Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens

Introduction  Alterations in protein kinase (PKA) protein levels have been implicated in the regulation of responses to and development of cocaine addiction. However, the contribution of differences in PKA intracellular cascade to the known sex differences in responses to cocaine is not well understood. This study examined whether there are intrinsic or cocaine-induced alterations in PKA-mediated responses, such as phosphorylation of cyclic AMP response element binding protein, in male and female rats. Materials and methods  To this end, protein levels of PKA and phosphorylated CREB (pCREB) in the caudate putamen (CPu) and nucleus accumbens (NAc) of male and female rats were measured basally or after acute (one 30-mg/kg intraperitoneal injection) or chronic (twice-daily 15-mg/kg injections for 14 days) cocaine administration. Behavioral responses to both cocaine administration paradigms were also studied. Results  Similar to previous findings, ambulatory, rearing, and stereotypic activities were higher in female rats after acute cocaine administration. Sex differences in cocaine-induced responses were also observed after chronic cocaine administration: While males developed a robust sensitization in ambulatory activities to cocaine, females developed tolerance in cocaine-induced rearing and stereotypic activities. In the basal group, females had significantly higher PKA protein levels in the NAc. Regardless of the cocaine administration paradigm, PKA protein levels in the NAc were higher overall in females than in males. Furthermore, after cocaine administration, while pCREB protein levels in male rats were induced for a longer amount of time than in female rats, the magnitude of change on pCREB levels were higher in female than male rats. However, in the CPu, no sex differences in PKA or pCREB protein levels were observed either in the basal group or after acute or chronic cocaine administration. Discussion  Taken together, these findings suggest that sex differences in basal and cocaine-induced alterations in the PKA signaling regulation in the NAc may contribute to sex differences in the psychomotor responses to cocaine.     

Differential neurochemical and behavioral adaptation to cocaine after response contingent and noncontingent exposure in the rat

Rationale In naive rats, passive administration of drugs of abuse preferentially increases extracellular dopamine (DA) in the nucleus accumbens (NAc) shell as compared to the core. Repeated exposure to the same drugs results in behavioral and biochemical sensitization characterized by stereotyped activity and reduction of the shell/core DA response ratio. Objectives The aim of this work is to study the neurochemical and behavioral effects of response-contingent vs response-noncontingent drug administration in rats, who were bilaterally implanted with chronic intracerebral guide cannulae and trained to self-administer cocaine by nose poking in daily 1-h sessions for 3 weeks (5 days/week). Nose poking in the active hole by master rats resulted in intravenous injection of cocaine (0.25 mg/kg) in master rats and in rats yoked to them. Dialysate DA was monitored before, during, and for 30 min after cocaine availability on alternate days by inserting the probe into the NAc shell and core. Stereotyped and non-stereotyped behavior was recorded during the sessions. Results In master rats, dialysate DA increased preferentially in the NAc shell during cocaine self-administration throughout the 3 weeks of cocaine exposure. In yoked rats, DA increased preferentially in the shell but to a lesser extent than in master rats. With continued exposure to cocaine, the shell/core ratio of DA changes decreased progressively and, on the third week, was reversed so that DA increased more in the core than in the shell. Yoked rats showed a progressive and faster increase in stereotyped behaviors than master rats. Conclusions Response-noncontingent cocaine administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.     

Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor activity and dopamine release in the nucleus accumbens

The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may be related in part to the ability of 5-HT to modulate the function of the dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male Sprague-Dawley rats. Systemic administration of either fluoxetine or fluvoxamine enhanced cocaine-induced locomotor activity in a dose-dependent manner; fluoxetine (10 mg/kg, IP) also enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. To test the hypothesis that the NAc serves as the locus of action underlying these effects following systemic cocaine administration, fluoxetine (1 and 3 micro g/0.2 micro l/side) or fluvoxamine (1 and 3 micro g/0.2 micro l/side) was microinfused into the NAc shell prior to systemic administration of cocaine (10 mg/kg, IP). Intra-NAc shell infusion of 3 micro g of fluoxetine or fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux in the NAc is mediated in part by local actions of the SSRIs in the NAc.     

