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Evaluating the Neurobiology of Sexual Reward

Article in ILAR journal / National Research Council, Institute of Laboratory Animal Resources · February 2008
DOI: 10.1093/ilar.50.1.15 · Source: PubMed

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 Evaluating the Neurobiology of Sexual Reward

Raúl G. Paredes

Abstract reward and reinforcement, which are frequently used inter-

changeably but have different meanings. In the following
There is much evidence that naturally occurring behaviors section I describe methods for evaluating motivational as-
(e.g., the ingestion of food and water) and social behaviors pects of sexual behavior: operant responding, partner prefer-
(e.g., play, maternal behavior) can induce a reward state. ence, the T-maze, sexual incentive motivation, and the
This review includes definitions to distinguish between “re- conditioned place preference (CPP1) paradigm, with a focus
ward” and “reinforcement,” and a description of methods to on the latter because it is the most frequently used in the
assess reward and demonstrate that social interactions can study of rewarding properties of different stimuli, including
indeed produce a positive affective (PA) state. Operant re- naturally occurring behaviors such as sexual behavior. Next
sponses, partner preference, and sexual incentive motivation I explain the use of these methods to assess approach and the
are all effective methods for evaluating approach behaviors rewarding properties of male and female sexual behavior, as
under different conditions. The method most frequently well as the use of CPP to evaluate other social behaviors. In
used to evaluate a positive affective or reward state is condi- the final section I describe the possible brain areas involved
tioned place preference (CPP), which entails modification in the rewarding aspects of sexual behavior in males and
of an animal’s initial preference after alternating exposure females.
to a control stimulus in one chamber and a rewarding condi-
tion in the other. At the end of the training the animal shows
a clear preference for the compartment associated with the Reward and Reinforcement
rewarding stimulus. CPP demonstrates that it is possible to
Although frequently used interchangeably, reinforcement
use different treatments and naturally occurring behaviors
and reward are clearly different. In a purely behaviorist
(e.g., water or food consumption, exercise) to induce a re-
sense, reinforcement refers to an increase in the probability
ward state. Sexual interactions and other social behaviors
of a response; this increase can be associated with the pre-
also produce a clear change of preference, indicating the in-
sentation of a positive stimulus or with removal of an aver-
duction of a reward or PA state. The reward state in males
sive one, and it is measured as the strength of a behavioral
and females is mediated by opioids, and the medial preoptic
response. In contrast, reward refers to the ability to elicit an
area of the anterior hypothalamus is a crucial site for sexual
approach behavior, similar to incentive motivation (an incen-
reward.
tive is defined as any stimulus that activates an approach
behavior2).
Key Words: approach behavior; conditioned place prefer-
The reason for the interchangeable use of the two terms
ence (CPP); partner preference; positive affective (PA) states;
may be that reward induces changes in observable behavior
reward; sexual incentive motivation
and serves as a positive reinforcer, increasing the frequency
of the behavior (Schultz 2006). In this article I use the term
Introduction reinforcement in a purely behaviorist sense to mean strength-
ening a stimulus-response habit (as defined by Hull 1951) or

T
his review presents a general description of the differ- increasing the rate or probability of a response (as defined by
ent aspects relevant to the study of sexual reward in Skinner 1938). It is thus purely descriptive and measures the
males and females (although studies have used differ-
ent laboratory animals, most have been done in rats, which
are therefore the primary focus of this review). The first sec- 1Abbreviations used in this article: CPP, conditioned place preference; DA,
tion provides an explanation of the distinction between dopamine; MPOA/AH, medial preoptic area/anterior hypothalamus; PA,
positive affective; VMH, ventromedial nucleus of the hypothalamus

Raúl G. Paredes, PhD, is a professor at the Instituto de Neurobiología of the 2There are two categories of stimuli: hedonically positive and hedonically
Universidad Nacional Autónoma de México in Juriquilla. negative. The former are associated with approach behaviors and are called
Address correspondence and reprint requests to Dr. Raúl G. Paredes, positive incentives (Di Chiara and Bassareo 2007). Not all approach
Instituto de Neurobiología, Universidad Nacional Autónoma de México, behavior is positive (e.g., aggression), but in this review I focus on approach
Apartado Postal 1-1141, Querétaro, Qro. 76001, México or email rpare- behaviors in response to a positive incentive (for further discussion, see
[email protected]. Ågmo 1999; 2007, 1-22).

