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Sex Differences in the BrainFrom Genes to Behavior$

Jill B. Becker, Karen J. Berkley, Nori Geary, Elizabeth Hampson, James P. Herman, and Elizabeth Young

Print publication date: 2007

Print ISBN-13: 9780195311587

Published to Oxford Scholarship Online: January 2010

DOI: 10.1093/acprof:oso/9780195311587.001.0001

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Sex Differences in Motivation

Sex Differences in Motivation

(p.177) Chapter 10 Sex Differences in Motivation
Sex Differences in the Brain

Jill B. Becker

Jane R. Taylor

Oxford University Press

Abstract and Keywords

This chapter develops the thesis that sexually dimorphic development of the neural systems involved in motivation has evolved due to sex differences in care of young. It proposes that sex differences in the neural systems important for maternal motivation result in sex differences in motivated behaviors in general. In particular, the greater oxytocin projection to the nucleus accumbens (NAcc) in females is hypothesized to play an important role in these sex differences. In addition, there are effects of gonadal hormones that modulate the reward system. Specifically, estradiol enhances the rewarding value of potential targets, while progesterone counteracts the effect of estradiol.

Keywords:   sex differences, maternal motivation, neural systems, oxytocin, nucleus accumbens, gonadal hormones, estradiol

This chapter develops the thesis that sexually dimorphic development of the neural systems involved in motivation has evolved due to sex differences in care of young. We proposed that sex differences in the neural systems important for maternal motivation result in sex differences in motivated behaviors in general. In particular, the greater oxytocin projection to the nucleus accumbens (NAcc) in females is hypothesized to play an important role in these sex differences. In addition, there are effects of gonadal hormones that modulate the reward system. Specifically, estradiol enhances the rewarding value of potential targets, while progesterone counteracts the effect of estradiol. Ultimately, research on the neurobiological mechanisms of sex differences in motivation will aid in the treatment and understanding of motivation-related pathologies for females and males.

What is Motivation?

In psychological terms motivation is the internal state that induces or drives an animal to engage in a specific behavior. There are a number of naturally-occurring motivated behaviors, where it is assumed that an animal engages in these behaviors in order to gain a particular reward i.e., eating, drinking, and engaging in sexual behavior. There are also motivated behaviors that are acquired through experience with reinforcers, such as drugs of abuse. The proximal or immediate motivation to engage in these behaviors is the acquisition of the rewarding item: the food item, a liquid to drink, a sex partner, or a drug of abuse. Sex differences in the motivation to engage in parental behavior, the motivation to engage in sexual behavior, and the motivation to take drugs of abuse exist. In this chapter, we will address sex differences in the neurobiological (p.178) systems that induce an animal to seek a reward; but first we will examine motivation from an evolutionary perspective, as we believe this view will provide some insight into the neural systems that mediate motivation.

Why are there Sex Differences in Motivation?

We have learned a great deal in recent years about the proximal causes for sex differences in motivation. We propose that to make further advances in our knowledge requires an evolutionary approach to how we think about motivation. The fundamental premise of natural selection is that traits are selected that result in an increase in an individual’s genes being represented in subsequent offspring, in other words—traits that enhance reproductive success and inclusive fitness. As the behaviors needed to enhance reproductive success are different for males and females, the ultimate (i.e., evolutionary) pressures on the neural systems that mediate motivation have resulted in the evolution of sex differences in motivational systems.

Reproductive success for a male mammal requires insemination of female conspecifics; so the primary reproductive motivation1 of a male is to gain access to females for the purpose of mating. For non-parental males, which is the majority (90%) of mammalian species, the strategy is to inseminate as many females as possible, thereby increasing the chance that the male’s genes will be represented in surviving animals that go on to reproduce. In the male, this is a system that is activated by testosterone and its metabolites, and it is always “on” except in seasonal breeders or when environmental constraints limit testicular function or mating opportunities.

Reproductive success for the female mammal requires a series of related, but distinct behaviors and neuroendocrine processes. The female must select the best mate, and then achieve successful fertilization, implantation, pregnancy, parturition, and subsequent maternal behavior to promote survival of her offspring. In other words, the primary reproductive motivation of the female, after she has chosen to mate, is production of and care for her young; in effect, ensuring that her genes will survive in subsequent generations. Each of the functions that contribute to reproductive success in the female is activated by estradiol and progesterone, with contributions from hypothalamic hormones and releasing factors. Different selection pressures operating on female versus male sexual strategies have produced different, but related neural systems to mediate the various components of the behaviors that contribute to reproductive success.

Different areas of the female brain are important for sexual ability (i.e., the ability to exhibit the lordosis reflex) and sexual motivation as well as maternal behavior and maternal motivation. Further on, these roles are discussed in the context of the neural mechanisms of motivation.

As should be apparent from this brief discussion, the neural systems important for motivation and engaging in behaviors essential for reproductive success are different for males and females. The premise that we will be developing in this chapter is that there are sex differences in motivation and that the sexes differ along three dimensions. First, motivation in females varies with reproductive status (i.e., estrous cycle or pregnancy), but is constant in males. Therefore, motivation in females is modulated by gonadal hormones, and the female brain is more vulnerable to be co-opted by exogenous agents that induce constant activation (e.g., drugs of abuse) than are males.

There are neuroanatomical differences in the motivational systems beyond sex itself that are still related to reproduction. In females, neural systems that lead to formation of the mother-infant bond operate in ways that are different than in males, even in males that form paternal attachments where these neural systems may be present, but normally, are inactive. Sex differences in neural circuitry of attachment may spill over into other motivation systems too, including non-reproductive motivations for drugs. The development of strong attachments, and addictions or compulsive behaviors may occur through activation of the neural system that mediates maternal motivation; thus, females can become addicted to drugs more rapidly than males.

(p.179) Lastly, we emphasize that sex differences in motivation that have been discovered in non-human animals are also likely to be present in humans, since humans have been subject to many of the same evolutionary constraints. In a recent cross-cultural analysis in the behavior of men and women, it was concluded that sex differences in cognitive function present in humans is an evolutionary consequence of specialization of behaviors by the sexes, and in particular behaviors related to female reproductive capacity and maternal behavior (Wood & Eagly, 2002). Even though pregnancy and maternal care of the young may no longer dictate a woman’s reproductive success, women retain a brain that evolved under these constraints and understanding the neurobiological factors that underlie these differences should be an emerging area of clinical and preclinical research (Cahill, 2006).

The Neural Systems that Mediate Motivation

The areas of the brain that are thought to be especially important for the neurobiology of motivation are illustrated in Figure 10.1 in a generic form. Based primarily on data from males, we see that there is a major role for the ascending dopamine systems that project from the substantia nigra to the dorsal striatum and from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc), amygdala (AMY) and frontal cortex.