Progesterone and allopregnanolone are induced by cocaine in serum and brain tissues of male and female rats

Acute and chronic-cocaine administration increase serum levels of progesterone in both male and female rats. This study aimed to determine whether progesterone and its bioactive metabolite allopregnanolone (ALLOP) are altered in the hippocampus and striatum (areas known to modulate cocaine-induced behavioral response) after acute cocaine administration. To this end, male and female rats were administered 20 mg/kg and 5 mg/kg of cocaine, respectively (doses that produce equivalent behavioral responses between the sexes). Thirty minutes after drug treatment, serum and brain were collected and later analyzed for progesterone and ALLOP levels using HPLC measurements. At these cocaine doses, no sex differences in the overall behavioral responses after drug treatment were observed. In saline-treated controls, female rats had overall higher levels of progesterone in the serum than did male rats. After cocaine administration, progesterone and ALLOP levels in serum, hippocampus, and striatum were increased at similar levels in both sexes. In the hippocampus, progesterone levels were increased in both males and females, but ALLOP levels were increased only in females.     

Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system

RATIONALE: Toluene is a solvent found in many commercial products and is frequently abused by inhalation. Whether previous exposure to toluene alters subsequent responses to other drugs of abuse is not known. OBJECTIVES: This study determined the effects of repeated toluene exposure on the acute motor-stimulant response to cocaine and on cocaine-induced dopamine (DA) concentrations in the nucleus accumbens (NAc). METHODS: One week following bilateral cannulae implantation over the NAc, 27 adult, male Wistar rats began a daily 30-min exposure regimen to either toluene (8,000 ppm) or air for ten sessions. Approximately 24 h or 96 h after their last exposure, animals were injected with either saline or cocaine (15 mg/kg, i.p.) and locomotor activity and DA concentrations in the NAc were measured. RESULTS: Exposure to toluene rendered the rats immobile, and the time required for recovery of normal posture decreased across the ten sessions. In all animals tested, systemic cocaine administration enhanced both locomotor activity and DA concentrations in the NAc. These increases, however, were significantly greater in rats previously exposed to toluene. CONCLUSIONS: Overall, these findings show that repeated toluene exposure enhances behavioral and neurochemical responses to subsequent cocaine administration.     

Effects of prenatal and postnatal exposure to amitraz on norepinephrine, serotonin and dopamine levels in brain regions of male and female rats

The effects of maternal exposure to amitraz on brain region monoamine levels of male and female offspring rats at 60 days of age were observed. Maternal and offspring body weight, physical and general activity development were unaffected by the exposure of dams to amitraz (20mg/kgbw, orally on days 6-21 of pregnancy and 1-10 of lactation). Male and female offspring were sacrificed at 60 days of age and possible alterations in the content and metabolism of NE, DA and 5-HT were determined in brain regions by HPLC. The results showed that all these neurotransmitter systems were altered in a brain regional-related manner. In male and female offspring, amitraz induced a significant decrease in the prefrontal cortex 5-HT and its metabolite 5-HIAA and DA and its metabolites DOPAC and HVA levels with interaction of sex. Nevertheless, we verified that striatum DA and 5-HT and corresponding metabolite contents decreased in male and female offspring without statistical distinction of sex. In contrast, amitraz did not modify 5-HT content, but caused an increase in 5-HIAA content in the medulla oblongata and hippocampus in male and female offspring. Alterations in the hippocampus DA, DOPAC and HVA levels after amitraz exposure were also observed displaying a sex interaction. NE levels also showed a decrease after amitraz treatment in the prefrontal cortex and striatum without statistical sex interaction, but MHPG levels decreased in both regions with a sex interaction. Amitraz evoked increases in 5-HT turnover in the prefrontal cortex as well as in DA turnover in the striatum and hippocampus but decreases in NE turnover in the hypothalamus, prefrontal cortex and striatum. The present findings indicated that maternal exposure to amitraz altered noradrenergic, serotonergic and dopaminergic neurochemistry in their offspring in the prefrontal cortex, striatum and hippocampus, and those variations could be related to several alterations in the functions in which these brain regions are involved.     

Behavioral sensitization to quinpirole is not associated with increased nucleus accumbens dopamine overflow

This study assessed the relationship between extracellular nucleus accumbens (NAc) dopamine (DA) concentrations and sensitized locomotor activation following repeated administration of the DA D2-like receptor agonist quinpirole. Locomotor activity measures and nucleus accumbens microdialysis samples were collected concurrently in response to the first (acute) and tenth (repeated) quinpirole injection (0.5 mg/kg s.c., every other day). Results indicate that acute quinpirole produced locomotor activation and that repeated quinpirole resulted in locomotor sensitization. Acute quinpirole significantly decreased the detection of extracellular concentrations of DA and the DA metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAc. Following repeated quinpirole, basal NAc DA levels were decreased, whereas basal DOPAC levels were increased. Nevertheless, quinpirole challenge elicited a significant decrease in DA, DOPAC and HVA following repeated treatment. In addition, although acute quinpirole did not affect NAc levels of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA), quinpirole challenge produced a significant increase in 5-HIAA levels following repeated treatment. Taken together, these data indicate that functional DA autoreceptor subsensitivity is not a necessary condition for the expression of behavioral sensitization to quinpirole. Instead, it appears that behavioral sensitization to quinpirole occurs predominantly as a consequence of neuroadaptations that are post-synaptic to DA release.     

Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats

Rationale

Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activity, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-h “binge” in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected.

Objective

This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited-access self-administration “binge.”

Methods

Long-Evans rats underwent episodic social defeat and were assessed 10 days later for either (1) behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, i.p.), (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3) intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited-access “binge.”

Results

Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer “binge” in both sexes, females had a significantly longer “binge” duration than males.

Conclusions

These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization.     

Implication of the nucleus accumbens shell, but not core, in the acute and sensitizing effects of cocaine in rats

Expression of cocaine-evoked motor behaviors appears to be dependent on dopamine neurotransmission particularly in the target area of the mesolimbic system, i.e. the nucleus accumbens (NAc). To test potential anatomical component of the locomotor effects of cocaine and expression of its behavioral sensitization, male Wistar rats were implanted with bilateral cannulae aimed at the two subregions of the NAc (the shell or the core) and then intracranially injected with cocaine (locomotor activity) or injected with cocaine given either systemically or intracranially following the repeated (5 days) systemic drug administration (sensitization). Sensitization was measured at early (5-day) and late (21-day) withdrawal periods. Acute administration of intra-NAc shell cocaine (6.73-50 microg/side) in a dose-dependent manner increased locomotor activity in rats; significant hyperactivation was observed after 25 and 50 microg/side of cocaine. Intra-NAc core injection of cocaine (12.5-50 microg/side) did not change rats' locomotor activity. After 5- or 21-day withdrawal, behavioral sensitization (ca. 2 times higher locomotor activity than that after acute drug administration) was observed when cocaine was injected either systemically (10 mg/kg) or intra-NAc shell (12.5-25 microg/side) in animals repeatedly treated with cocaine (10 mg/kg). No difference was observed in the response to the challenge with intra-NAc core cocaine (12.5-25 micorg/side) in rats treated repeatedly with cocaine at either withdrawal period. The above findings show the differential regulation of motor responses to cocaine within the subregions of the NAc. They also indicate a preferential effect for the NAc shell in expression of the acute and sensitizing effects of cocaine in rats.     

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.     

Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine.

