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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

Chapter:
(p.177) Chapter 10 Sex Differences in Motivation
Source:
Sex Differences in the Brain
Author(s):

Jill B. Becker

Jane R. Taylor

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780195311587.003.0010

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.

Summary

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.

Acknowledgments

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.

References

Bibliography references:

Acheson A, Farrar AM, Patak M, Hausknecht KA, Kieres AK, Choi S, et al. (2006). Nucleus accumbens lesions decrease sensitivity to rapid changes in the delay to reinforcement. Behavioural Brain Research, 173:217–228.

Adler NT. (1969). Effects of the male’s copulatory behavior on successful pregnancy of the female rat. J Comp Physiol Psychol, 69:613–622.

Adler NT. (1974). The behavioral control of reproductive physiology. Adv Behav Biol, 11:259–286.

Adler NT. (1978). On the mechanisms of sexual behavior and their evolutionary constraints. In Biological De terminants of Sexual Behavior (Hutchison JB (Ed.), pp 657–694. New York: Wiley and Sons, Ltd.

Ahmed SH, Koob. GF (1998). Transition from moderate to excessive drug intake: change in hedonic set point. Science, 282:298–300.

Arai Y, Matsumoto A, Nishizuka M. (1985). Sexually dimorphic pattern in the hypothalamic and limbic brain. Int J Neurol, 19–20:133–143.

Arnold AP, Gorski RA. (1984). Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci, 7:413–442.

Arnold AP, Rissman EF, De Vries GJ. (2003). Two perspectives on the origin of sex differences in the brain. Ann N Y Acad Sci, 1007:176–188.

(p.192) Avena NM, Hoebel BG. (2003). A diet promoting sugar dependency causes behavioral cross-sensitization to a low dose of amphetamine. Neuroscience, 122:17–20.

Avena NM, Long KA, Hoebel BG. (2005). Sugardependent rats show enhanced responding for sugar after abstinence: evidence of a sugar deprivation effect. Physiol Behav, 84:359–362.

Balleine BW, Killcross AS, Dickinson A. (2003). The effect of lesions of the basolateral amygdala on instrumental conditioning. J Neurosci, 23:666–675.

Baum MJ. (2002). Neuroendocrinology of sexual behavior in the male. In Becker JB, Breedlove SM, Crews D, McCarthy MM, (Eds.). Behavioral Endocrinology, 2nd Edition (pp 153–203). Cambridge: The MIT Press.

Bazzett TJ, Albin RL, Becker JB. (2000). Malonic acid and the chronic administration model of excitotoxicity. Mitochondrial Inhibitors and Neurodegenera tive Disorders, 219–231.

Bechara A. (2003). Risky business: emotion, decision-making, and addiction. J Gambl Stud, 19:23–51.

Becker J, Ramirez VD. (1980). Dynamics of endogenous catecholamine release from brain fragments of male and female rats. Neuroendocrinology, 31:18–25.

Becker JB. (1999). Gender differences in dopaminergic function in striatum and nucleus accumbens. Phar macology Biochemistry and Behavior, 64:803–812.

Becker JB, Ramirez VD. (1981). Sex differences in the amphetamine stimulated release of catecholamines from rat striatal tissue in vitro. Brain Res, 204:361–372.

Becker JB, Beer ME. (1986). The influence of estrogen on nigrostriatal dopamine activity: behavioral and neurochemical evidence for both pre- and postsynaptic components. Behav Brain Res, 19:27–33.

Becker JB, Cha JH. (1989). Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis. Behav Brain Res, 35:117–125.

Becker JB, Rudick CN, Jenkins WJ. (2001). The role of dopamine in the nucleus accumbens and striatum during sexual behavior in the female rat. J Neuro- science, 21:3236–3241.

Berke JD, Hyman SE. (2000). Addiction, dopamine, and the molecular mechanisms of memory. Neuron, 25:515–532.

Bermant G. (1961). Response latencies of female rats during sexual intercourse. Science, 133:1771–1773.

Bermant G. (1967). Copulation in rats. Psychology Today, pp 52–60.

Bradley KC, Boulware MB, Jiang H, Doerge RW, Meisel RL, Mermelstein PM.(2005). Sexual experience generates distinct patterns of gene expression within the nucleus accumbens and dorsal striatum of female Syrian hamsters. Genes, BrainandBehavior, 4:31–44.

Brady KT, Randall CL. (1999). Gender differences in substance use disorders. Psychiatr Clin North Am, 22:241–252.

Bridges RS, Hay LE. (2005). Steroid-induced alterations in mRNA expression of the long form of the prolactin receptor in the medial preoptic area of female rats: effects of exposure to a pregnancy-like regimen of progeserone and estradiol. Molecular Brain Research, 140:10–16.

Brog JS, Salyapongse A, Deutch AY, Zahm DS. (1993). The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. J Comparative Neu rology, 338:255–278.

Brown AG, Leite RS, Strauss JF, III. (2004). Mechanisms underlying “functional” progesterone withdrawal at parturition. Annals of the New York Academy of Sciences, 1034:36–49.

Cador M, Robbins TW, Everitt BJ. (1989). Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum. Neurosciece, 30:77–86.

Cahill., (2006). Why sex matters for neuroscience. Nat Rev Neurosci, 7:477–484.

Cahill L, Haier RJ, White NS, Fallon J, Kilpatrick L, Lawrence C, et al. (2001). Sex-related difference in amygdala activity during emotionally influenced memory storage. Neurobiol Learn Mem, 75:1–9.

Camp DM, Robinson TE. (1988a). Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic D-amphetamine treatment on locomotion, stereotyped behavior and brain monoamines. Behav Brain Res, 30:55–68.

Camp DM, Robinson TE. (1988b). Susceptibility to sensitization. II. The influence of gonadal hormones on enduring changes in brain monoamines and behavior produced by the repeated administration of D-amphetamine or restraint stress. Behav Brain Res, 30:69–88.

Canli T, Desmond JE, Zhao Z, Gabrieli JD. (2002). Sex differences in the neural basis of emotional memories. Proc Natl Acad Sci U S A, 99:10789–10794.

Cardinal RN, Parkinson JA, Hall J, Everitt BJ. (2002). Emotion and motivation: the role of the amygdala, ventral striatum and prefrontal cortex. Neurosci Biobehav Rev, 26:321–352.

Carroll M, Lynch W, Roth M, Morgan A, Cosgrove K. (2004a). Sex and estrogen influence drug abuse. Trends in Pharmacological Sciences, 25:273–279.

Carroll ME, Morgan AD, Lynch WJ, Campbell UC, Dess NK. (2002). Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology, (Berl) 161:304–313.

Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP. (2004b). Sex and estrogen influence drug abuse. Trends Pharmacol Sci, 25:273–279.

Champagne F, Diorio J, Sharma S, Meaney M. (2001). Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogeninducible central oxytocin receptors. ProcNatlAcad Sci USA, 98:12736–12741.

(p.193) Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib MA, Craven LA, et al. (2005). Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats. Psy chopharmacology, (Berl) 180:258–266.

Chudasama Y, Robbins TW. (2003). Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex. J Neurosci, 23:8771–8780.

Cooke BM, Tabibnia G, Breedlove SM. (1999). A brain sexual dimorphism controlled by adult circulating androgens. Proc Natl Acad Sci USA, 96:7538–7540.

Craig W. (1918). Appetites and aversions as constituents of instincts. Biological Bulletin of Woods Hole, 34:91–107.

Damsma G, Pfaus JG, Wenkstern D, Phillips AG, Fibiger HC. (1992). Sexual behavior increases dopamine transmission in the nucleus accumbens and striatum of male rats: comparison with novelty and locomotion. Behavioral Neurosci, 106:181–191.

De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, Auger CJ, et al. (2002). A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neu rosci, 22:9005–9014.

Di Paolo T, Poyet P, Labrie F. (1981). Effect of chronic estradiol and haloperidol treatment on striatal dopamine receptors. Eur J Pharmacol, 73:105–106.

Di Paolo T, Levesque D, Daigle M. (1986). A physiological dose of progesterone affects rat striatum biogenic amine metabolism. Eur J Pharmacol, 125:11–16.

Dluzen DE, Ramirez VD. (1984). Bimodal effect of progesterone on in vitro dopamine function of the rat corpus striatum. Neuroendocrinol, 39:149–155.

Dluzen DE, Ramirez VD. (1990). In vitro progesterone modulation of amphetamine-stimulated dopamine release from the corpus striatum of ovariectomized estrogen-treated female rats: response characteristics. Brain Res, 517:117–122.

Elman I, Karlsgodt KH, Gastfriend DR. (2001). Gender differences in cocaine craving among non-treatment-seeking individuals with cocaine dependence. Am J Drug Alcohol Abuse, 27:193–202.

Erskine MS. (1989). Solicitation behavior in the estrous female rat: a review. Hormon Behav, 23:473–502.

Erskine MS. (1995). Prolactin release after mating and genitosensory stimulation in females. Endocr Rev, 16:508–528.

Erskine MS, Hanrahan SB. (1997). Effects of paced mating on c-fos gene expression in the female rat brain. J Neuroendocrinology, 9:903–912.

Erskine MS, Kornberg E, Cherry JA. (1989). Paced copulation in rats: effects of intromission frequency and duration on luteal activation and estrus length. Physiol Behav, 45:33–39.

Evans SM, Haney M, Fischman MW, Foltin RW. (1999). Limited sex differences in response to “binge” smoked cocaine use in humans. Neuropsychophar macology, 21:445–454.

Everitt BJ. (1990). Sexual motivation: a neural and behavioural analysis of the mechanisms underlying appetitive and copulatory responses of male rats. Neurosci Biobehav Rev, 14:217–232.

Everitt BJ, Stacey P. (1987). Studies of instrumental behaviour with sexual reinforcement in male rats (Rattus norvegicus): II Effects of preoptic area le sions, castration and testosterone. J Comparative Psychology, 101:407–419.

Everitt BJ, Robbins TW. (2005). Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci, 8:1481–1489.

Everitt BJ, Dickinson A, Robbins TW. (2001). The neuropsychological basis of addictive behaviour. Brain Res Brain Res Rev, 36:129–138.

Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW. (1999). Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems. Ann N Y Acad Sci, 877:412–438.

Ferguson J, Aldag J, Insel T, Young L. (2001). Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci, 21:8278–8285.

Fernandes MS, Pierron V, Michalovich D, Astle S, Thornton S, Peltoketo H, et al. (2005). Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinology, 187:89–101.

Flanagan LM, Pfaus JG, Pfaff DW, McEwen BS. (1993). Induction of FOS immunoreactivity in oxytocin neurons after sexual activity in female rats. Neu roendocrinology, 58:352–358.

