo https://orcid.org/0000-0002-4782-7430
neuroadaptations in the reward circuits, which regulate drug and food Hermina Nedelescu https://orcid.org/0000-0003-1300-672X
motivation independently of energy homeostasis, may serve as com- Matthew W. Buczynski https://orcid.org/0000-0001-5931-7107
mon targets for treating compulsive behaviours across drug addiction, Ann M. Gregus https://orcid.org/0000-0001-6851-1382
eating disorders, obesity and putative 'food addiction'. Our findings Thomas C. Jhou https://orcid.org/0000-0001-8811-0156
reveal a need for systematic investigations of this possibility. Eric P. Zorrilla https://orcid.org/0000-0003-2288-7899
Remi Martin-Fardon https://orcid.org/0000-0002-7470-5885
ACKNOWLEDGEMEN TS Eisuke Koya https://orcid.org/0000-0002-5039-4875
This work was supported by Extramural and Intramural funding Friedbert Weiss https://orcid.org/0000-0001-6211-6058
from National Institute on Drug Abuse as well as National Institute Nobuyoshi Suto https://orcid.org/0000-0002-8994-2592
LAQUE ET AL. 19

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