Volume 50, Number 1 2009 15

strength or rate of a behavioral response (Berridge and Rob- animal, scientists assume that the approach behavior is in-
inson 1998). trinsically rewarding.
Some authors have dissociated reward into “wanting” Of the various methods to assess partner preference one
and “liking,” which are distinguishable with the appropriate of the most common (and the one we have used most often)
method of measurement (Berridge and Robinson 1998). The consists of a wooden box with three compartments of equal
“wanting” aspect of reward is usually inferred by measures size (32 × 36 × 34 cm) arrayed in a row. The middle com-
of consumption, a preference test, or performance of an in- partment is painted gray and communicates through sliding
strumental task. According to Berridge and Robinson (1998), doors (10 × 10 cm) with the lateral compartments, which are
with these behavioral measures “liking” is only inferred in- painted white and have wood shavings on the floor. Each
directly from “wanting,” and evaluation of “liking” requires lateral compartment contains a stimulus animal—a sexually
the use of affective reaction measures such as the taste reac- active male in one and a sexually receptive female in the
tivity test (see Berridge and Robinson 1998 and references other (the stimulus animals may vary depending on the aim
therein for a discussion). of the study). The stimulus animals wear a harness attached
Another important component to the study of social re- to the rear of the compartment with flexible rope, enabling
wards is the evaluation of positive affective (PA1) states. them to freely display coital behavior but with a limited ac-
Evaluation of PA states in humans uses self-reports or ques- tion radius within their compartment.
tionnaires that ask subjects about their level of happiness or During testing, a subject is placed in the middle com-
other feelings, whereas evaluation in animals relies largely partment for 1 minute; then the sliding doors are removed
on the observation of approach and consummatory behav- and during a 15-minute test an observer records the subject’s
iors (Burgdorf and Panksepp 2006). time spent in each of the lateral compartments and its coital
In short, reward, wanting, liking, and positive affect are interactions with the stimulus animals. For male subjects,
interrelated concepts and in some instances difficult to sepa- the preference score is calculated by dividing the amount
rate. But liking and positive affect are intrinsically rewarding of time spent with the receptive female by the amount of
and are measurable by approach, consummatory responses, time spent with the receptive female plus the amount of
or affective reactions. time spent with the sexually active male (the calculation
is adapted accordingly for female subjects). A score of 0.5
indicates no preference; a higher score indicates preference
Methods to Evaluate Reward for the receptive female, and a lower score a preference
for the male (Romero-Carbente et al. 2006). The amount
Operant Behavior of time spent with each stimulus animal is also a measure
of preference.
Some studies have used sex as a positive reinforcer to de-
An alternative to the three-compartment box uses a
velop operant behaviors (i.e., behaviors guided by their con-
straight runway to assess the subject’s motivation to ap-
sequences). For example, female rats have learned to press
proach a goal box containing either a male or female target,
a lever to obtain access to a male rat for sexual contact
in which the measure of preference is the time to reach the
(Bermant 1961; Bermant and Westbrook 1966), as have males
goal box: the shorter the time the higher the motivation to be
for access to and mating with a sexually receptive female
with the stimulus animal. This approach compares the time
(Everitt and Stacey 1987). However, an operant (also called
to reach different stimulus animals among subjects (Lopez
instrumental) response is sometimes maintained by a sec-
et al. 1999).
ond-order reinforcement (such as a light that comes on in
Earlier studies used the increasing barrier method to ana-
conjunction with the lever press), which may complicate in-
lyze how much of an aversive stimulus an animal was will-
terpretation of the results. There is also clear evidence that
ing to overcome to reach a goal. In this method, a female
sexual reinforcers are less effective than other types (e.g.,
subject had to cross an electric grid to get from the starting
food) in strengthening and maintaining an operant response
cage to the goal cage, which held a sexually vigorous male.
(Matthews et al. 1997). Moreover, something that is rein-
The grid current increased across trials, and scientists as-
forcing is not necessarily rewarding, thus the pressing of a
sumed that the greater the pain endured, the greater the mo-
lever may serve to measure the strength or rate of a behav-
tivation to be with the stimulus animal. A classic early study
ioral response but does not necessarily reflect an approach
using this method showed that intact females during the pre-
behavior associated with a PA or reward state (Ågmo 2007,
estrous-estrous stage tolerated higher levels of grid current
257-291).
(Meyerson and Lindstrom 1973).

Partner Preference
T-Maze and Sexual Behavior
The partner preference test is another effective method of
evaluating approach and consummatory behaviors associ- The T- or Y-maze, a variation of the three-compartment box
ated with sexual and other social interactions: if subjects re- for evaluating partner preference, involves placing the sub-
peat a choice or show a clear preference for a stimulus ject in a starting box and, after about 1 minute, opening a

16 ILAR Journal
sliding door into a runway leading to a choice point (the T or stimulus animals and percentage of choice to each stimulus
Y junction), where the subject can go to either side where the animal (Kindon et al. 1996; Paredes and Baum 1995).
stimulus animals are located (Figure 1). Some studies use
only one stimulus animal, leaving the other goal box empty;
others place different stimulus animals in each goal box— Sexual Incentive Motivation
for example, if the subject is a sexually experienced male,
the stimulus animals could be a sexually receptive female on Many sexual preference tests allow sexual interaction be-
one side and a nonreceptive female on the other. When the tween the subject and stimulus animals, to enable the com-
subject reaches the goal box he can interact with the stimulus bined measurement of approach and consummatory
animal or, in a test of sexual incentive motivation, he may be behaviors, or they may limit physical contact between sub-
separated from the stimulus animal by a wire mesh to enable jects and stimulus animals in order to assess the incentive
the measurement of approach behavior without consumma- value of the stimulus (i.e., a stimulus that activates an ap-
tory responses. proach behavior). In these tests, the subjects can see, hear,
The T- and Y-maze tests measure the subject’s percent- and smell the stimulus animals (the incentives) but do not
age of choices of each stimulus animal or its time to reach have physical contact with them because the stimuli are con-
the goal box. In early studies (Paredes and Baum 1995) we fined behind wire mesh. Approach behavior is induced by a
used this procedure to evaluate partner preference in male social or sexual stimulus, male or female; the subjects’ re-
and female ferrets after lesions of the medial preoptic area. peated approach to the stimulus animals likely indicates an
We placed the subject in the start box and after 30 seconds associated PA state. Other procedures to evaluate approach
raised the door to the maze. When the subject reached the behaviors depend on measures of response speed or rate,
goal box we opened the screen door and allowed the subject making them very sensitive to manipulations that affect mo-
and stimulus animal to interact for 1 minute. We then sepa- tor functions, or they involve different kinds of learned re-
rated the animals and returned the subject to the start box to sponses, further complicating interpretation. The incentive
run another trial, and recorded the latency to approach the motivation test is a more direct way of evaluating approach