Forgie ML, Stewart J. (1994). Sex difference in amphetamine-induced locomotor activity in adult rats: role of testosterone exposure in the neonatal period. Pharmacol, Biochem Behav, 46.

Freeman WM, Brebner K, Lynch WJ, Robertson DJ, Roberts DC, Vrana KE. (2001). Cocaine-responsive gene expression changes in rat hippocampus. J Neu rosci, 108:371–380.

Frick KM, Gresack JE. (2003). Sex differences in the behavioral response to spatial and object novelty in adult C57BL/6 mice. Behav Neurosci, 117:1283–1291.

Fuchs RA, Evans KA, Mehta RH, Case JM, See RE. (2005). Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaineseeking behavior in rats. Psychopharmacology (Berl), 179:662–672.

Garcia-Horsman P, Paredes RG. (2004). Dopamine antagonists do not block conditioned place preference induced by paced mating behavior in female rats. Behavioral Neuroscience, 118:356–364.

Gatewood JD, Wills A, Shetty S, Xu J, Arnold AP, Burgoyne PS, Rissman EF. (2006). Sex chromosome complement and gonadal sex influence aggressive and parental behaviors in mice. J Neuroscience, 26:2335–2342.

(p.194) Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM. (2003). It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci, 26:184–192.

Ghitza UE, Gray SM, Epstein DH, Rice KC, Shaham Y. (2006). The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF1 receptors. Neuropsychopharmacology, 31:2188–2196.

Gilman DP, Mercer LF, Hitt JC. (1979). Influence of female copulatory behavor on the induction of pseudopregnancy in the female rat. Physiol Behav, 22:675–678.

Gordon JH. (1980). Modulation of apomorphine-induced stereotypy by estrogen: time course and dose response. Brain Res Bull, 5:679–682.

Gottfried JA, O’Doherty J, Dolan RJ. (2003). Encoding predictive reward value in human amygdala and orbitofrontal cortex. Science, 301:1104–1107.

Gresack JE, Frick KM. (2003). Male mice exhibit better spatial working and reference memory than females in a water-escape radial arm maze task. Brain Res, 982:98–107.

Gresack JE, Frick KM. (2004). Environmental enrichment reduces the mnemonic and neural benefits of estrogen. Neuroscience, 128:459–471.

Gresack JE, Frick KM. (2006). Post-training estrogen enhances spatial and object memory consolidation in female mice. PharmacolBiochemBehav, 84:112–119.

Griffin ML, Weiss RD, Lange U. (1989). A comparison of male and female cocaine abuse. Arch Gen Psychia try, 46:122–126.

Grimm JW, See RE. (1997). Cocaine self-administration in ovariectomized rats is predicted by response to novelty, attenuated by 17-beta estradiol, and associated with abnormal vaginal cytology. Physiology & Behavior, 61:755–761.

Gubernick DJ, Sengelaub DR, Kurz EM. (1993). A neuroanatomical correlate of paternal and maternal behavior in the biparental California mouse (Peromyscus californicus). BehavioralNeuroscience, 107:194–201.

Haber SN, Fudge JL, McFarland NR. (2000). Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci, 20:2369–2382.

Hagan MM, Wauford PK, Chandler PC, Jarrett LA, Rybak RJ, Blackburn K. (2002). A new animal model of binge eating: key synergistic role of past caloric restriction and stress. Physiol Behav, 77:45–54.

Hamann S. (2005). Sex differences in the responses of the human amygdala. Neuroscientist, 11:288–293.

Hamann S, Canli T. (2004). Individual differences in emotion processing. Curr Opin Neurobiol, 14:233–238.

Harmer CJ, Phillips GD. (1998). Enhanced appetitive conditioning following repeated pretreatment with d-amphetamine. Behav Pharmacol, 9:299–308.

Harrod SB, Booze RM, Welch M, Browning CE, Mactutus CF. (2005). Acute and repeated intravenous cocaine-induced locomotor activity is altered as a function of sex and gonadectomy. Pharmacol Biochem Behav, 82:170–181.

Hauser H, Gandelman R. (1985). Lever pressing for pups: evidence for hormonal influence upon maternal behavior of mice. Horm Behav, 19:454–468.

Hecht GS, Spear NE, Spear LP. (1999). Changes in progressive ratio responding for intravenous cocaine throughout the reproductive process in female rats. Developmental Psychobiology, 35:136–145.

Hildebrandt H, Brokate B, Hoffmann E, Kroger B, Eling P. (2006). Conditional responding is impaired in chronic alcoholics. J Clin Exp Neuropsychol, 28:631–645.

Hiroi N, White NM. (1991). The lateral nucleus of the amygdala mediates expression of the amphetamineproduced conditioned place preference. JNeurosci, 11:2107–2116.

Hitchcott PK, Harmer CJ, Phillips GD. (1997). Enhanced acquisition of discriminative approach following intra-amygdala d-amphetamine. Psychopharmacology, (Berl) 132:237–246.

Holland PC, Gallagher M. (1999). Amygdala circuitry in attentional and representational processes. Trends Cognitive Science, 3:65–73.

Holland PC, Petrovich GD. (2005). A neural systems analysis of the potentiation of feeding by conditioned stimuli. Physiol Behav, 86:747–761.

Hruska RE. (1988). 17ßEstradiol regulation of DA receptor interactions with G-proteins. Soc Neurosci, Abstr 14:454.

Hruska RE, Silbergeld EK. (1980). Increased dopamine receptor sensitivity after estrogen treatment using the rat rotation model. Science, 208:1466–1468.

Hu M, Crombag HS, Robinson TE, Becker JB. (2004). Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology, 29:81–85.

Hyman SE, Malenka RC. (2001). Addiction and the brain: the neurobiology of compulsion and its persistence. Nature Reviews Neuroscience, 2:695–703.

Jackson LR, Robinson TE, Becker JB. (2005). Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology, 31(1):129–138.

Jenkins WJ, Becker JB. (2003a). Dynamic increases in dopamine during paced copulation in the female rat. European Journal of Neuroscience, 18:1997–2001.

Jenkins WJ, Becker JB. (2003b). Female rats develop conditioned place preferences for sex at their preferred interval. Hormones and Behavior, 43:503–507.

(p.195) Jentsch JD, Taylor JR. (1999). Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology, (Berl) 146:373–390.

Jentsch JD, Taylor JR. (2003). Sex-related differences in spatial divided attention and motor impulsivity in rats. Behav Neurosci, 117:76–83.

Jentsch JD, Roth RH, Taylor JR. (2000). Role for dopamine in the behavioral functions of the prefrontal corticostriatal system: implications for mental disorders and psychotropic drug action. Prog Brain Res, 126:433–453.

Jentsch JD, Olausson P, De La Garza R, II, Taylor JR. (2002). Impairments of reversal learning and response perseveration after repeated, intermittent cocaine administrations to monkeys. Neuropsychopharmacology, 26:183–190.

Jonasson Z. (2005). Meta-analysis of sex differences in rodent models of learning and memory: a review of behavioral and biological data. Neurosci Biobehav Rev, 28:811–825.

Joyce JN, Smith RL, Van Hartesveldt C. (1982). Estradiol suppresses then enhances intracaudate dopamineinduced contralateral deviation. Eur J Pharmacol, 81:117–122.

Justice AJ, de Wit H. (1999). Acute effects of damphetamine during the follicular and luteal phases of the menstrual cycle in women. Psychopharma cology, (Berl) 145:67–75.

Justice AJ, De Wit H. (2000). Acute effects of damphetamine during the early and late follicular phases of the menstrual cycle in women. Pharmacol Biochem Behav, 66:509–515.

Justice AJ, de Wit H. (2000). Acute effects of estradiol pretreatment on the response to d-amphetamine in women. Neuroendocrinology, 71:51–59.

Kalivas PW, McFarland K. (2003). Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology, (Berl) 168:44–56.

Kandel DB, Warner MPP, Kessler RC. (1995). The epidemiology of substance abuse and dependence among women. In Wetherington CL, Roman AR, (Eds.), Drug Addiction Research and the Health of Women (pp. 105–130). Rockville, MD: US Depart ment of Health and Human Services.

Karteris E, Zervou S, Pang Y, Dong J, Hillhouse EW, Randeva HS, Thomas P. (2006). Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Molecular Endocrinology, 20:1519–1534.

Kelley AE. (2004). Ventral striatal control of appetitive motivation: role in ingestive behavior and rewardrelated learning. Neurosci Bio behavRev, 27:765–776.

Kilts CD, Gross RE, Ely TD, Drexler KP. (2004). The neural correlates of cue-induced craving in cocaine-dependent women. Am J Psychiatry, 161:233–241.

Kippin TE, Fuchs RA, Mehta RH, Case JM, Parker MP, Bimonte-Nelson HA, See RE. (2005). Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus. Psychopharmacology, (Berl) 182:245–252.

Klein S, Smolka MN, Wrase J, Grusser SM, Mann K, Braus DF, Heinz A/ (2003)/ The influence of gender and emotional valence of visual cues on fMRI activation in humans. Pharmacopsychiatry, 36(Suppl 3):S191–S194.

Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ. (1993). Gender differeces in cocaine use and treatment response. J Subst Abuse Treat, 10:63–66.

Kosten TR, Rounsaville BJ, Kleber HD. (1985). Ethnic and gender differences among opiate addicts. Int J Addict, 20:1143–1162.

Lee A, Clancy S, Fleming AS. (2000). Mother rats barpress for pups: effects of lesions of the mpoa and limbic sites on maternal behavior and operant responding for pup-reinforcement. [republished from Behav Brain Res. 1999;100(1–2):15–31; PMID: 102 12050]. Behavioural Brain Research, 108:215–231.

Lee AW, Brown RE. (2002). Medial preoptic lesions disrupt parental behavior in both male and female California mice (Peromyscus californicus). Beha vioral Neuroscience, 116:968–975.

Lee HJ, Groshek F, Petrovich GD, Cantalini JP, Gallagher M, Holland PC. (2005). Role of amygdalo-nigral circuitry in conditioning of a visual stimulus paired with food. J Neurosci, 25:3881–3888.

Li CS, Kosten TR, Sinha R. (2005a). Sex differences in brain activation during stress imagery in abstinent cocaine users: a functional magnetic resonance imaging study. Biol Psychiatry, 57:487–494.

Li CS, Kemp K, Milivojevic V, Sinha R. (2005b). Neuroimaging study of sex differences in the neuropathology of cocaine abuse. Gend Med, 2:174–182.

Li M, Fleming AS. (2003). Differential involvement of nucleus accumbens shell and core subregions in maternal memory in postpartum female rats. Beha vioral Neuroscience, 117:426–445.

London ED, Ernst M, Grant S, Bonson K, Weinstein A. (2000). Orbitofrontal cortex and human drug abuse: functional imaging. Cereb Cortex, 10:334–342.

Lonstein JS, Morrell JI. (2006). Neuroendocrinology and neurochemistry of maternal motivation and behavior. In Blaustein JD, (Ed.), Behavioral Neurobiology (Stress, Memory, Agggression, Endocrine Inuences) 3rd Edition, in press. New York, NY.

Lonstein JS, Morrell JI. (2007). Neuroendocrinologya nd neurochemistry of maternal motivation and behavior. In Blaustein JA, (Ed.) Behavioral Neurochemistry and Neuroendocrinology, 3rd Edition, (p 954). Berlin: Springer-Verlag.

Lonstein JS, Simmons DA, Swann JM, Stern JM. (1998). Forebrain expression of c-fos due to active maternal behaviour in lactating rats. Neuroscience, 82:267–281.

Lonstein JS, Greco B, De Vries G, Stern JM, Blaustein JD. (2000). Maternal behavior stimulates c-fos activity within estrogen receptor alpha-containing neurons in lactating rats. Neuroendocrinology, 72:91–101.

Lonstein JS, Dominguez JM, Putnam SK, De Vries GJ, Hull EM. (2003). Intracellular preoptic and striatal monoamines in pregnant and lactating rats: possible role in maternal behavior. Brain Research, 970:149–158.

(p.196) Lovell-Badge R, Robertson E. (1990). XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy. Development, 109:635–646.

Lynch WJ, Carroll ME. (1999). Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology, (Berl) 144:77–82.

Lynch WJ, Carroll ME. (2000). Reinstatement of cocaine self-administration in rats: sex differences. Psychopharmacology, (Berl) 148:196–200.

Lynch WJ, Taylor JR (2004) Sex differences in the behavioral effects of 24-h/day access to cocaine under a discrete trial procedure. Neuropsychopharmacology 29:943–951.

Lynch WJ, Taylor JR. (2005). Decreased motivation following cocaine self-administration under extended access conditions: effects of sex and ovarian hormones. Neuropsychopharmacology, 30:927–935.

Lynch WJ, Roth ME, Carroll ME. (2002a). Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology, (Berl) 164:121–137.

Lynch WJ, Roth ME, Carroll ME. (2002b). Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology, 164:121–137.

Lynch WJ, Roth ME, Mickelberg JL, Carroll ME. (2001). Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats. Pharmacol Biochem Behav, 68:641–646.

Lynch WJ, Kiraly DD, Caldarone BJ, Picciotto MR, Taylor JR. (2006). Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats. Psychopharmacology (Berl), 191(2): 263–271.

Malkova L, Gaffan D, Murray E. (1997). Excitotoxic lesions of the amygdala fail to produce impairment in visual learning for auditory secondary reinforcement but interfere with reinforcer devaluation effects in rhesus monkeys. J Neuroscience, 17:6011–6020.

Maren S, De Oca B, Fanselow MS. (1994). Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. Brain Res, 661:25–34.

Martinez I, Paredes RG. (2001). Only self-paced mating is rewarding in rats of both sexes. Hormones and Behavior, 40:510–517.

Mattson BJ, Morrell JI. (2005). Preference for cocaineversus pup-associated cues differentially activates neurons expressing either Fos or cocaine- and amphetamine-regulated transcript in lactating, maternal rodents. Neuroscience, 135:315–328.

Mattson BJ, Williams SE, Rosenblatt JS, Morrell JI. (2003). Preferences for cocaine- or pup-associated chambers differentiates otherwise behaviorally identical postpartum maternal rats. Psychopharmacology, 167:1–8.

McCarthy MM, Becker JB. (2002). Neuroendocrinology of sexual behavior in the female. In Becker JB, Breedlove SM, Crews D, McCarthy MM, (Eds.) Behavioral Endocrinology, 2nd Edition, (pp 117–151). Cambridge, MA: MIT Press/Bradford Books.

McClintock MK. (1984). Group mating in the domestic rat as context for sexual selection: consequences for the analysis of sexual behavior and neuroendocrine responses. Adv Study of Behav, 14:1–50.

McClintock MK, Adler NT. (1977). The role of the female during copulation in wild and domestic Norway rats. Behaviour, LXVII:67–96.

Meisel RL, Mullins AJ. (2006). Sexual experience in female rodents: cellular mechanisms and functional consequences. Brain Research, 1126:56–65.

Meisel RL, Camp DM, Robinson TE. (1993). A microdialysis study of ventral striatal dopamine during sexual behaivor in female Syrian hamsters. Behav Brain Res, 55:151–157.

Meisel RL, Joppa MA, Rowe RK. (1996). Dopamine receptor antagonists attenuate conditioned place preference following sexual behavior in female Syrian hamsters. Eur J Pharmacol, 309:21–24.

Mendelson JH, Weiss R, Griffin M, Mirin SM, Teoh SK, Mello NK, Lex BW. (1991). Some special considerations for treatment of drug abuse and dependence in women. NIDA Res Monogr, 106:313–327.

Mermelstein PG, Becker JB. (1995). Increased extracellular dopamine in the nucleus accumbens and striatum of the female rat during paced copulatory behavior. Behavioral Neuroscience, 109:354–365.

Moore H, West AR, Grace AA. (1999). The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry, 46:40–55.

Morissette M, Di Paolo T. (1993). Effect of chronic estradiol and progesterone treatments of ovariectomized rats on brain dopamine uptake sites. J Neurochem, 60:1876–1883.

Nestler EJ. (2001). Molecular neurobiology of addiction. Am J Addict, 10:201–217.

Nishimori K, Young L, Guo Q, Wang Z, Insel T, Matzuk M. (1996). Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci U S A, 93:11699–11704.

Nishizuka M, Arai Y. (1981). Sexual dimorphism in synaptic organization in the amygdala and its dependence on neonatal hormone environment. Brain Res, 212:31–38.

Nishizuka M, Arai Y. (1983). Male-female differences in the intra-amygdaloid input to the medial amygdala. Exp Brain Res, 52:328–332.

O’Doherty JP. (2004). Reward representations and reward-related learning in the human brain: insights from neuroimaging. Curr Opin Neurobiol, 14:769–776.

(p.197) O’Donnell P, Grace AA. (1995). Synaptic interactions among excitatory affects to nucleus accumbens neurons: hippocampal gating of prefrontal cortical inputs. J Neurosci, 15:3622–3639.

Olausson P, Jentsch JD, Taylor JR. (2003). Repeated nicotine exposure enhances reward-related learning in the rat. Neuropsychopharmacology, 28:1264–1271.

Olausson P, Jentsch JD, Taylor JR. (2004). Nicotine enhances responding with conditioned reinforcement. Psychopharmacology, (Berl) 171:173–178.

Oldenberger WP, Everitt BJ, De Jonge FH. (1992). Conditioned Place Preference Induced by Sexual Interaction in Female Rats. Hormones and Behavior, 26:214–228.

Paredes RG, Alonso A. (1997). Sexual behavior regulated (paced) by the female induces conditioned place preference. Behavioral Neuroscience, 111:123–128.

Paredes RG, Vazquez B. (1999). What do female rats like about sex? Paced mating. Behavioural Brain Research, 105:117–127.

Paredes RG, Martinez I. (2001). Naloxone blocks place preference conditioning after paced mating in female rats. Behavioral Neuroscience, 115:1363–1367.

Parkinson JA, Robbins TW, Everitt BJ. (2000). Dissociable roles of the central and basolateral amygdala in appetitive emotional learning. Eur J Neurosci, 12:405–413.

Parkinson JA, Olmstead MC, Burns LH, Robbins TW, Everitt BJ. (1999). Dissociation of effects of lesions of nucleus accumbens core and shell in appetitive Pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. J Neurosci, 16:2401–2411.

Parkinson JA, Crofts HS, McGuigan M, Tomic DL, Everitt BJ, Roberts AC. (2001). The role of the primate amygdala in conditioned reinforcement. J Neurosci, 21:7770–7780.

Pecina S, Smith KS, Berridge KC. (2006). Hedonic hot spots in the brain. Neuroscientist, 12:500–511.

Pedersen C, Vadlamudi S, Boccia ML, Amico J. (2006). Maternal behavior deficits in nulliparous oxytocin knockout mice. Genes Brain Behav, 5:274–281.

Peris J, Decambre N, Coleman-Hardee M, Simpkins J. (1991). Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated [3H]dopamine release. Brain Res, 566:255–264.

Perkins KA, Gerlach D, Vender J, Grobe J, Meeker J, Hutchison S. (2001). Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine Tob Res, 3:141–150.

Petrovich GD, Holland PC, Gallagher M. (2005). Amygdalar and prefrontal pathways to the lateral hypothalamus are activated by a learned cue that stimulates eating. J Neurosci, 25:8295–8302.

Petrovich GD, Setlow B, Holland PC, Gallagher M. (2002). Amygdalo-hypothalamic circuit allows learned cues to override satiety and promote eating. J Neurosci, 22:8748–8753.

Petrovich GD, Ross CA, Gallagher M, Holland PC. (2006). Learned contextual cue potentiates eating in rats. Physiol Behav, 28;90(2–3):362–367.

Pfaus JG, Phillips AG. (1991). Role of dopamine in anticipatory and consummatory aspects of sexual behavior in the male rat. Behavioral Neurosci, 105:727–743.

Pfaus JG, Damsma G, Wenkstern D, Fibiger HC. (1995). Sexual activity increases dopamine transmission in the nucleus accumbens and striatum of female rats. Brain Res, 693:21–30.

Pfaus JG, Damsma G, Nomikos GG, Wenkstern DG, Blaha CD, Phillips AG, et al. (1990). Sexual behavior enhances central dopamine transmission in the male rat. Brain Res, 530:345–348.

Pleim ET, Matochik JA, Barfield RJ, Auerbach SB. (1990). Correlation of dopamine release in the nucleus accumbens with masculine sexual behavior in rats. Brain Res, 524:160–163.

Polston EK, Heitz M, Barnes W, Cardamone K, Erskine MS. (2001). NMDA-mediated activation of the medial amygdala initiates a downstream neuroendocrine memory responsible for pseudopregnancy in the female rat. J Neuroscience, 21:4104–4110.

Quinn JJ, Hitchcott PK, Umeda EA, Arnold AP, Taylor JR. (in press). Sex chromosome complement regulates habit formation. Nature Neuroscience.