The NAcc is composed of the core and shell, which differ in their afferent input and efferent projections. The hippocampus projects to both core and shell, with the dorsal subiculum projecting to the core and the ventral subiculum projecting to the shell (not illustrated). Prelimbic prefrontal cortex projects to the core of the NAcc while infralimbic and piriform cortex project to the shell. (Brog et al., 1993).

Specific subcompartments of the AMY also project to the core versus. shell (Wright et al., 1996). Both core and shell receive input from dopamine neurons in the VTA, and this input is topographically organized. The output from the NAcc core connects to the ventral pallidum, subthalamic nucleus, and substantia nigra, while the shell projects more to the subcortical limbic system, but also projects to the ventral pallidum and substantia nigra. Information from the core and the shell of the NAcc is integrated at the level of the thalamus. Cortical areas (AMY, and orbitofrontal, perhaps the cingulate cortex) are important for learning the association between a conditioned stimulus (CS) and reward (Schoenbaum et al., 2000; Chudasama & Robbins, 2003; Saddoris et al., 2005) as well as mediating changes in the incentive salience of stimuli (Berridge, 2006).

                      Sex Differences in Motivation

Figure 10.1. The reward system. This is a simplified schematic diagram of the neural systems important for reward. While no brain region is involved in only one aspect of behavior, the brain regions depicted here have been shown to be important for reward in a number of different paradigms. Dopamine (DA) projections are depicted on the left side of the brain. DA cell bodies in the substantia nigra (SN) project to the striatum. DA cell bodies in the ventral tegmental area (VTA) project to all parts of the the amygdala (AMY; BL = basolateral, M = medial, c = central), the nucleus accumbens core (NAc) and shell (NAs), as well as the prefrontal cortex (PFCTX). On the right side of the diagram associations among these various nuclei are illustrated. VP = ventral pallidum, THAL = thalamus.

When males and females are compared, variation from the generic version of motivational systems can be seen. There is also variation from this generic scheme for each specific motivated behavior. We (p.180) know that the brain of males and females are different and that sex differences can be observed in the neurobiological basis of motivation. Research in sexual motivation, paternal behavior, and in the motivation to take drugs of abuse has been done in both male and female rats. These are the behaviors for which we know the most about sex differences in motivation, and the neural systems that underlie these sex differences.

Sex Differences in Sexual Motivation

Male Sexual Behavior

Sexual behavior has both appetitive (motivational) and consummatory components (sexual ability) as do many other behaviors (Craig, 1918). This has been elegantly demonstrated in experiments from the Everitt laboratory with male rats (Everitt & Stacey, 1987; Everitt, 1990).

Using a second order schedule of reinforcement, Everitt and collaborators demonstrated that male rats could be trained to bar press for access to a sexuallyreceptive female rat. Bar pressing was established using a red light as a CS after pairing the red light with odors from a sexually-receptive female rat. Once bar pressing was established on a fixed-interval schedule of 5 minutes, experiments were performed to demonstrate that bar pressing was a measure of sexual motivation and the ability to engage in sexual behavior was measured when the female was delivered into the testing chamber.

These investigators went on to show that castration reduced both bar pressing for the female (i.e., sexual motivation) as well as sexual behavior (i.e., sexual ability). As would be predicted from a large body of research (reviewed in Hull et al, 2006), lesions of the medial preoptic area (POA) resulted in a severe impairment of male copulatory behavior.2 But, strikingly had little effect on the operant responding for access to the female. On the other hand, lesions of the basolateral amygdala (blAMY) reduced bar pressing for access to the female rat (i.e., sexual motivation), but failed to affect sexual ability (Everitt & Stacey, 1987; Everitt, 1990).

The results of these experiments clearly demonstrated that there are distinct neural substrates necessary for sexual motivation versus sexual ability. Furthermore, when amphetamine was delivered to the NAcc of male rats with a blAMY lesion, bar pressing for access to the female was reinstated (Everitt, 1990). Since there are projections from the blAMY to the NAcc, dopamine in the NAcc—released by amphetamine—was implicated in sexual motivation. Subsequently, a number of investigators have demonstrated that extracellular dopamine concentrations increase in the NAcc of male rats in anticipation of gaining access to a sexually receptive female as well as during sexual behavior. (Pfaus et al., 1990; Pleim et al., 1990; Pfaus & Phillips, 1991; Damsma et al., 1992).

To summarize, the areas of the brain that are primarily important for the ability to engage in copulatory behavior (i.e., sexual ability) in the male (Fig. 10.2) include the POA, the medial amygdala (mAMY), and the bed nucleus of the stria terminalis (BNST). The blAMY, NAcc, and striatum are more involved in the motivation to engage in sexual behavior (Baum, 2002). The connections among these brain regions involved in sexual motivation and sexual ability are described in more detail in Figure 10.2.

Female Sexual Behavior

While both male and female rats may exhibit an increase in extracellular concentrations of dopamine in the NAcc during sexual behavior (Pfaus et al., 1990; Mermelstein & Becker, 1995; Pfaus et al., 1995), in the female, this increase in NAcc dopamine depends upon the context in which the sexual behavior occurs. This is due to the fact that sexual behavior is rewarding to the female rat only under specific conditions (Oldenberger et al., 1992; Paredes & Alonso, 1997; Paredes & Vazquez, 1999; Martinez & Paredes, 2001; Jenkins & Becker, 2003b). In other words, for the female the context and timing of the sexual encounter is critical to whether sexual behavior is rewarding.

In laboratory experiments on sexual behavior, animals have historically been studied in a small chamber where contacts are initiated by the male who engages in a series of mounts and intromissions that ultimately lead to ejaculation (Bermant, 1961; Bermant, (p.181) 1967; Adler, 1969). Under these conditions, the male controls the rate of copulation and will intromit with a female at a relatively rapid rate—approximately once every 30 seconds—until ejaculation occurs after 9 or 10 intromissions.

                      Sex Differences in Motivation

Figure 10.2. The neural systems mediating male sexual behavior. On the left are indicated the neural systems that are most critical for the ability of the male rat to engage in copulatory behaviors. On the right are depicted the neural systems in the male that are involved in the motivation or desire to engage in sexual behavior. The projections from mAMY to BNST and POA are vasopressin containing neurons. BNST = bed nucleus of the stria terminalis, POA = preoptic area.

On the other hand, if sexual behavior takes place in a chamber where the female can escape from the male, she will establish and maintain longer latencies between sexual contacts (Adler, 1969; Adler, 1978; McClintock, 1984; Erskine et al., 1989). For laboratory rodents, the female will remove herself from the presence of the male after an intromission and return to the male about 2 minutes later (Jenkins & Becker, 2003b).