Figure 1 In the T- or Y-maze the subject leaves the starting cage and when it reaches the “choice point” can interact with one of the stimulus
animals located in one or both of the goal boxes.

Volume 50, Number 1 2009 17

behaviors to an intrinsically rewarding incentive (Ågmo Conditioned Place Preference
1999, 2003b).
There are different ways to measure such responses, but The methods described above use operant behavior, partner
all require no direct physical contact between the subject and preference, a T-maze, and sexual incentive motivation to
the stimulus animals (Ågmo 2003a,b; Meerts and Clark measure consummatory and approach behaviors related to
2006; Portillo and Paredes 2004). In our studies we evaluate the wanting aspect of sex, and from these measures scientists
sexual incentive motivation in a box of black acrylic infer the liking of sex. For example, if a female spends more
(100 × 50 cm) with incentive animals (a sexually receptive time in the incentive zone of a sexually experienced male or
female and a sexually experienced male rat) in cages outside runs a maze faster in order to have contact with or be close
but adjoining the box at diagonally opposed corners (Figure 2). to such a male we conclude that the female prefers and in-
A floor-level opening (25 × 25 cm) in the box wall com- deed likes to be close to the male. In this section I describe a
municates with each incentive animal cage, but a wire method to evaluate this liking aspect of sexual behavior.
mesh separates the incentive and subject animals. An area The original study demonstrating that rats learned to
(20 × 30 cm) outside each incentive animal’s enclosure is the spend more time in a compartment where they received a
incentive zone. To start the experiment, the subjects are ha- subcutaneous injection of morphine was the work of Horace
bituated to the testing environment during three 10-minute D. Beach (1957). Years later investigators found that mor-
sessions (each preceded by a cleaning of both the box and phine injections produced a PA state and that rats preferred
incentive animal cages with a 0.1% solution of glacial acetic to spend more time in the place where they experienced this
acid in water). During the 10-minute test, the subject can rewarding state (Rossi and Reid 1976). These studies used
hear, see, and smell the incentive animals in the two cages, the conditioned place preference paradigm, which is now the
but no direct physical interaction is possible. We register the most common method of evaluating PA states and the re-
time that the experimental rats spend in each incentive zone warding aspects of drugs as well as of naturally occurring
as well as the number of visits to it (De Gasperin-Estrada et behaviors and other stimuli (reviewed in Tzschentke 2007).
al. 2008; Portillo and Paredes 2004). A summary of the advantages and disadvantages of CPP

Figure 2 In the sexual incentive motivation test the incentive animals are in cages located outside the acrylic box and separated by a wire
mesh from the experimental subject. An area outside each incentive animal cage is designated as the incentive zone.