Quinn JJ, Hitchcott PK, Pesquera FR, Arnold AP, Taylor JR. (2006). Sex differences in habit formation and sensitization to cocaine: Independent contributions of chromosomal sex and gonadal sex. Third Annual Interdisciplinary Women’s Health Research Symposium, National Institutes of Health.

Quinones-Jenab V, Perrotti LI, Mc Monagle J, Ho A, Kreek MJ. (2000). Ovarian hormone replacement affects cocaine-induced behaviors in ovariectomized female rats. Pharmacology Biochemistry and Behavior, 67:417–422.

Robbins SJ, Ehrman RN, Childress AR, O’Brien CP. (1999a). Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend, 53:223–230.

Robbins SJ, Ehrman RN, Childress AR, O’Brien CP. (1999b). Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend, 53:223–230.

Robbins TW, Everitt BJ. (1996). Neurobehavioural mechanisms of reward and motivation. Curr Opin Neurobiol, 6:228–236.

Robbins TW, Everitt BJ. (1999). Drug addiction: bad habits add up. Nature, 398:567–570.

Roberts AC, Wallis JD. (2000). Inhibitory control and affective processing in the prefrontal cortex: neuropsychological studies in the common marmoset. Cereb Cortex, 10:252–262.

Roberts DC, Bennett SA, Vickers GJ. (1989a). The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology, (Berl) 98:408–411.

(p.198) Roberts DC, Brebner K, Vincler M, Lynch WJ. (2002). Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure. Drug Alcohol Depend, 67:291–299.

Roberts DCS, Bennett SAL, Vickers GJ. (1989b). The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology, 98:408–411.

Robinson TE. (1984). Behavioral sensitization: characterization of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats. Psychopharmacology, (Berlin) 84:466–475.

Robinson TE, Kolb B. (1999). Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur J Neurosci, 11:1598–1604.

Robinson TE, Becker JB, Presty SK. (1982). Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences. Brain Res, 253:231–241.

Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, et al. (1999). Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophandepleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology, 20:322–339.

Rosenblatt JS. (1992). Hormone-behavior relations in the regulation of maternal behavior. In Becker JB, Breedlove SM, Crews D, (Eds.), Behavioral Endocrinology, 1st Edition (pp 219–259). Cambridge, MA: MIT Press/Bradford Books.

Rosenblatt JS, Ceus K. (1998). Estrogen implants in the medial preoptic area stimulate maternal behavior in male rats. Hormones and Behavior, 33:23–30.

Rosenblatt JS, Hazelwood S, Poole J. (1996). Maternal behavior in male rats: effects of medial preoptic area lesions and presence of maternal aggression. Hormones and Behavior, 30:201–215.

Roth ME, Carroll ME. (2004a). Sex differences in the acquisition of IV methamphetamine selfadministration and subsequent maintenance under a progressive ratio schedule in rats. Psychopharmacology, (Berl) 172:443–449.

Roth ME, Carroll ME. (2004b). Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav, 78:199–207.

Roth ME, Cosgrove KP, Carroll ME. (2004). Sex differences in the vulnerability to drug abuse: a review of preclinical studies. Neurosci Biobehav Rev, 28:533–546.

Saddoris MP, Gallagher M, Schoenbaum G. (2005). Rapid associative encoding in basolateral amygdala depends on connections with orbitofrontal cortex. Neuron, 46:321–331.

Sanchez H, Quinn JJ, Taylor JR. (2006). Sex differences in contextual fear conditioning: A role for dorsal hippocampus 17-estradiol. Society for Neuroscience, Online.

Sandstrom NJ, Kaufman J, Huettel SA (1998). Males and females use different distal cues in a virtual environment navigation task. Brain Res Cogn Brain Res, 6:351–360.

Schoenbaum G, Chiba AA, Gallagher M. (2000). Changes in functional connectivity in orbitofrontal cortex and basolateral amygdala during learning and reversal training. J Neuroscience, 20:5179–5189.

Schoenbaum G, Roesch MR, Stalnaker TA. (2006). Orbitofrontal cortex, decision-making and drug addiction. Trends Neurosci, 29:116–124.

Sell SL, Thomas ML, Cunningham KA. (2002). Influence of estrous cycle and estradiol on behavioral sensitization to cocaine in female rats. Drug Alcohol Depend, 67:281–290.

Sheehan PM. (2006). A possible role for progesterone metabolites in human parturition. Australian and New Zealand Journal of Obstetrics and Gynaecology, 46:159–163.

Sircar R, Kim D. (1999). Female gonadal hormones differentially modulate cocaine-induced behavioral sensitization in Fischer, Lewis and Sprague-Dawley rats. J Pharmacol, 289(1):54–65.

Sofuoglu M, Babb DA, Hatsukami DK. (2002). Effects of progesterone treatment on smoked cocaine response in women. Pharmacol Biochem Behav, 72:431–435.

Taylor JR, Robbins TW. (1984). Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens. Psychopharmacology, (Berl) 84:405–412.

Taylor JR, Robbins TW. (1986). 6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine. Psychopharmacology, (Berl) 90:390–397.

Taylor JR, Jentsch JD. (2001). Repeated intermittent administration of psychomotor stimulant drugs alters the acquisition of Pavlovian approach behavior in rats: differential effects of cocaine, d-amphetamine and 3, 4- methylenedioxymethamphetamine (“Ecstasy”). Biol Psychiatry, 50:137–143.

Thompson TL, Moss RL. (1994). Estrogen regulation of dopamine release in the nucleus accumbens: genomic- and nongenomic-mediated effects. J Neurochem, 62:1750–1756.

Tornatzky W, Miczek KA. (2000). Cocaine self-administration “binges”: transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology, (Berl) 148:289–298.

Toufexis DJ, Myers KM, Davis M. (2006). The effect of gonadal hormones and gender on anxiety and emotional learning. Horm Behav, 50:539–549.

(p.199) Trinko R, Sears RM, Guarnieri DJ, DiLeone RJ. (2007). Neural mechanisms underlying obesity and addiction. Physiol Behav, In press Jan 16; [Epub ahead of print].

Tucker KA, Browndyke JN, Gottschalk PC, Cofrancesco AT, Kosten TR. (2004). Gender-specific vulnerability for rCBF abnormalities among cocaine abusers. Neuroreport, 15:797–801.

Van Etten ML, Anthony JC. (1999). Comparative epidemiology of initial drug opportunities and transitions to first use: marijuana, cocaine, hallucinogens and heroin. Drug Alcohol Depend, 54:117–125.

Van Etten ML, Neumark YD, Anthony JC. (1999). Male-female differences in the earliest stages of drug involvement. Addiction, 94:1413–1419.

van Haaren F, Meyer ME. (1991a). Sex differences in locomotor activity after acute and chronic cocaine administration. Pharmacol Biochem Behav, 39:923–927.

van Haaren F, Meyer M. (1991b). Sex differences in the locomotor activity after acute and chronic cocaine administration. Pharmacol Biochem Behav, 39:923–927.

Van Hartesveldt C, Cottrell GA, Meyer ME. (1989). Effects of intrastriatal hormones on the dorsal immobility response in male rats. Pharmacol Biochem Behav, 35:307–310.

Vanderschuren LJ, Di Ciano P, Everitt BJ. (2005). Involvement of the dorsal striatum in cue-controlled cocaine seeking. J Neurosci, 25:8665–8670.

Verimer T, Arneric SP, Long JP, Walsh BJ, Abou Zeit-Har MS. (1981). Effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior in rats. Psychopharmacol, 75:273–276.

Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, et al. (2006). Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci, 26:6583–6588.

Wang Z. (1994). Testosterone effects on development of vasopressin messenger RNA expression in the bed nucleus of the stria terminalis and medial amygdaloid nucleus in male rats. Brain Res Dev Brain Res, 79:147–150.

Wang Z, Ferris CF, De Vries GJ. (1994a). Role of septal vasopressin innervation in paternal behavior in prairie voles (Microtus ochrogaster). Proc Natl Acad Sci USA, 91:400–404.

Wang Z, Smith W, Major DE, De Vries GJ. (1994b). Sex and species differences in the effects of cohabitation on vasopressin messenger RNA expression in the bed nucleus of the stria terminalis in prairie voles (Microtus ochrogaster) and meadow voles (Microtus pennsylvanicus). Brain Res, 650:212–218.

Wetherington CL, Roman AR, (Eds.) (1995) Drug Addiction Research and the Health of Women. Rockville, MD: US Department of Health and Human Services.

White FJ. (2002). A behavioral/systems approach to the neuroscience of drug addiction. J Neuroscience, 22:3303–3305.

Wilson SJ, Sayette MA, Fiez JA. (2004). Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci, 7:211–214.

Wiseman SL, Lynch WJ, Olausson P, Taylor JR. (2005). Sex differences in reward-related learning after repeated nicotine exposure during adolescence. Society for Neuroscience, Online Abstract Viewer/ Itinerary Planner. Washington, DC.

Wood GE, Shors TJ. (1998). Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones. Proc Natl Acad Sci U S A, 95:4066–4071.

Wood W, Eagly AH. (2002). A cross-cultural analysis of the behavior of women and men: implications for the origins of sex differences. Psychological Bulletin, 128:699–727.

Wrase J, Klein S, Gruesser SM, Hermann D, Flor H, Mann K, Braus DF, Heinz A. (2003). Gender differences in the processing of standardized emotional visual stimuli in humans: a functional magnetic resonance imaging study. Neurosci Lett, 348:41–45.

Wright C, Beijer A, Groenewegen HJ. (1996). Basal amygdaloid complex afferent to the rat nucleus accumbens are compartmentally organized. J Neurosci, 16:1877–1893.

Wyvell CL, Berridge KC. (2000). Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward “wanting” without enhanced “liking” or response reinforcement. J Neurosci, 20:8122–8130.

Wyvell CL, Berridge KC. (2001). Incentive sensitization by previous amphetamine exposure: increased cuetriggered “wanting” for sucrose reward. J Neurosci, 21:7831–7840.

Yin HH, Knowlton BJ, Balleine BW. (2004). Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur J Neurosci, 19:181–189.

Yin HH, Knowlton BJ, Balleine BW. (2005a). Blockade of NMDA receptors in the dorsomedial striatum prevents action-outcome learning in instrumental conditioning. Eur J Neurosci, 22:505–512.

Yin HH, Knowlton BJ, Balleine BW. (2006). Inactivation of dorsolateral striatum enhances sensitivity to changes in the action-outcome contingency in instrumental conditioning. Behav Brain Res, 166:189–196.

Yin HH, Ostlund SB, Knowlton BJ, Balleine BW. (2005b). The role of the dorsomedial striatum in instrumental conditioning. Eur J Neurosci, 22:513–523. (p.200)

Notes:

(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).