In the wild, rats engage in mating in groups of several females and the dominant male. Under these conditions the male is able to achieve his preferred rapid rate of intromissions with different females. The females, in turn, achieve their preferred rate of copulation by withdrawing from the male and then returning after the preferred interval (McClintock, 1984). Achieving the preferred rate of copulation is important for the female rodent to optimize the rate of vaginocervical stimulation received from a male which activates a neuroendocrine reflex that is necessary for pregnancy to occur (Adler, 1969; McClintock & Adler, 1977; Adler, 1978; McClintock, 1984; Erskine, 1989).

The female’s repeated approach and withdrawal from the male during a sexual encounter is known as pacing behavior (Erskine et al., 1989). Pacing behavior allows the female to control both the rate and duration of the copulatory bout. Importantly, sexual behavior is rewarding to the female rat when she achieves her preferred rate of copulation (Paredes & Alonso, 1997; Paredes & Vazquez, 1999; Martinez & Paredes, 2001; Jenkins & Becker, 2003b), whether or not she is actively pacing the rate of copulation (Jenkins & Becker, 2003a).

In support for a role for dopamine in sexual motivation in females, NAcc-dopamine increases only when female rats are receiving copulatory stimulation at their preferred rate of intromissions; not when they receive similar numbers of intromissions at a rate that is too fast or too slow. This can be accomplished either by the female actively controlling or “pacing” the rate of copulation or if the experimenter removes the male and then returns him to the female’s chamber at appropriate intervals during copulation (Mermelstein & Becker, 1995; Becker et al., 2001). Female hamsters also exhibit an increase of dopamine in dialysate during sexual behavior (Meisel et al., 1993).

It should be noted that female rats engaging in sexual behavior at their preferred pacing interval had greater increases in dopamine in dialysate from the NAcc than did animals in which the male rat was removed and then returned to the female’s chamber either too rapidly or much later (Becker et al., 2001). Furthermore, dopamine increases in the NAcc occurred prior to coital stimulation when intromissions were received at the female’s preferred pacing interval, but not during the interval when coital stimulation occurred under other conditions (Jenkins & Becker, 2003a). Thus, increases in NAcc dopamine are not induced by coital stimulation or escape from/ removal of the male rat; instead, the NAcc-dopamine (p.182) increases occur in anticipation of coital stimulation that occurs at a specific interval. These data support the hypothesis that dopamine increases in the NAcc signal the impending receipt of coital stimulation at the female’s preferred pacing interval, and that NAcc dopamine plays a role in sexual motivation.

The increase in dopamine in the NAcc is apparently not always necessary for a female to find sexual behavior rewarding. In hamsters, pretreatment of females with the D2-dopamine receptor antagonist raclopride blocked conditioned place preferences for the place in which mating occurred (Meisel et al., 1996). On the other hand, Paredes et al. found that pretreatment with the dopamine antagonists flupentixol or raclopride did not block conditioned place preference induced by paced mating in female rats (Garcia-Horsman & Paredes, 2004), while the m-opiate antagonist naloxone prevented establishment of conditioned place preference induced by paced mating (Paredes & Martinez, 2001).

These results suggest that activation of D2 dopamine receptors may not be necessary for sexual behavior to be rewarding, while μ-opioid receptor mediated activation—with the downstream effects on GABA, dopamine, and glutamate neurotransmission—is important for sexual motivation in the female rat. The study by Garcia-Horseman and Paredes (2004) used a relatively low dose of raclopride, leaving open the possibility that this dose is not sufficient to completely block the rewarding effect of dopamine. Alternatively, it is possible that the way the conditioned place preference test is conducted (animals are placed into the test apparatus for conditioned place preference training immediately after receiving an ejaculation) is particularly sensitive to the effect of opioid antagonists.

To summarize, the brain regions involved in the female rat’s lordosis reflex (the behavior that makes it possible for the male to achieve intromission) include the POA, the ventral medial hypothalamus (VMH), the mAMY and the lateral septum (LS) (McCarthy & Becker, 2002). In order to activate a neuroendocrine reflex that promotes implantation and maintains pregnancy as well as for sexual motivation, the NAcc, dorsal striatum, and mAMY have to be involved (Fig. 10.3) (Erskine & Hanrahan, 1997; Becker et al., 2001; Polston et al., 2001; Bradley, 2005).

In particular, dopamine in the NAcc is implicated in the anticipation of sexual behavior that is rewarding. Sexual behavior of the female rat requires new considerations and interpretations of the role of dopamine in reward. Female rats find sexual behavior rewarding and have increased NAcc dopamine when they engage in sex at their preferred interval (Mermelstein & Becker, 1995; Paredes & Alonso, 1997; Becker et al., 2001; Martinez and Paredes, 2001). Sexual experience also plays a role in sexual motivation, with experience enhancing the reinforcing properties of sexual behavior in the female (Meisel & Mullins, 2006).

                      Sex Differences in Motivation

Figure 10.3. The neural systems mediating female sexual behavior. On the left are indicated the neural systems that are most critical for the ability of the female rat to engage in copulatory behaviors. On the right are depicted the neural systems in the female that are involved in the motivation or desire to engage in sexual behavior. LS = lateral septal nucleus, VMH = ventromedial nucleus of the hypothalamus.

Sex that is rewarding has been shown to be associated with the triggering of a neuroendocrine reflex necessary for pregnancy (Adler, 1974; Gilman et al., 1979; Erskine et al., 1989). One possibility of this is that the changes in dopamine observed here represent a coupling of the sexual interaction and its physiological consequences, both of which may be necessary for sexual behavior to be rewarding in the female. In other words, increases in dopamine predict the receipt (p.183) of coital stimulation, but only when the coital stimulation occurs at such a rate that it triggers the neuroendocrine reflex necessary for successful pregnancy to occur. Coital stimulation is known to induce the release of oxytocin in rats and other species (Flanagan et al., 1993). The neuroendocrine reflex that is activated in the female rat also results in the release of prolactin (Erskine, 1995). Since oxytocin is thought to induce the release of prolactin, one possibility is that activation of the intrahypothalamic neurons necessary for coital-induced release of prolactin and oxytocin also enhances dopamine release in the NAcc.

Maternal Motivation: a Sexual Dimorphic Behavior

The neuroendocrinology and neurochemistry of maternal motivation has recently been reviewed quite thoroughly (Lonstein & Morrell, 2007), and we refer the reader to this excellent review for additional details. The hormones of pregnancy and parturition prime the brain for the onset of maternal behaviors which begin at parturition as a consequence of the exposure to pups. As is true of sexual behavior, there are brain regions important for the ability to engage in the behaviors that comprise maternal behavior and other brain regions important for the motivation to engage in these behaviors.

Maternal behavior consists of a set of behaviors that includes: parturition-related behaviors, nest building, pup retrieval, pup licking, the nursing posture (kyphosis), and maternal aggression. These behaviors are initially dependent on hormones for their rapid establishment at parturition. Once maternal behaviors have been induced, their expression continues to occur without additional hormones, and can be induced more rapidly by exposure to pups, indicating that establishment of maternal behaviors results in long-term changes in the brain.

The hormones necessary for the rapid establishment of maternal behaviors in the rat are estradiol, progesterone, prolactin (and the related hormones decidual luteotrophin and placental lactogens I and II) and oxytocin. During pregnancy, estradiol acts in the POA to prime the brain so that the female rapidly displays maternal behavior at parturition (Rosenblatt, 1992). Progesterone is elevated throughout most of pregnancy, and its withdrawal at the end of pregnancy is necessary, in most species, for the onset of labor, initiation of lactation, and the estradiol-triggered onset of maternal behavior (Rosenblatt, 1992; Lonstein & Morrell, 2007).

The decline in progesterone is thought to result in an increase in prolactin receptors in the POA, which allows the full expression of maternal behaviors (Bridges & Hay, 2005). Interestingly, in humans progesterone does not decline until after parturition, but there is a shift in the type of progesterone receptors in the myometrium pre-partum that decreases the response to progesterone while enhancing stimulation induced by estradiol which is necessary for parturition (Brown et al., 2004; Fernandes et al., 2005; Karteris et al., 2006; Sheehan, 2006).

Prolactin and related lactogenic hormones are transported into the brain via an active receptortransport mechanism in the choroid plexus (Lonstein & Morrell, 2007). In the POA, prolactin has been shown to facilitate the onset of maternal behavior in the estradiol primed female rat (Rosenblatt, 1992; Lonstein & Morrell, 2007). Other brain regions where prolactin is thought to influence maternal behavior include the mAMY, lateral septum, anterior hypothalamus.

Finally, oxytocin is thought to act in the POA, NAcc and olfactory-related brain regions to influence maternal behavior (Rosenblatt, 1992; Lonstein & Morrell, 2007). The role of oxytocin in maternal behavior was called into question when it was observed that the oxytocin knock-out (OTKO) mouse had normal reproductive behavior (Nishimori et al., 1996). Recent studies, however, have found that the OTKO mouse has deficits in pup-licking as well as maternal motivational deficits (Pedersen et al., 2006) and social recognition problems (Ferguson et al., 2001). Interestingly, oxytocin is necessary for licking behavior post-partum and is not maintained without oxytocin, as it is reduced by an oxytocin antagonist (Champagne et al., 2001).

To summarize, as illustrated in Figure 10.4, the POA, NAcc, striatum, lateral septum, and paraventricular nucleus (PVN) are thought to be important for maternal behaviors and the rapid formation of the mother-infant bond immediately after parturition (Lonstein et al., 1998; Lonstein et al., 2000; Lonstein et al., 2003; Gatewood et al., 2006; Lonstein and Morrell, 2006). Hormonal regulation of the initiation of maternal behavior converges on the POA, with contributions from the mAMY (which are inhibitory), (p.184) the paraventricular nucleus (PVN; where oxytocin cell bodies are found), and perhaps the VTA, lateral septum and the anterior hypothalamus.

                      Sex Differences in Motivation

Figure 10.4. The neural systems mediating maternal behavior. On the left are indicated the neural systems that are most critical for the ability of the female rat to engage in maternal behaviors. On the right are depicted the neural systems in the female that are involved in the motivation or desire to engage in maternal behavior. The projections from the PVN (paraventricular nucleus) contain oxytocin.

The neurobiology of maternal motivation has only recently become a topic of research study, although it has been known for some time that female rats will cross electrified grids to gain access to pups (Lonstein & Morrell, 2007). Pup retrieval is the behavior studied most frequently, as recently-parturient female rats will readily learn to bar press for access to pups and will bar press for hours, retrieving hundreds of pups (reviewed in [Lonstein & Morrell, 2007]). Importantly, the withdrawal of progesterone is necessary for dams to bar press for pups, as progesterone treatment prevents responding for pups in pregnancy terminated females (Hauser & Gandelman, 1985). Thus, progesterone appears to dampen maternal motivation.

Operant responding has also been used to identify the areas of the brain that are necessary for bar pressing for access to pups. Lesions of the POA or blAMY reduced bar pressing for access to pups whereas lesions of the NAcc did not (Lee et al., 2000). All lesions disrupted pup retrieval in the home cage (Lee et al., 2000). It is important to note that the operant responding in this experiment was maintained on an FR1 schedule, and that bar-pressing behavior was established with Froot Loops during pregnancy and then parturient dams were given pups when the bar was pressed post-partum. In other paradigms, lesion of the NAcc have been shown to decrease sensitivity to changes in the delivery of reinforcers (Acheson et al., 2006), so it is possible that after NAcc lesions the bar pressing by parturient rats may reflect a learning deficit, rather than lack of involvement of NAcc in maternal motivation. The finding that lesions of the NAcc shell disrupt pup retrieval, but not locomotor activity, argues that the NAcc is involved in some aspect of maternal motivation (Li & Fleming, 2003).

Using c-Fos immunoreactivity to designate brain regions that are active, Morrell and colleagues have shown that cues associated with pups in a conditioned place preference task result in activation of neurons in the POA, prefrontal cortex, NAcc, and the blAMY, but not the dorsal striatum (Mattson et al., 2003; Mattson & Morrell, 2005). Based on their analysis of the neural systems mediating maternal motivation, Lonstein and Morrell (Lonstein & Morrell, 2007) propose that increased dopamine activity in the ascending mesolimbic circuits is necessary for many of active components of maternal behavior. Interestingly, the hedonic impact (i.e., liking) of food and sex may also be regulated by opioid systems within these mesolimbic dopaminergic circuits that control reward motivation (Pecina et al., 2006). Studies of sex differences in these so called “hedonic hot spots” in the NAcc shell and ventral pallidum also would be predicted to reveal a sexually dimorphic pattern of regulation.

It is interesting to note that in biparental species, such as the prairie vole, males display parental behavior in response to vasopressin in the lateral septum (Wang, 1994; Wang et al., 1994a; Wang et al., 1994b) (see Young & Carter, Chapter 8 in this volume). In biparental mice, lesions of the POA reduce parental behavior in both males and females (Gubernick et al., 1993; Lee & Brown, 2002), suggesting that the neural basis of parental behavior is similar in males and females. Male rats can be induced to show parental (p.185) behaviors by presentation of pups (Rosenblatt et al., 1996); and estradiol given systemically or estradiol implants in the POA enhance the onset of maternal behaviors in male rats (Rosenblatt et al., 1996; Rosenblatt & Ceus, 1998). It takes longer, however, to induce these behaviors in males than in females (Rosenblatt et al., 1996; Rosenblatt & Ceus, 1998). The neural basis of paternal motivation (or maternal motivation in males) is unstudied to date.