18 ILAR Journal
procedures follows (for extensive reviews see, e.g., Carboni described above). There are also differences in conditioning
and Vacca 2003; Schechter and Calcagnetti 1993; Tzschentke methods and in the number of sessions required to test the
2007). subjects, but the consistent focus of evaluation is the increase
in the time the subjects spend in the compartment associated
with the rewarding stimuli after conditioning (Carboni and
Advantages Vacca 2003; Schechter and Calcagnetti 1993; Tzschentke
2007).
With conditioned place preference testing it is possible to I describe here the method we have used successfully to
detect a PA or reward state as well as aversive effects after evaluate the reward state induced by sexual behavior in male
conditioning. The technique is effective for measuring the and female rats. We use a three-compartment box in which
rewarding effects of naturally occurring behaviors (e.g., eat- the middle, gray-painted compartment communicates with
ing, play). If drugs are used for the training, (1) the animals the lateral compartments through sliding doors (Figure 3).
are drug-free during the test, (2) relatively low doses are suf- One lateral white-painted compartment has sawdust on the
ficient to induce CPP, (3) those that produce CPP are also floor, and the contralateral compartment is painted black and
rewarding in other behavioral paradigms, (4) it is possible to moistened with a 2% acetic acid solution; the two compart-
induce CPP with one drug (or stimulus) pairing as well as ments thus offer stimuli that are distinct in color, texture, and
multiple pairings, and (5) effects of the drug associated with odor.
the rewarding or aversive properties do not influence the In the pretest, we placed the subject in the middle com-
measure of the time spent in the drug-paired environment partment for 1 minute before opening the doors to the lateral
(because, again, the animal is drug-free during the test). compartments for a 10-minute test, during which we re-
corded the time spent in each of the lateral compartments
Disadvantages and noted the animal’s preference. For the conditioning, we
injected the animal with saline (1 ml/kg) and placed it for
The main criticism of CPP is that it may not be clear what 30 minutes in the preferred compartment. In alternating ses-
exactly the procedure has measured. For example, if drugs sions, we exposed subjects to the reinforcing event (mor-
are used, are the animals really expressing a drug preference phine injection or sexual behavior) and placed them in the
or an effect of the motor, sedative, or anxiolitic actions of the originally nonpreferred compartment for 30 minutes. After
drug? There is also a concern that the procedure may pro- three alternating reinforced and nonreinforced sessions, we
duce deficits in performance from drug-state dependency, tested the animals in exactly the same way as in the pretest.
because the subjects are trained in one state (injected with a If the reinforcing event induced a PA state, we modified the
drug) and tested in a different state (drug-free). These limita- original preference and the animals spent more time in the
tions, which are important to consider when testing the re- compartment associated with the reinforcing event.
warding properties of drugs, are eliminated or greatly A particular advantage of our method of evaluating the
reduced in evaluations of the PA of naturally occurring be- rewarding aspects of sexual behavior is that the animals’
haviors, although another criticism is that the subject’s nov- sexual behavior takes place in a mating cage before their
elty-seeking behavior can confound the evaluation of transfer to the conditioning cage, thus ensuring that we eval-
preference. uate the physiological state induced by mating and not the
effect of the behavior itself on conditioning. That is, we are
not measuring the approach or consummatory aspects of
CPP Methods mating but rather the physiological consequence or the lik-
ing aspect of mating.
The number of studies using CPP to evaluate PA or reward
states has increased significantly in the past 10 years
(Tzschentke 2007). Use of the procedure has revealed that Evaluating Reward in Sexual Behavior
the reward state can be induced by treatments such as drugs,
In the following sections I briefly describe uses of the para-
hormones, and kindling-like stimulation as well as by natu-
digms mentioned above to evaluate sexual approach behav-
rally occurring behaviors such as drinking water, eating, and
ior, PA, or reward states.3 The descriptions are not intended
exercising or using a running wheel (Carboni and Vacca
to be a detailed review of each paradigm but rather to give
2003; Paredes and Fernández-Guasti 2008; Schechter and
the reader a general idea of their use. I focus on CPP because
Calcagnetti 1993; Tzschentke 2007). Moreover, as I describe
it is the method most often used to directly evaluate reward
below, social behaviors also induce CPP, suggesting that
states.
they too produce a reward or PA state.
There are different ways to determine whether a treat-
ment induces CPP. The most basic approach requires a box
with two compartments that are different in texture, color, 3Ido not include a description of male and female sexual behavior as this is
and odor (in many studies a third, neutral compartment com- available in many specialized reviews (e.g., Ågmo 1997; Meisel and Sachs
municates with the other two in a three-compartment box as 1994).

Volume 50, Number 1 2009 19

Figure 3 The place preference conditioning apparatus consists of a box with three compartments that offer distinct stimuli in odor, color, and
floor texture. The middle compartment is painted grey and communicates with the lateral compartments through sliding doors. One of the
lateral compartments is white with wood shavings on the floor, the other is black and its walls are moistened with a 2% solution of glacial
acetic acid before the subject is placed in it.

Male Sexual Behavior and PA States nadectomized (GDX) rats show a preference for receptive
females, although the preference is restored for the latter
Most humans would consider it very simplistic to say that group after treatment with testosterone propionate (Ågmo
sexual behavior is rewarding. But the observation is actually 2003b; Paredes et al. 1998).
quite relevant for many other species of mammals: if sex is Odors also play an important role in partner preference
rewarding, the behavior will be repeated and will thus favor since they can be conditioned with the PA states associated
reproduction and the survival of the species.4 I focus here on with mating. For example, if almond odor is paired with the
the rewarding aspects of male sexual behavior in rats, which reward state induced by ejaculation in males, they will ejacu-
have been the subjects of most studies in this area. late more frequently with almond-scented females when
given the choice to copulate with scented and unscented fe-
males (Kippin and Pfaus 2001a,b; Kippin et al. 2001).5
Factors That Affect Male Sexual Behavior

