Jill B. Becker

Gender differences in dopaminergic function in striatum and nucleus accumbens

In female rats the gonadal hormones estrogen and progesterone modulate dopamine (DA) activity in the striatum and nucleus accumbens. For example, there is estrous cycle-dependent variation in basal extracellular concentration of striatal DA, in amphetamine (AMPH)-stimulated DA release, and in striatal DA-mediated behaviors. Ovariectomy attenuates basal extracellular DA, AMPH-induced striatal DA release, and behaviors mediated by the striatal DA system. Estrogen rapidly and directly acts on the striatum and accumbens, via a G-protein-coupled external membrane receptor, to enhance DA release and DA-mediated behaviors. In male rats, estrogen does not affect striatal DA release, and removal of testicular hormones is without effect. These effects of estrogen also result in gender differences in sensitization to psychomotor stimulants. The effects of the gonadal hormones on the striatum and ascending DA systems projecting to the striatum and nucleus accumbens are hypothesized to occur as follows: estrogen induces a rapid change in neuronal excitability by acting on membrane receptors located in intrinsic striatal GABAergic neurons and on DA terminals. The effect of these two actions results in enhanced stimulated DA release through modulation of terminal excitability. These effects of gonadal hormones are postulated to have important implications for gender differences in susceptibility to addiction to the psychomotor stimulants. It is suggested that hormonal modulation of the striatum may have evolved to facilitate reproductive success in female rats by enhancing pacing behavior.

Sex differences in drug abuse.

Sex differences are present for all of the phases of drug abuse (initiation, escalation of use, addiction, and relapse following abstinence). While there are some differences among specific classes of abused drugs, the general pattern of sex differences is the same for all drugs of abuse. Females begin regularly self-administering licit and illicit drugs of abuse at lower doses than do males, use escalates more rapidly to addiction, and females are at greater risk for relapse following abstinence. In this review, sex differences in drug abuse are discussed for humans and in animal models. The possible neuroendocrine mechanisms mediating these sex differences are discussed.

Are adolescents the victims of raging hormones : evidence for activational effects of hormones on moods and behavior at adolescence

The literatures on hormone changes at adolescence, hormonal influences on moods and behavior in nonhuman animals and adult humans, and mood and behavioral changes at adolescence and the small but burgeoning literature on hormonal influences at adolescence are examined. The focus is on moods and behaviors often identified as typically adolescent (e.g., mood lability, mood intensity, irritability, conflict with parents) and the primary hormones of puberty (i.e., the adrenal androgens, gonadotropins, and sex steroids). Through an integration of these literatures evidence is assessed for specific hormone-mood and hormone-behavior associations, as well as for more general types of hormone-outcome relations that transcend specific hormones or outcomes. Non-biological factors that appear to be important in moderating the role of hormones in adolescent moods and behavior are identified. Implications for the design of future studies in this area are detailed.

Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding

The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone leptin modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system.

Long-Term Facilitation of Amphetamine-Induced Rotational Behavior and Striatal Dopamine Release Produced by a Single Exposure to Amphetamine" Sex Differences

Amphetamine (AMPH)-induced rotational behavior in non-lesioned rats and AMPH-stimulated dopamine (DA) release from striatal tissue fragments in vitro were used to study the long-term effects of a single injection of AMPH on activity in the mesostriatal DA system. A single injection of a low dose of AMPH (1.25 mg/kg) greatly enhanced the rotational behavior produced by a second injection of AMPH given 3-4 weeks later in intact female, ovariectomized female and castrated male rats. The effect of AMPH pretreatment in intact males differed from that in the other groups. When only 7-8 days separated the two test sessions both intact male and female rats showed sensitization of rotational behavior, but the magnitude of the change was greater in females. In addition, a single injection of 1.25 mg/kg of AMPH in vivo produced a long-lasting (3-5 weeks) enhancement of AMPH-stimulated DA release from striatal tissue in vitro. It is suggested that: (1) repeated injections of AMPH are not necessary to produce a long-lasting facilitation of behaviors mediated by the mesostriatal DA system; (2) gender and/or hormonal state influences the development of long-term changes in the mesostriatal DA system; and (3) changes in DA release from presynaptic terminals may contribute to the behavioral sensitization produced by stimulant drugs. The phenomena reported here may provide complementary in vitro and in vivo models for studying neuroplasticity in brain DA systems.

Sex difference and estrous cycle variations in amphetamine-elicited rotational behavior

The experiments reported here were designed to determine if there are sex- and/or estrus cycle-dependent differences in amphetamine (AMPH)-elicited rotational behavior in unlesioned rats. Whole brain or striatal levels of AMPH produced by systemic administration of the drug were also measured. At all doses tested (1.0-10.0 mg/kg) systemic administration of AMPH resulted in significantly higher brain levels of AMPH in females than in males. A systemic dose was then calculated which produced equivalent brain levels of AMPH in males and females. Even with equivalent brain levels of AMPH, males produced significantly fewer net rotations than females in estrus, diestrus 2, or proestrus. In female rats the brain levels of AMPH produced by systemic administration did not vary with the estrous cycle. However, the amount of AMPH-elicited rotational behavior did. On the day of estrus, female produced significantly more net rotations than they did 24 h later, on the day of diestrus 1. It is suggested that sex and estrous cycle dependent differences in rotational behavior may be due to the direct or indirect modulation of mesostriatal dopamine activity by gonadal steroid hormone.