Sex Differences in Drug Abuse

Once sex differences in motivational circuits had evolved, we postulate that there were unforeseen consequences that resulted in many other motivations systems being sexually dimorphic as well. Nowhere is this so striking as in drug addiction. Sex differences emerge in all phases of the addiction process including initiation and prevalence of use, patterns and levels of use, the progression to addiction, withdrawal, and relapse. We focus our discussion here on cocaine use, but the same patterns of sex differences in addiction are present for all drugs of abuse (Lynch et al., 2002b; Carroll et al., 2004a).

Cocaine addiction is characterized by the transition from casual, recreational use, to habitual or compulsive, including binge patterns. Such changes are hypothesized to be in part due to changes in motivation to use the drug over time. Here we briefly review clinical and pre-clinical evidence for sex/gender differences in addiction, with an emphasis on psychostimulant addiction, and suggest that sex differences in motivation for drug taking, as well as other reinforcers may be due to evolutionary priorities that are the consequence of variations in hormonal status and/or sex-chromosome complement.

Sex Differences in Drug Abuse in Humans

Although the rates of drug abuse are currently lower in women, the number of women using and abusing licit and illicit drugs is on the rise. Adult men are 2 to 3 times more likely than women to have a drug abuse/ dependence disorder (SAMHSA, 1996), although some evidence suggests that the gender difference in prevalence of drug use may be due to differences in opportunity, rather than vulnerability to drug use (Van Etten & Anthony, 1999; Van Etten et al., 1999).

Cocaine abuse in particular has increased in the last decade among women so that of the 1.8 million Americans who use cocaine, approximately 30% are now female (Wetherington & Roman, 1995). According to a recent report, 9% of women age 12 and over have used cocaine. The only illicit drug used more by women is marijuana (28% have used marijuana) (Kandel et al., 1995). Among women who have used cocaine, prevalence of lifetime dependence for cocaine is 14.9±2.0% (mean ±S.D.). This is in contrast to alcohol where 79% have used alcohol, but only 9.2±0.8% have developed lifetime dependence (Kandel et al., 1995). The use of all illicit drugs has been increasing among women in the past decade, and stimulant drug use and dependence among women, in particular, is a growing public health concern (Wetherington & Roman, 1995; Lynch et al., 2002b; Carroll et al., 2004a). In particular, recent evidence suggests that women are more vulnerable to some aspects of cocaine abuse.

Women begin using cocaine and enter treatment at earlier ages than men (Griffin et al., 1989; Mendelson et al., 1991) and have more severe cocaine use at intake than men (Kosten et al., 1993). Thus, the progression to dependence may differ between men and women, with women progressing through the landmark stages from initial use to dependence at a faster rate (Kosten et al., 1985; Brady & Randall, 1999). This telescoping effect reflects a briefer time course for the development of medical consequences and behavioral/psychological factors characteristic of a dependence disorder. An increased vulnerability in women may also account for higher rates of relapse. Although cocaine-addicted women and men typically report similar levels of cocaine use (Evans et al., 1999), abstinent women report higher levels of craving following exposure to cocaine-related cues (Robbins et al., 1999a). Such differences may be due to sociocultural factors or to biological factors. If there are biological factors that impact the rate at which women become addicted, it could be that neural mechanisms that mediate the rapid formation of the mother-infant bond play a role in other types of associations and addiction in particular.

Repeated exposure to addictive drugs may cause sexually dimorphic neuroadaptive alterations in cortico-limbic-striatal circuits that contribute to alterations in motivational function that are critical for craving and relapse (Lynch et al., 2006). Consequently, sex differences in motivation may contribute (p.186) to, and be a consequence of, addiction. Specifically, neuroadaptations in motivational processes with increased control over behavior by drug-associated cues may be more evident in women than men, which likely contributes to aspects of compulsive drugseeking and drug-taking behavior. Furthermore, cocaine cues induce more drug craving in female than male addicts (Robbins et al., 1999b). Collectively, these results suggest that women may be more sensitive to the addictive properties of cocaine than men. However, this evidence is based primarily on retrospective reports, and relatively little is known about the neurobiological basis for sex differences in motivational processes in general.

Sex Differences in Animal Models of Drug Use

Basic research on the role of sex and ovarian hormones in the neurochemical and behavioral responses to acute and repeated exposure to drugs of abuse also finds sex differences. The acute behavioral response to psychomotor stimulants that rodents exhibit can reflect both sex differences and be modulated by gonadal hormones in males and females. Research on rodents and humans indicates that the behavioral effects of drugs of abuse, and the psychomotor stimulants in particular, are both sexually dimorphic and modulated by the gonadal steroid hormones (e.g., (Gordon, 1980; Hruska & Silbergeld, 1980; Becker & Ramirez, 1981; Di Paolo et al., 1981; Joyce et al., 1982; Dluzen & Ramirez, 1984; Becker & Beer, 1986; Di Paolo et al., 1986; Hruska, 1988; Van Hartesveldt et al., 1989; Dluzen & Ramirez, 1990; Bazzett et al., 2000; Lynch et al., 2002b; Sell et al., 2002; Carroll et al., 2004a).

With repeated exposure to psychomotor stimulants there is an increase in the psychomotor activating effects of the drug, known as behavioral sensitization. Behavioral sensitization can be different in males and females, and can be differentially affected by gonadal steroid hormones.

If one considers sensitization of amphetamine or cocaine-induced psychomotor behavior to be the absolute increase in the behavioral response exhibited when two tests are compared, females exhibit more robust sensitization than do intact males (Robinson et al., 1982; Robinson, 1984; Camp & Robinson, 1988b, a; van Haaren & Meyer, 1991b; Forgie & Stewart, 1994).

Following ovariectomy (OVX) of female rats the expression of sensitization to amphetamine is attenuated (Robinson et al., 1982; Robinson, 1984; Camp & Robinson, 1988b, a; Forgie and Stewart, 1994) or suppressed all together (van Haaren & Meyer, 1991b; Sircar & Kim, 1999).

Estradiol treatments in OVX rats enhance sensitization of locomotor activity induced by amphetamine or cocaine (Peris et al., 1991; Forgie & Stewart, 1994). These studies demonstrate that the neurobiological response to stimulant drugs is sexually dimorphic, but they do not address how this biological difference impacts sex differences in the motivation to take drugs.

Sex Differences in Stimulant Self-Administration in Animals

The animal model of human drug-taking behavior that has the most face validity is self-administration. In self-administration studies, animals are trained to bar press or nose poke in order to receive an i.v. infusion of a drug. The animal’s pattern of drug taking can be studied during acquisition, maintenance, and relapse. It is also possible to manipulate the schedule of reinforcement in order to determine motivation to take a drug.

Sex differences have been reported during all phases of the addiction process as assessed using various self-administration paradigms (see Lynch et al., 2002a; Carroll et al., 2004b; Roth et al., 2004). When a low dose of drug is used, female rats acquire cocaine self-administration at a faster rate (Lynch & Carroll, 1999; Carroll et al., 2002; Hu et al., 2004). Further, when responding for low doses of cocaine is assessed under a schedule in which the number of responses required in order to obtain a cocaine infusion progressively increases, female rats reach much higher final ratios than do males suggesting that females are more motivated to obtain cocaine (Roberts et al., 1989a).

Similar sex differences have been observed under reinstatement testing conditions designed to parallel relapse in humans (Lynch & Carroll, 2000; Roth & Carroll, 2004b, a; Kippin et al., 2005; but see, Fuchs et al., 2005). It should be noted that sex differences are most robust at lower doses of cocaine; and at higher doses, differences are less evident. This literature has been reviewed extensively, so the review here will be brief. The reader is referred to recent reviews for additional information.

(p.187) There has been a recent emphasis on developing animal cocaine self-administration procedures that model the transitional process from use/abuse to addiction (e.g., Ahmed & Koob, 1998; Tornatzky & Miczek, 2000; Roberts et al., 2002). Using a procedure similar to that developed by Roberts et al. (2002), female rats binge for a longer initial period of time, take more cocaine over a 7-day access period, and show a greater loss of diurnal control over cocaine intake than do males (Lynch & Taylor, 2004).

When the role of estradiol in binge-cocaine intake and subsequent motivational changes is examined, estradiol benzoate (EB) treatment increases the initial binge length and total levels of cocaine selfadministration (Lynch & Taylor, 2005). In the experiment under discussion, OVX female rats with and without EB replacement were compared under a 24-hr discrete trial cocaine self-administration procedure (4 trials/hr, 1.5 μg /kg/infusion) over a 7-day period.

Results revealed that following a 1-day abstinence period, motivation to obtain cocaine was decreased in OVX rats treated with vehicle, but not in OVX rats treated with EB. These results show that estradiol influences both cocaine self-administration under high access conditions and that there are subsequent motivational changes resulting from such access. An important question remains as to how genetic sex and/ or hormonal differences interact and whether differences in the biology of motivational function can explain sex differences that promote uncontrolled and dysregulated patterns of intake that are the hallmark of addiction.

Evidence from studies in both humans and animals indicate that ovarian hormones modulate selfadministration of stimulants and thus may influence sex differences during different phases of cocaine addiction. In humans, the subjective effects of stimulants vary across the menstrual cycle (Justice & de Wit, 1999, 2000; Justice & De Wit, 2000). For example, several of the positive subjective effects of damphetamine such as euphoria, desire, increased energy and intellectual efficiency are potentiated during the follicular phase—when estradiol levels are low, at first, and rise slowly; progesterone levels are low—relative to the luteal phase when estradiol levels are moderate and progesterone levels are high. Additionally, administration of estradiol during the follicular phase further increases the subjective effects of d-amphetamine (Justice & de Wit, 2000). In contrast, progesterone administered during the follicular phase has been reported to attenuate the subjective response to repeated self-administered cocaine (Sofuoglu et al., 2002).

Hormonal fluctuations in the rat estrous cycle likewise have been reported to influence behavioral responses to stimulants. Self-administration of cocaine varies as a function of estrous cycle phase (Roberts et al., 1989b). Female rats will also work harder for cocaine during the estrous phase of the cycle than during other phases of the cycle, and females work harder than male rats (Roberts et al., 1989b). The finding that the motivation to self-administer cocaine is greater during the estrous phase of the cycle may be related to the finding that stimulant-induced DA release is enhanced during estrus, relative to diestrus (Becker & Ramirez, 1980; Becker & Cha, 1989).

In contrast, sucrose self-administration does not vary across the estrous cycle (Hecht et al., 1999) suggesting that drug-taking behavior taps into a slightly different motivation circuit or that drugs of abuse are more effective at activating these neural circuits and so effects of the estrous cycle are observed.

Estradiol administration to OVX females affects many psychostimulant drug-induced behaviors, including self-administration (Verimer et al., 1981; Peris et al., 1991; Morissette & Di Paolo, 1993; Thompson & Moss, 1994; Grimm & See, 1997; Becker, 1999; Sircar & Kim, 1999; Quinones-Jenab et al., 2000; Freeman et al., 2001). For example, Hu et al. (2004) found that in OVX female rats, exogenous estradiol treatment alone was sufficient to facilitate acquisition of cocaine self-administration. Estradiolfacilitated cocaine self-administration has also been found in other studies (Roberts et al., 1989b; Freeman et al., 2001). Finally, acquisition of cocaine self-administration is markedly reduced by OVX and restored by estradiol replacement (Lynch et al., 2001).

In contrast to estradiol, the subjective effects of psychomotor stimulant drugs are negatively correlated with salivary progesterone levels in women (White, 2002). In rodents, progesterone inhibits cocaine-mediated behaviors, such as estradiol-enhanced locomotor activity and sensitization of cocaine-induced stereotyped behavior, compared to OVX females treated with estradiol. For example, Peris et al. (1991) reported that OVX female rats treated with estradiol had the greatest amount of striatal DA release following injections of amphetamine compared to OVX females treated with either progesterone alone or (p.188) progesterone plus estradiol. Recently, it was reported that concurrent administration of progesterone with estradiol counteracts the effect of estradiol on acquisition of cocaine self-administration behavior (Jackson et al., 2005).

Taken together, a wealth of data now indicate that ovarian hormones contribute to sex differences in cocaine self-administration and that estradiol in particular is a key factor influencing the reinforcing effects of cocaine in female rats. Over the course of the estrous cycle and menstrual cycle, there are peaks and valleys during which females are more or less susceptible to the reinforcing properties of cocaine. The effect of progesterone may be similar to the hormonal influences on maternal behavior, where withdrawal from progesterone is necessary for the rapid onset of maternal behavior at parturition.

Castration (CAST) of males has been reported to enhance sensitization of amphetamine- or cocaineinduced psychomotor behavior (e.g., Robinson, 1984; Camp & Robinson, 1988a, b), although this result has not been found consistently (van Haaren & Meyer, 1991b; Forgie & Stewart, 1994).

It has been hypothesized that if CAST enhances the induction and/or expression of behavioral sensitization, that testosterone treatment should reverse this effect. This is not the case, however, as testosterone treatment has not been found to affect behavioral sensitization in CAST males (Forgie & Stewart, 1994). Furthermore, there is no effect of CAST on acquisition of cocaine self-administration behavior and a dose of estradiol that enhances self-administration in female rats has no effect on cocaine self-administration behavior in male rats (Jackson et al., 2005). Thus, the effects of estradiol on the acquisition of cocaine self-administration are sexually dimorphic.