There is much evidence that for male rats receptive females CPP and Male Sexual Behavior
are unconditioned sexual incentives that activate approach
behavior (Ågmo 2007, 1-22). For example, sexually active A number of research groups have shown that male sexual
males show a clear partner preference for receptive females behavior induces CPP in male rats (Ågmo and Berenfeld
over other sexually active males (Ågmo 2003b; Eliasson and 1990; Harding and McGinnis 2004; Hughes et al. 1990;
Meyerson 1981; Lopez et al. 1999; Paredes et al. 1998; Vega Kippin and van der Kooy 2003; Mehrara and Baum 1990;
Matuszczyk et al. 1994). This preference depends on the age
of the male and its levels of testosterone rather than on previ-
ous heterosexual experience, since it is also observed in 5We have also shown, however, that noncopulating males (those that are
sexually naïve rats (Ågmo 2003b; Eliasson and Meyerson repeatedly tested with sexually receptive females but fail to display any
1981; Lopez et al. 1999). For example, neither prepubertal sexual behavior) show no preference when given the choice to interact with
male rats (37 days old) with or without sexual experience a sexually receptive female or a sexually active male (Portillo and Paredes
(Vega Matuszczyk et al. 1994) nor sexually experienced go- 2003). A similar lack of preference for a receptive female was observed in
noncopulating males in tests of sexual incentive motivation where sexual
interaction was not possible (Portillo and Paredes 2004). Interestingly,
4A discussion of the function of sexual behavior is beyond the scope of this preliminary observations from our laboratory indicate that the noncopulating
article; I refer interested readers to a recent book by Anders Ågmo (2007, males develop CPP to a morphine injection, suggesting that the general
1-22) for a thorough review. reward function is normal in these males.

20 ILAR Journal
Miller and Baum 1987) and mice (Kudwa et al. 2005; Popik females controlled the rate of sexual interaction. For these
et al. 2003). The early studies allowed the subjects to copu- experiments, females in a mating cage with an acrylic barrier
late in the nonpreferred compartment of the conditioning with a hole could pass back and forth through the hole to the
cage and after the conditioning the males spent more time side of the cage where the male was confined (Figure 4) and
in the originally nonpreferred compartment (i.e., where they thus controlled the sexual interaction. One group of males
mated with receptive females), whereas control animals copulated without the barrier and another with the barrier; in
that did not mate did not develop CPP (Hughes et al. 1990; the second group the females controlled the rate of sexual
Mehrara and Baum 1990; Miller and Baum 1987). stimulation. Both groups of males mated until ejaculation,
There were two limitations to these studies: (1) because but only the males that copulated without the barrier devel-
the subjects mated in the conditioning cage, it was difficult oped a clear CPP; males that mated with the barrier (with
to determine whether CPP was associated with sexual behavior females controlling the sexual interaction) did not modify
or with the presence of a receptive female; and (2) CPP could their original preference.
have been associated with the execution of the behavior but These results suggest that only when males control the
not with the physiological state induced by mating. Ågmo rate of the interaction does sexual behavior induce a reward
and colleagues addressed the latter by mating males until state as evaluated by CPP (Martinez and Paredes 2001). In a
ejaculation in a mating cage and then transferring them to follow-up study we evaluated whether males would continue
the conditioning cage (Ågmo and Berenfeld 1990). Using mating with females that paced the sexual interaction despite
this method they showed that ejaculation can induce a change the absence of CPP when males do not control the sexual
of preference similar to a morphine injection and that the interaction. We divided subjects into three groups: the con-
reward state is of sufficient intensity and duration to induce trol group never mated, the second group mated once a week
conditioning (Ågmo and Berenfeld 1990). without the barrier for 10 weeks, and the third group mated
The experiments described above took place in a tradi- with the barrier once a week for 10 weeks. Only the males
tional mating chamber in which the males controlled the rate that mated without the barrier developed CPP. The group
of sexual stimulation. However, as we discuss in the next that mated with females pacing the behavior through the bar-
section, for females the ability to control the rate (pacing) of rier mated consistently during the 10 weeks of testing but did
sexual stimulation is a crucial factor in the development of a not develop a reward state as evaluated by CPP. There may
PA or reward state. In a series of experiments we evaluated be two explanations for these results: (1) sexual behavior
whether sexual behavior could be rewarding for males when and estrous females are powerful incentives for the male,

Figure 4 The pacing chamber consists of a mating cage equally divided by a removable partition with a small hole through which the female
can enter or exit the half of the cage where the male is confined. The hole is too small for the male to go through, allowing the female to pace
the sexual interaction.