Stimulation of central serotonin2C receptor (5-HT(2C)R) inhibits dopamine (DA)-dependent neurochemical and behavioral effects of cocaine, while 5-HT(2C)Rs locally expressed into the ventral tegmental area (VTA) and the nucleus accumbens (NAc) exert opposite functional control over cocaine-induced behavioral effects. Using in vivo microdialysis in halothane-anesthetized rats, we tested the hypothesis that this functionally opposite regulation of the mesoaccumbens DA pathway relies on the ability of 5-HT(2C)Rs in the VTA and the NAc to inhibit and enhance respectively cocaine-induced accumbal DA outflow. Intra-VTA injection of the 5-HT(2C)R agonist Ro 60-0175 at 5 microg/0.2 microl, but not 1 microg/0.2 microl, attenuated the increase in accumbal DA outflow induced by the systemic administration of 10 mg/kg of cocaine. Intra-VTA injection of the 5-HT(2C)R antagonist SB 242084 at either dose (0.1 or 0.5 microg/0.2 microl) did not modify the effects of cocaine. Intra-NAc application of Ro 60-0175 dose-dependently excited (0.1 microM) and inhibited (1 microM) cocaine-induced DA outflow. In contrast, intra-NAc application of SB 242084 resulted in diametrically opposite effects when applied at these concentrations. These results further support the idea that the overall action of central 5-HT(2C)Rs on accumbal DA output is dependent, at least in part, on the functional balance between different 5-HT(2C)R populations within the NAc and within the mesoaccumbens DA pathway (VTA vs NAc).     

Individual differences in cocaine-induced locomotor activity in rats: behavioral characteristics, cocaine pharmacokinetics, and the dopamine transporter.

Outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor response to acute cocaine. Concomitant measurement of dopamine clearance in these rats revealed that the differential behavioral responses are associated with the magnitude of dopamine transporter (DAT) inhibition by cocaine. Here, we investigated several factors that might contribute to cocaine-induced behavioral variability and its association with differential inhibition of DAT function. In rats classified as LCRs or HCRs after 10 mg/kg cocaine injection, we found no differences in (1) novelty-induced locomotion, (2) cocaine levels in dorsal striatum or nucleus accumbens (NAc), (3) DAT number or affinity in NAc, or (4) DAT affinity for cocaine in NAc. In rats given 20 mg/kg cocaine, behavior was more uniform across individuals, but still warranted separation into LCR/HCR categories. Additionally, we analyzed the stability of the LCR/HCR classification made during the first test with 10 or 20 mg/kg cocaine by retesting rats 7 days later with saline or cocaine (10 or 20 mg/kg). Before injection, HCRs were more active relative to LCRs and to their own behavior on the first test day. Following cocaine, LCRs and HCRs exhibited similar drug-induced changes in locomotion, but there were unique effects that depended on the cocaine dose given on the first and second test days. Our results argue against several likely explanations for individual differences in cocaine-induced behavior and highlight the influence of a single cocaine exposure on subsequent behavioral responses to the drug.     

Iptkalim inhibits cocaine challenge—induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up—regulating Kir6.1 and Kir6.2 mRNA expression

目的:研究钾通道开放剂埃他卡林对急慢性可卡因应用引起的伏隔核、纹状体和额叶皮层的多巴胺和谷氨酸水平变化的影响及其机制。方法:采用高效液相色谱与电化学检测、荧光检测联用的方法测定各脑区谷氨酸和多巴胺的含量;采用半定量逆转录聚合酶链反应(RT-PCR)研究ATP敏感性钾通道亚单位Kir6.1、Kir6.2、SUR1和SUR2 mRNA表达的变化。结果:埃他卡林不影响急性可卡因应用引起纹状体和伏隔核中多巴胺和谷氨酸水平的增高(P>0.05),能够逆转激发剂量可卡因诱导的慢性成瘾大鼠纹状体和伏隔核的多巴胺含量增高(P<0.05),对激发后皮层和伏隔核谷氨酸水平增高有降低趋势但差异无显著性(P>0.05)。激发剂量可卡因能提高可卡因预处理组和埃他卡林预处理组纹状体和伏隔核的Kir6.1和Kir6.2 mRNA表达以及皮层的Kir6.2 mRNA表达,而且IPT预处理组的升高幅度显著高显著高于可卡因慢性处 理组。结论:埃他卡林通过上调Kir6.1和Kir6.2 mRNA表达抑制可卡因激发引起的纹状体和伏隔核的多巴胺水平的增高。     

Sensitivity to cocaine conditioned reward depends on sex and age

Human and animal laboratory studies show that females and males respond differently to drugs and that drug administration during adolescence leads to different behavioral effects than during adulthood. Adult female rats are more sensitive to the behavioral effects of cocaine than adult males, but it is not known if the same effect of sex exists during adolescence. In the present study, sensitivity to the conditioned reward of cocaine was evaluated using a conditioned place preference (CPP) paradigm where adolescent (PND 34) and adult (PND 66) male and female rats were trained and tested for the development of CPP to multiple doses of cocaine. Female rats developed CPP at lower doses than males, regardless of age. In addition, adolescent male and female rats established a CPP at lower doses of cocaine than adult male and female rats, respectively. Thus, both age and sex altered cocaine conditioned reward with the order of sensitivity being adolescent females > adult females > adolescent males > adult males. These data show that adolescents are more sensitive to the conditioned rewarding properties of cocaine than adults and that females respond to lower doses of cocaine compared to males regardless of age.     

Subregion-specific down-regulation of 5-HT3 immunoreactivity in the nucleus accumbens shell during the induction of cocaine sensitization

Repeated exposure to psychostimulants such as cocaine and amphetamine can result in behavioral sensitization, which is believed to model the onset of drug addiction, as well as neural adaptations that occur after repeated drug abuse that lead to addictive behaviors. Dopamine (DA) in the nucleus accumbens (NAc) has been shown to play an integral role in this phenomenon. However, cocaine also acts on the serotonin (5-HT) system, which has been shown to modulate psychostimulant-induced increases in motor behavior and DA release in the NAc. Recently, it has been demonstrated that the shell portion of the NAc can no longer be considered a homogeneous structure and can be subdivided into at least five separate regions. The present study examines 5-HT(3) receptors in the subdivisions of the NAc in cocaine-sensitized rats. Rats received a sensitization-inducing regimen of cocaine (twice-daily injections of 15 mg/kg ip for five consecutive days). Two or 14 days following the last injection, rats were given a challenge injection of cocaine (15 mg/kg ip) and sacrificed 2 h later. Sections of the NAc were processed for 5-HT(3) immunoreactivity (5-HT(3)-IR), and the number of puncta was quantified in each of the subregions of the shell, as well as the core of the accumbens. Repeated cocaine administration resulted in robust sensitization that correlated with a transient decrease in the density of 5-HT(3) immunoreactive puncta in the intermediate zone of the accumbens shell. After a 2-week withdrawal period, sensitized animals no longer showed any differences in any of the areas examined. These data suggest a possible role for 5-HT(3) receptors in the intermediate zone during the induction of cocaine sensitization.     

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain.

1. The effects of single-dose regimens of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine (DA) release and metabolism were evaluated in the frontal cortex, hypothalamus, nucleus accumbens and striatum. The regimens selected are known to produce substantial behavioural effects. 2. 3-Methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used to assess DA metabolism by catechol-O-methyltransferase and monoamine oxidase respectively. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3. The effects of amphetamine on 3MT production and DOPAC steady-state levels were similar in all regions, suggesting similar pharmacodynamic actions. Amphetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced only in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine-induced increase in DA release occurred at the expense of intraneuronal DA metabolism and did not require stimulation of synthesis. 4. Nomifensine elevated 3MT formation in all regions. A similar effect was produced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3MT production only in the hypothalamus, the striatum and the nucleus accumbens. 5. Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC formation in striatum and hypothalamus. GBR 12909 elevated DOPAC formation in all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Progesterone inhibits behavioral responses and estrogen increases corticosterone levels after acute cocaine administration