Chromosomal Mechanisms Underlying Sex Differences in Motivation

Although gonadal hormones regularly account for sex differences in a variety of behaviors (Arnold & Gorski, 1984), it is also possible that some sex differences may be accounted for by the complement of sex chromosomes (XX vs. XY) alone or in combination with gonadal hormone influences. Such potential contributions become most evident in cases where sexual phenotype appears to be insensitive to the effects of sex hormones during development or in cases where sex differences develop before the onset of sex-specific patterns of gonadal secretions (Arnold et al., 2003). Until recently, parsing the influences of gonadal hormones and sex chromosome complement was extremely difficult. However, mouse models are now available in which gonadal hormone status (ovaries vs. testes) is independent of sex chromosome complement (XX vs. XY; see Chapter 3).

Mice with a deletion of the testis-determining Sry gene from the Y chromosome develop ovaries even when the Y chromosome is present. Absence of the Sry gene in these mice (XY) as well as in normal females (XX) results in the development of ovaries and a gonadally female phenotype (Lovell-Badge & Robertson, 1990). These mice allow us to assess independently the influences of gonadal hormones and sex chromosome complement on the neurobiology of sex differences in both normal and pathological behavior (De Vries et al., 2002). There are no reports of sex differences in behaviors relevant to addiction where these two influences have been assessed independently. However, we have recently found that sex chromosome complement, independent of gonadal hormone status, influences the rate of habit formation (Quinn et al., 2006a).

Specifically, XX mice acquired a food-reinforced habit faster than XY mice, independent of gonadal hormone status. In addition, we have examined the well-documented sex difference in cocaine-induced locomotor sensitization, e.g., (van Haaren & Meyer, 1991a; Harrod et al., 2005) using a similar approach. We found that female mice show greater locomotor sensitization to cocaine compared to males, replicating the previous literature. Critically, this effect depended upon the gonadal hormone status rather than sex chromosome complement (Quinn et al., 2006b). Studies of other motivational processes, rather than food or drug motivated responding, using these mice would be of interest (Sanchez et al., 2006). Clearly sexual dimorphism in the development of habit formation could also have important implications for drug addiction (Everitt & Robbins, 2005).

Functional Roles of Cortico-LimbicStriatal Circuits

Cortical and limbic glutamatergic inputs to the ventral striatum (from prefrontal, hippocampal and amygdalar anterior cortices) cingulate, modulate NAcc function and its subsequent outputs to motor (p.189) circuits (O’Donnell & Grace, 1995; Moore et al., 1999; Haber et al., 2000). These limbic-striatal circuits are involved in emotional responsivity and motivational function that contribute to incentive learning. These effects are also critically dependent on DA and/or glutamatergic activity (Kelley, 2004). Specifically, the representation of the incentive value of stimuli and rewards, including drug-associated conditioned stimuli is mediated by the amygdala (Cador et al., 1989; Hiroi & White, 1991; Robbins & Everitt, 1996; Holland & Gallagher, 1999).

Lesions of the BLA impair the ability of conditioned stimuli to affect instrumental responding (Malkova et al., 1997; Balleine et al., 2003); and this area may thus be involved in establishing stimulusreward associations that contribute to reward-motivated behavior, and for the transfer of information about the current incentive value of conditioned stimuli to instrumental responding (Everitt et al., 1999; Robbins & Everitt, 1999; Everitt et al., 2001). Moreover, the central nucleus of the amygdala is connected with hypothalamic and brainstem regions involved in autonomic and consummatory responses to incentive stimuli and in the acquisition of stimulusreward associations (Parkinson et al., 2000; Cardinal et al., 2002).

By contrast, the NAcc DA innervation may mediate the behavioral impact of motivational state (Wyvell & Berridge, 2000, 2001) and conditioned reinforcers (Taylor & Robbins, 1984, 1986; Parkinson et al., 1999; Parkinson et al., 2000; Parkinson et al., 2001) on behavior. Indeed, the NAcc has been argued to mediate the influence of incentive information on reward-motivated behavior.

The prefrontal cortical (PFC) has been shown to play an important role in craving, reinstatement of drug-seeking and in higher-order processing of reward information/salience and drug cues in both humans and animals (London et al., 2000; Gottfried et al., 2003; Kalivas & McFarland, 2003; O’Doherty, 2004; Wilson et al., 2004). In combination with its welldescribed involvement in inhibitory control (Roberts & Wallis, 2000), the PFC is critical for decisionmaking and response-selection that is impaired in alcoholics and in drug addicts (Rogers et al., 1999; Bechara, 2003; Hildebrandt et al., 2006; Schoenbaum et al., 2006).

The nigrostriatal projection mediates a number of relevant functions such as processing of reward information, reward-related learning, goal-directed actions and the formation of habits (Gerdeman et al., 2003; Yin et al., 2004; Everitt & Robbins, 2005; Vanderschuren et al., 2005; Yin et al., 2005a; Yin et al., 2005b; Volkow et al., 2006; Yin et al., 2006).

Together, these regions appear to be part of a distributed network responsible for several levels of reward processing. Moreover, a number of studies have demonstrated adaptations in synaptic functions, intracellular signaling pathways and changes in dendritic morphology (Robinson & Kolb, 1999; Nestler, 2001) that may play a critical role in aberrant plasticity within these circuits (Berke & Hyman, 2000; Hyman & Malenka, 2001). Studies of sex differences and the regulation by estrogen within these circuits would provide critical information with regards aspects of motivational function associated with obesity and addiction that may differ between men and women.

Sex Differences in Amygdalostriatal Function

Sex differences in motivation may be the result of sexdifferences in reward-related learning mechanisms (and vice versa) that impact on various emotional and cognitive processes (Maren et al., 1994; Sandstrom et al., 1998; Wood & Shors, 1998; Frick & Gresack, 2003; Gresack & Frick, 2003, 2004; Jonasson, 2005; Gresack & Frick, 2006).

Of particular interest, studies in men and women have found that women exhibit greater recall of emotional memory and patterns of brain activation, most notably in the AMY; and that men and women are different, particularly, when processing both positive and negative emotional stimuli (Cahill et al., 2001; Canli et al., 2002; Klein et al., 2003; Wrase et al., 2003; Hamann & Canli, 2004; Hamann, 2005). This suggests that AMY-dependent emotional memory formation may occur via different (by degree) neural substrates in males and females, with the net result being enhanced memory strength in females at the time of retrieval.