Volume 50, Number 1 2009 21

even in situations in which the rewarding value of sex is re- to induce pregnancy (or pseudopregnancy) and changes in
duced, or (2) sexual behavior is indeed rewarding even when prolactin levels, whereas when females cannot pace their
the female controls the sexual stimulation but the CPP para- sexual contacts about ten intromissions are necessary to in-
digm is not sensitive enough to reveal a reward state (see duce this progestational state, suggesting that paced intro-
Camacho et al. 2004 for a discussion). missions are more effective in inducing physiological
It is also important for males to follow an adequate se- changes that favor reproduction (Erskine 1989).
quence of sexual stimulation for sex to be rewarding. For In order for the female to pace the rate of sexual interac-
example, if males are injected with 8-OH-DPAT, a com- tion the mating cage is usually divided by a partition with a
pound that facilitates sexual behavior by reducing the num- hole large enough to allow the female, but not the male, to
ber of intromissions necessary to achieve ejaculation, they move back and forth to the compartment in which the male
ejaculate after about two intromissions but do not develop is confined (Erskine 1989). From the studies described here
CPP (Camacho et al. 2007).6 it is evident that, for female rats, the ability to control the rate
of sexual stimulation and thereby reduce the aversive com-
ponents of mating is a factor to consider when designing
Female Sexual Behavior and PA States tests of and evaluating PA states or approach behavior.
Mating for the female rodent has both appetitive and aver-
sive consequences (see Paredes and Vázquez 1999 for a dis-
Early Studies of Female Sexual Behavior
cussion), which are enhanced and reduced, respectively, by
limiting physical contact. Thus the results of a test of sexual
As mentioned above, early studies of approach behavior in
incentive motivation where no physical contact is possible
females used the grid crossing method. Both intact females
differ from those of partner preference tests that allow mat-
during the preestrous-estrous stage of the estrous cycle
ing. For example, females in a test that did not permit con-
(Meyerson and Lindstrom 1973) and ovariectomized (GDX)
tact with the stimulus male showed greater interest in the
female rats treated with estradiol benzoate or testosterone
male than in a test that did (Meerts and Clark 2006 and refer-
propionate endured more grid crossings to approach a sexu-
ences therein). An early study also showed that GDX hor-
ally active male than to approach a castrated male or an anes-
monally primed females spent more time in the middle
trous female (McDonald and Meyerson 1973; Meyerson
compartment of a three-compartment box although they
and Lindstrom 1973). Similarly, in studies using the runway
mated with both of the tethered sexually experienced males
method, intact cycling females and GDX hormonally primed
confined to the lateral compartments. When one of the stim-
females ran faster to sexually active males that achieved in-
ulus males was castrated, the female spent more time with
tromissions than to passive males (Hill and Thomas 1973).
this animal than with the intact male, although sexual inter-
And in typical partner preference tests sexually receptive fe-
actions occurred with both stimuli. Moreover, if the females
males show a clear preference for sexually active males
had a choice between a GDX female treated with testoster-
when they have a choice between an intact male and a GDX
one propionate to induce mounting behavior and a sexually
hormonally primed female or between an intact male and a
active male, they spent more time with the stimulus female
GDX male (Paredes and Vázquez 1999).
(Broekman et al. 1988). Similarly, in a study using the sexual
Earlier studies also used sex as a positive reinforcer. Fe-
incentive motivation test, we demonstrated that both noncop-
male rats learned to press a lever to obtain the company of
ulating, sexually sluggish (males that start mating but do
a sexually experienced male for copulation. After a sexual
not reach ejaculation in several 30-minute tests) and copulat-
contact—either a mount or intromission, with or without
ing males are equally attractive to a sexually receptive fe-
ejaculation—the male was removed until the female pressed
male—that is, females spent the same amount of time in the
the lever again. A series of studies revealed that sexual con-
incentive zone of both types of animals because they have
tacts are positively reinforcing for females if they are able to
similar incentive value (De Gasperin-Estrada et al. 2008).
control or pace the intervals of sexual stimulation and that
One crucial component of these paradigms is the signifi-
they will actually work to avoid continued sexual stimula-
cance of paced mating for females. The ability of female rats
tion (Bermant 1961; Bermant and Westbrook 1966).
to control the rate of sexual interactions (pacing) has impor-
Another study showed that female rats allowed to choose
tant physiological (Erskine 1989) and behavioral conse-
between two sexually active males by pressing a lever devel-
quences (Erskine 1989; Paredes and Vázquez 1999) that
oped a preference for one of them even when the males were
favor reproduction. One of the physiological consequences
rotated in the holding cages (French et al. 1972). More re-
of paced mating is that fewer intromissions are needed to
cent studies using a multiple partner preference test yielded
induce the progestational state of pregnancy. When females
a similar observation. A sexually receptive female was al-
pace the sexual interaction, five intromissions are sufficient
lowed to pace her sexual contacts with four sexually active
males. Four cylinders, each with a small hole through which
6On the other hand, we found that females that experienced at least 10 paced only the female could move freely from one cylinder to
intromissions developed a clear CPP, indicating the induction of a PA state another, were assembled with a sexually active male in
(Paredes and Vázquez 1999). each and a female in the central compartment. Although the

22 ILAR Journal
females could mate with any of the four males, they spent a lations in a test where they paced the sexual interaction did
significantly longer time with only one of them (Ferreira- develop a clear change of preference, indicating the induc-
Nuño et al. 2005). These results indicate that female rats tion of a reward state. In a study by Pfaus and colleagues
have a very active role during mating that favors the develop- (Coria-Avila et al. 2006), females of the Wistar or Long-
ment of a PA state. Evans strain that were allowed to pace the sexual interaction
with males of both strains developed a preference for the
male with which they paced the interaction regardless of its
CPP and Female Sexual Behavior strain (although the preference was enhanced with males of
the same strain). The authors suggest that female rats have
In the first study to determine whether sexual behavior in an unconditioned preference for males of the same strain,
female rats could induce a reward state, as evaluated by CPP, but this preference can change in favor of a male of a differ-
mating took place in the conditioning cage (Oldenburger ent strain if it is associated with the sexual reward induced
et al. 1992). But if mating has both appetitive and aversive by paced copulation (Coria-Avila et al. 2006).8
components, the latter could affect conditioning and reduce
the possible rewarding effects. Indeed, the results were not
clear and a change of preference was observed only if the The Importance of Pacing for Both Males
test time was divided into three intervals of 5 minutes each. and Females
With this artificial division a change of preference occurred
only in the second 5-minute interval (Oldenburger et al. 1992).7 Taken together, the results of these studies clearly indicate
Another study showed that manual vaginocervical stim- that mating is rewarding for the animal (male or female) that
ulation induces CPP (Walker et al. 2002), whereas a separate controls the rate of sexual interaction. In natural or seminat-
study demonstrated that sexual interaction with a male pro- ural environments, both sexes control the rate of sexual in-
duced CPP in female Syrian hamsters even when vaginal teraction and are highly promiscuous—male and female rats
stimulation was prevented by a vaginal mask or topical lido- mate with several partners and change partners in the middle
caine, suggesting that other stimuli are effective and suffi- of copulation without an ordered sequence of behavioral
cient to produce CPP during mating in female hamsters events (as is characteristic of laboratory testing). They copu-
(Kohlert and Olexa 2005). late in groups with several males present and when estrus is
To reduce the influence of confounding variables and en- synchronized in females that live together (McClintock and
hance the rewarding aspects of mating, in my laboratory we Adler 1978; McClintock and Anisko 1982; McClintock et al.
combined CPP and paced sexual behavior to evaluate PA 1982; Meerts and Clark 2007). A female can receive an ejac-
states in female rats. In most of our studies we use ovariec- ulation with few intromissions if she encounters a male that
tomized female rats hormonally primed with estradiol ben- has already experienced intromissions with other females;
zoate (EB, 25 µg/rat) 48 hours before testing and with thus she gets the benefit of reproduction and controlled cop-
progesterone (P, 1 mg/rat) 4 hours before placement with a ulation. And a male can achieve intromissions with one or
sexually experienced male. Females that were treated with several females. Both sexes experience a similar amount of
EB alone and had the opportunity to pace the sexual interac- copulation (McClintock and Anisko 1982; McClintock et al.
tion did not develop CPP (Paredes and Alonso 1997; Paredes 1982), controlling the sexual interaction and thus ensuring
and Vázquez 1999), whereas females treated with EB plus P the induction of a PA state.
or with EB and 1 metabolite of P did change their original It could be argued, then, that sexual behavior in the rat
preference, indicating the development of a reward state has evolved to allow both sexes to control the rate of sexual
(Gonzalez-Flores et al. 2004). These results show that pro- stimulation and to ensure that females obtain the best physi-
gesterone is crucial for the development of a reward state ological conditions for pregnancy. And the reward state in-
after mating, and since progesterone is necessary for the dis- duced by mating outlasts the execution of the behavior for
play of proceptive behaviors (Blaustein and Erskine 2002; both sexes (Ågmo and Berenfeld 1990; Paredes and Martinez
Erskine 1989), which are also crucial for paced mating, it 2001). As mentioned above, if sex is rewarding for both
could be argued that proceptive behaviors contribute to the sexes then the likelihood of repeating the behavior increases,
PA or reward state induced by mating. which in turn favors the reproduction of the species. The PA
We have also shown that intact females developed a re- or reward state associated with sexual behavior could then
ward state after paced mating. Females that received three be a biologically important mechanism that contributes to
ejaculations in a situation in which they did not control the the survival of the species.
rate of sexual stimulation did not change their original pref-
erence. In contrast, females that received at least three ejacu- 8One study indicates that females that mate with the same male throughout
the test develop CPP whether or not they pace the sexual interaction (Meerts
and Clark 2007). However, preliminary studies done in our laboratory under
7A study done in hamsters showed a change of preference after mating, but the same testing conditions as in the experiments of Meerts and Clark have
the possible rewarding effects could not be attributed directly to mating not produced an increase in the time spent in the reinforced compartment—
because the high levels of aggression characteristic of hamster sexual i.e., no change of preference was observed—further supporting the im-
behavior complicate interpretation of the results (Meisel and Joppa 1994). portance of paced mating for the induction of a reward state.