Accumulating evidence suggests that estrogen and progesterone contribute to the sexually dimorphic behavioral response to cocaine. In this study, we tested the hypothesis that varying the level of estrogen or progesterone affects cocaine-induced locomotive behavior in female rats. Ovariectomized (OVX) rats received estrogen (0, 5, 10, 20, or 50 μg) 48 h or progesterone (0, 50, 100, 250, or 500 μg) 24 h before acute saline or cocaine (15 mg/kg) administration. Although estrogen did not affect cocaine-induced ambulatory and rearing behaviors, it affected stereotypic behaviors regardless of cocaine administration (animals receiving 50 μg had higher stereotypic counts than did the OVX group). In contrast, progesterone affected rearing activity dose-dependently: 50 and 500 μg of progesterone inhibited, whereas 100 μg and 250 μg stimulated, rearing in response to cocaine. That estrogen and progesterone did not affect overall baseline behavioral activity suggests their effects are mediated in part through interactions with cocaine. Progesterone administration did not affect corticosterone levels in saline- or cocaine-treated rats. Estrogen administration, however, affected levels of corticosterone both at baseline and after cocaine treatment. After accounting for baseline differences, we found that rats receiving 5 or 10 μg of estrogen and cocaine had higher percentage increases in serum corticosterone levels than did the control group that did not receive estrogen. On the basis of these observations, we suggest that progesterone fluctuations during the estrous cycle impact cocaine-induced behavioral responses, whereas estrogen may affect activity in the hypothalamic–pituitary–adrenal axis. Thus, dose-dependent effects of gonadal hormones may underlie some of the reported sex differences and reproductive cycle effects of cocaine.     

Sex differences and effects of cocaine on excitatory synapses in the nucleus accumbens

Human and animal studies indicate that drugs of abuse affect males and females differently, but the mechanism(s) underlying sex differences are unknown. The nucleus accumbens (NAc) is central in the neural circuitry of addiction and medium spiny neurons (MSNs) in the NAc show drug-induced changes in morphology and physiology including increased dendritic spine density. We previously showed in drug-na?ve rats that MSN dendritic spine density is higher in females than males. In this study, we investigated sex differences in the effects of cocaine on locomotor activity as well as MSN dendritic spine density and excitatory synaptic physiology in rats treated for 5 weeks followed by 17-21 days of abstinence. Females showed a greater locomotor response to cocaine and more robust behavioral sensitization than males. Spine density was also higher in females and, particularly in the core of the NAc, the magnitude of the cocaine-induced increase in spine density was greater in females. Interestingly, in cocaine-treated females but not males, cocaine-induced behavioral activation during treatment was correlated with spine density measured after treatment. Miniature EPSC (mEPSC) frequency in core MSNs also was higher in females, and increased with cocaine in both the core and shell of females more than males. We found no differences in mEPSC amplitude or paired-pulse ratio of evoked EPSCs, suggesting that sex differences and cocaine effects on mEPSC frequency reflect differences in excitatory synapse number per neuron rather than presynaptic release probability. These studies are the first to demonstrate structural and electrophysiological differences between males and females that may drive sex differences in addictive behavior.     

Sex differences and hormonal influences on acquisition of cocaine self-administration in rats.

Men and women differ in their response to cocaine, and a woman's 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.     

Estrous cyclicity and behavioral sensitization in female rats following repeated intravenous cocaine administration.

Repeated intermittent administration of cocaine is well known to produce behavioral sensitization in male animals. The present studies explored whether intact adult female rats maintained normal estrous patterns in response to repeated IV cocaine administration and whether behavioral sensitization occurred with this route of administration. Adult female Sprague-Dawley rats (N = 48) were surgically implanted with an intravenous access port. Animals received 3.0 mg/kg IV cocaine once/day for 14 days. Daily vaginal lavages indicated that female rats continued to cycle normally throughout the experiment. Estimates of statistical power for detecting alterations in estrous cycle length ranged from 0.61-0.95 for small (0.1) to large (0.4) effect sizes. Moreover, no cocaine-treated animals displayed persistent vaginal estrus or were acyclic and cocaine treatment did not decrease body weight. Immediately after the cocaine injection, animals were placed in IR photocell activity chambers for 60 min. Female rats displayed a significant 75% increase in locomotor activity across the 14-day time course of IV cocaine injections. These data indicate that 3.0 mg/kg of IV cocaine does not interfere with normal estrous cyclicity, and that behavioral sensitization occurs in female rats following repeated daily IV cocaine dosing. Collectively, these data suggest that the IV cocaine-dosing model may be particularly useful in exploring the gender-dependent effects of cocaine using intact female rats.