Further evidence for enhanced responsiveness to positive emotional stimuli in females comes from research on reactivity to cues associated with drugs of abuse (see previous) where sexual dimorphism in reward-related learning may contribute to the sex differences. As noted, female cocaine users report higher levels of craving when exposed to drug-associated cues than males (Robbins et al., 1999a; Elman et al., 2001) (p.190) and female smokers are more sensitive to the hedonic and reinforcing properties of cigarette-associated cues (Perkins et al., 2001). Similarly, in preclinical studies nicotine self-administration is potentiated by cues to a greater extent in female than male rats (Chaudhri et al., 2005). Neuroimaging studies are beginning to confirm gender-specific correlates of motivation and craving in cocaine dependent individuals (Kilts et al., 2004; Tucker et al., 2004; Li et al., 2005b; Li et al., 2005a).

Pavlovian learning processes are thought to participate in the process by which drug-associated cues come to control motivated behavior (see Everitt et al., 2001), and thus such sexual dimorphisms in cue reactivity may reflect sex differences in amydalo-striatal circuits that contribute to affective learning and subsequent motivational processing of emotional stimuli. Additionally, exposure to drugs of abuse, including amphetamine, cocaine, or nicotine, in male rats prior to the initiation of training enhances stimulus-reward learning (Hitchcott et al., 1997; Harmer & Phillips, 1998; Taylor & Jentsch, 2001; Olausson et al., 2003, 2004; Wiseman et al., 2005). Further studies using both male and female subjects are needed to characterize the potential interaction between sex and prior drug experience in this type of learning, as well as the involvement of gonadal hormones, and in anxiety-associated emotional learning (Toufexis et al., 2006).

Recently, the Taylor laboratory has directly examined whether females show enhanced appetitive emotional learning relative to males, measured by acquisition of food-reinforced stimulus-reward learning (Wiseman et al., unpublished observation). The investigators found that females exhibited facilitated learning on Pavlovian approach tasks relative to males. Ovariectomy, prior to training, resulted in impaired learning relative to sham-operated females, suggesting a role for circulating ovarian hormones in mediating the observed sex difference. These data suggest sexually dimorphic reward-related learning, which may contribute not only to sex differences in psychiatric disorders such as addiction, but also to eating disorders.

Interestingly, no published studies have investigated sex differences in cue-elicited eating and/or binge eating in animal models (Hagan et al., 2002; Petrovich et al., 2002; Holland & Petrovich, 2005; Lee et al., 2005; Petrovich et al., 2005; Ghitza et al., 2006; Petrovich et al., 2006) though such models of-ten use female rats (Avena & Hoebel, 2003; Avena et al., 2005). Sex differences in food motivational processes are known to exist and clinical evidence suggests that eating disorders are far more prevalent in women. Parallels between food and drug “addictive” disorders (see for review Trinko et al., 2007) and the biological parallels with respect to sex differences should be a focus of research.

We hypothesize that such sex differences in motivational function are also likely mediated by parallel limbic-striatal circuits (Jentsch & Taylor, 1999; Jentsch et al., 2000; Jentsch et al., 2002; Jentsch & Taylor, 2003). Moreover, sex differences in AMY structure and function have been demonstrated in both rodent and human studies (Nishizuka & Arai, 1981, 1983; Arai et al., 1985) (Cooke et al., 1999; Hamann, 2005). Further experiments using local manipulations of the AMY are required to directly test whether this structure mediates the sex difference observed in aspects of reward-related learning, as well as to identify which AMY subnucli are involved. Given that females have greater oxytocin projections from the paraventricular nucleus to the NAcc shell and AMY than do males, it is possible that oxytocin and dopamine activation in the AMY and NAcc are involved in enhanced motivational function associated with stimulus-reward learning and/or emotional behavior, irrespective of whether the reward is food, drugs or formation of mother-infant bond.


From this brief discussion it should be clear that there are sex differences in motivation. The pathways that we have proposed to mediate these sex differences in motivation have been inferred from studies that have approached the question of the neural basis of motivation from behavior-specific perspectives, rather from the perspective of investigating sex differences in motivation. This means that there are significant gaps in our knowledge, due to the lack of empirical data that would be generated from a systematic approach to the topic. Thus, some of the apparent sex differences may be due to a lack of data in one of the sexes. This indicates the need for additional experimental data generated from testing specific hypotheses about the neural bases for sex differences in motivation.

Studies of the response to cocaine in gonadectomized male and female rats provide the strongest data regarding the neural evidence for sex differences in (p.191) motivation. These data indicate that there is an underlying sex difference due to sexually dimorphic development of the brain that, in part, mediates the sex difference in motivated behaviors.

                      Sex Differences in Motivation

Figure 10.5. Sex differences in motivational systems. On the left are the neural systems critical for motivated behaviors in the male rat. On the right are the neural systems important for motivated behaviors in the female rat. The primary differences between males and females are in the vasopressin and oxytocin systems. In the male rat the vasopressin projections from medial amygdala to preoptic area modulates motivation, while in the female the oxytocin projection from the PVN to the POA and blAMY is modulating motivated behaviors.

Studies from mice in which the testes-determining Sry gene is deleted from the Y chromosome and inserted in an autosome indicate that these sex differences in motivation may, at least in part, be genetic in origin. The precise relationship between sex differences in learning and differences in motivation remains to be determined. It is possible that these learning differences may be due secondarily to primary differences in the motivational impact of the rewards that are being learned about, and consequently result from the motivational differences.

We hypothesize that the presence of the neural circuits that mediate maternal motivation, and in particular the greater oxytocin projection to the NAcc in females, may play an important role in this sex difference. In addition, there are effects of gonadal hormones that modulate the reward system. In particular, estradiol enhances the rewarding value of drugs, while progesterone counteracts the effect of estradiol. Ultimately research on the neurobiological mechanisms of sex differences in motivation will aid in the treatment and understanding of motivationrelated pathologies for females and males.


The authors would like to thank Kent Berridge, Elaine Hull, Joseph Lonstein, and Robert Meisel for their helpful comments on an earlier version of this manuscript. We would also like to thank the USPHS for funding for research discussed in this chapter (NS48141 and DA12677 to JBB and DA15222, DA1171 and DA16556 to JRT) and the Society for Women’s Health Research Isis Research Fund.


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(1.) We recognize that there is a distinction between proximate vs. ultimate causes of behavior, with ultimate causes being those contingencies that govern a behavior; and the ultimate causes being the evolutionary constraints that have selected for animals that engage in the behavior—constraints that the animal is unaware of. In a similar fashion, we propose that there are also proximate vs. ultimate motivations to engage in a behavior, with the animal being aware of the proximate motivation of gaining access to the reward (i.e., the female rat), while being unaware of the ultimate motivation (in this case generation of many off spring).

(2.) It should be noted that the POA may also be involved, at least to some extent in sexual motivation, as lesions of the POA decrease partner preferences, pursuit of females, and other indirect measures of sexual motivation (reviewed in Hull et al, 2006).