Volume 50, Number 1 2009 23

Other Social Behaviors and Influences sion of male sexual behavior is the medial preoptic area/an-
terior hypothalamus (MPOA/AH1) (for a review see Paredes
Other social behaviors also clearly induce approach behav- 2003). Although lesions to any of several different brain re-
ior and place preference conditioning. Maternal behavior gions disrupt masculine sexual behavior, lesions of the
and exposure to pups can induce approach behaviors (Kristal MPOA/AH produce the most dramatic effects that consis-
2008) and PA states (Mattson et al. 2001, 2003). And social tently inhibit male sexual behavior in a variety of vertebrate
play can be used as an incentive for maze learning (Humphreys species (Paredes 2003).
and Einon 1981) and CPP (Calcagnetti and Schechter 1992; For the expression of female sexual behavior there is evi-
Crowder and Hutto 1992). dence that the amygdala (ME), the ventromedial nucleus of
Panksepp and colleagues have proposed that 50 kHz ul- the hypothalamus (VMH1), and the MPOA/AH are crucial
trasonic vocalizations represent a positive affective state in (Blaustein and Erskine 2002; Erskine 1989; Pfaff et al.
rats; they have shown that rats made a higher percentage 1994). For example, studies of Fos activation after paced
of these vocalizations on the amphetamine-paired side than mating or after exposure to stimuli associated with paced
on the vehicle-paired side of a two-compartment chamber mating have shown activation of these three areas (Coria-Avila
(Knutson et al. 1999). Rats emit 50 kHz ultrasonic vocaliza- and Pfaus 2007; Erskine and Hanrahan 1997). This and other
tions in anticipation of rewarding brain stimulation or drugs evidence suggests that the affective consequences of mating
of abuse, and during rough and tumble play behaviors as originate in or can be mediated by these structures (Garcia
well as after “tickling.” Tickling consists of rapid initial fin- Horsman et al. 2008).
ger movements across the back focusing on the neck, fol- Association of the nucleus accumbens (NAcc) with both
lowed by rapidly turning the animals over on their backs, drug-induced and natural reward (Kalivas et al. 2006; Van
with vigorous tickling of their ventral surface for a few sec- Ree et al. 2000; Ward et al. 2006) has led to the assumption
onds. This tickling procedure is repeated throughout a ses- that it is also involved in the rewarding aspect of sexual be-
sion in which subjects received four consecutive cycles of havior. But a detailed and critical examination of the litera-
15-second stimulation followed by 15 seconds of no stimu- ture reveals no consistent evidence (for a review see Paredes
lation. The authors have proposed that 50 kHz calls reflect and Ågmo 2004).
an appetitive positive affective state similar to primitive hu- It is similarly possible to assume an association between
man “social joy” and laughter (Knutson et al. 2002; Panksepp dopamine (DA1) and sexual reward. The effects observed in
2007; Panksepp et al. 2002). For example, female rats that studies of drug self-administration, self-stimulation, and
show high levels of tickle-induced 50 kHz calls find the food and water ingestion indicate that DA is involved in re-
tickling stimulation more rewarding than low-responder ward, and other studies indicate that modification of do-
animals. Researchers have found a similar relationship be- paminergic transmission affects sexual behavior. However,
tween 50 kHz vocalizations and reward using place prefer- a recent critical review of the evidence (Paredes and Ågmo
ence (Burgdorf et al. 2007; Knutson et al. 2002; Panksepp 2004) reveals that there are no consistent effects on sexual
2007; Panksepp et al. 2007). See Brudzynski (2008) for behavior from drugs that modify dopaminergic transmission.
a detailed discussion of the significance of rats’ ultrasonic Moreover, many compounds that modulate DA affect motor
vocalizations. function or arousal, complicating interpretation of the results
In addition, odors from conspecifics can induce PA (Paredes and Ågmo 2004). Furthermore, there is no evidence
states. For example, an anesthetized estrous (Pankevich et al. implicating DA in the rewarding aspects of male sexual be-
2006) or nonestrous female and soiled bedding from estrous havior. For example, ejaculation-induced CPP is not blocked
females both produce CPP in males (Pierman et al. 2006). by the administration of the dopamine antagonist flupentixol
Home cage odors also can induce CPP (Fitchett et al. 2006). (Ågmo and Berenfeld 1990). Similar results have been de-
Elegant work by Pfaus and colleagues has shown that olfac- scribed in females where the rewarding effects of paced
tory cues can be associated and conditioned with sexual be- mating were not blocked by the specific DA antagonists flu-
havior; in their study, female rats that were allowed to pace pentixol or raclopride (although each compound blocked the
the sexual interaction with males carrying a particular scent CPP induced by the DA agonist amphetamine), indicating
(applied by the experimenter) or that mated in a nonpaced that DA is not involved in the rewarding aspects of mating
situation with unscented males showed a clear preference for (Garcia Horsman and Paredes 2004).
the males carrying the scent (Coria-Avila et al. 2005). See There is ample evidence that opioids are released during
Kelliher and Wersinger (2008) for a detailed discussion of sexual behavior. For example, pain threshold increases dur-
the impact of olfactory cues on social behavior. ing mating (Szechtman et al. 1981) and after ejaculation
(Forsberg et al. 1987) in males and after vaginocervical stim-
ulation in females (Komisaruk and Wallman 1977). We have
Neurobiology of Sexual Reward shown that the administration of an opioid agonist in the lat-
eral ventricle once copulation is initiated facilitates subse-
The neural control of sexual behavior in males and females quent sexual behavior, reducing the number of intromissions
involves different brain areas. Several lines of evidence and the ejaculation latency, further supporting the notion that
clearly indicate that the most important area for the expres- opioid release during sexual behavior facilitates ejaculation

24 ILAR Journal
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I thank Francisco Camacho Barrios, Leonor Casanova, De Gasperin-Estrada GP, Camacho FJ, Paredes RG. 2008. Olfactory dis-
crimination and incentive value of noncopulating and sexually sluggish
Lourdes Lara, Pilar Galarza, Omar Gonzalez, and Rafael male rats. Physiol Behav 93:742-747.
Silva for their technical assistance. Research supported by Di Chiara G, Bassareo V. 2007. Reward system and addiction: What do-
DGAPA IN204206 and CONACyT 53547 and V40286M. pamine does and doesn’t do. Curr Opin Pharmacol 7:69-76.

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