Biological Basis of Sex Differences in the Propensity to Self-administer Cocaine

Women are at greater risk for cocaine addiction than are men, and female rats similarly show a greater propensity to self-administer cocaine than do male rats. This could be due to the intrinsic sex differences in brain organization, to the activational effects of circulating gonadal hormones, or both. For example, estradiol enhances dopamine release in the striatum and nucleus accumbens, and facilitates the behavioral sensitization induced by repeated cocaine exposure. We report here that independent of circulating gonadal hormones, female rats acquire cocaine self-administration behavior more rapidly, and they self-administer more cocaine at a faster rate than do male rats. This indicates that there is an intrinsic difference between male and female subjects in the neural systems mediating drug-seeking behavior due to sexual differentiation of the brain. Furthermore, we find that the administration of estradiol to gonadectomized female subjects greatly facilitates the acquisition of cocaine self-administration. These data demonstrate that both intrinsic sex differences in brain organization and the actions of circulating estradiol contribute to increased vulnerability for cocaine use in female subjects.

Behavioral sensitization is accompanied by an enhancement in amphetamine-stimulated dopamine release from striatal tissue in vitro

The repeated administration of amphetamine (AMPH) produces a long-lasting facilitation in the behavioral responsiveness to subsequent AMPH injections. This sensitization has been demonstrated using different behavioral indices (e.g. ste-reotypy, locomotion, rotational behavior), and in many different species (Kokkinidis and Anisman, 1980). Since sensitization in non-human animals is considered a model of AMPH psychosis in humans , knowledge of the neural changes underlying sensitization may provide an insight into the neu-ral basis of AMPH psychosis (Kokkinidis and Anisman, 1980; Segal and Janowsky, 1978). Unfortunately , the neural substrate of sensitization has remained elusive (e.g., Conway and Uretsky, 1982). However, in a recent study we found that a single injection of AMPH produced a long-lasting (1 month) enhancement in AMPH-induced rota-tional behavior, and in AMPH-stimulated DA release from striatal tissue in vitro (Robinson et al., 1982). Therefore, we hypothesized that the behav-ioral sensitization produced by repeated AMPH injections would also be accompanied by an enhancement of striatal DA release. Male Hottzman rats were injected i.p. with either 5 mg/kg of d-AMPH sulfate (n= 18) or saline (n = 18) twice daily for 5 consecutive days. Drug injections were then discontinued for 10 days. On the eleventh day after the last AMPH injection 10 of the AMPH and 10 of the saline pretreated rats were placed in wire hanging cages. After a 30 rain habituation period they were injected with 3.0 mg/kg of AMPH and the occurrence of stereotyped behaviors was recorded every 5 min for 90 rain. using the same stereotypy rating scale as Conway and Uretsky (1982). Conway and Uretsky (1982) showed this paradigm produces behavioral sensitization. We replicated their results. The AMPH-pretreated rats had a significantly higher cumulative stereotypy score (42.7_+ 2.8 S.E.M.) than did saline pretreated rats (22.3 + 2.1; U = 3, P < 0.001). The remaining animals, plus 6 additional naive rats were used for measuring endogenous DA release in vitro. After decapitation the striatum was dissected out and placed in a perifusion chamber positioned in a constant temperature bath (37°C). A medium (modified Krebs phosphate buffer) flowed through the chamber at a rate of 100 ~l/min. After a 45 min equilibration period samples of the effluent were collected at 5 rain intervals , and these effluent samples assayed for DA. See Becker and Ramirez (1981) and Robinson et al. (1982) for a detailed description of the techniques. Normal medium was infused through the chamber for the …

Sex Differences and Hormonal Influences on Acquisition of Cocaine Self-Administration in Rats

Men and women differ in their response to cocaine, and a womans response varies with the menstrual cycle. For example, women have greater subjective responses to cocaine in the follicular phase of the menstrual cycle when estradiol is predominant, than they do during the luteal phase when both estradiol and progesterone are elevated. Similarly, female rats show significantly more cocaine-induced locomotor behavior and cocaine self-administration during behavioral estrus, shortly after estradiol peaks, than during other stages of the cycle, and estradiol administration to ovariectomized (OVX) females enhances the acquisition of cocaine self-administration. The purpose of this study was to expand upon these findings by studying the effects of progesterone administration to females, and estradiol administration to males, on acquisition of cocaine self-administration. We report here that there are both sex differences in and effects of circulating ovarian hormones on acquisition of cocaine self-administration. We demonstrate that although estradiol administration enhances acquisition of cocaine self-administration in OVX female rats, concurrent administration of progesterone with estradiol inhibits this effect of estradiol. In a separate experiment, we demonstrate that estradiol administration does not enhance acquisition of cocaine self-administration in castrated male rats. We conclude that (1) there is a sex difference in the effects of estradiol on cocaine self-administration: it facilitates acquisition in female, but not male rats; and that (2) in females concurrent progesterone treatment counteracts the facilitory effect of estradiol on cocaine self-administration.

Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance

Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRb(Nts) neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRb(Nts) neurons with local orexin (OX) neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRb(Nts) neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance.