Sex Differences in Dopamine Release in Nucleus Accumbens and Dorsal Striatum Determined by Chronic Fast Scan Cyclic Voltammetry: Effects of social housing and repeated stimulation.

We investigated sex differences in dopamine (DA) release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) using a chronic 16-channel carbon fiber electrode and fast-scan cyclic voltammetry (FSCV). Electrical stimulation (ES; 60Hz) induced DA release was recorded in the NAc of single or pair-housed male and female rats. When core (NAcC) and shell (NAcS) were recorded simultaneously, there was greater ES DA release in NAcC of pair-housed females compared with single females and males. Housing did not affect ES NAc DA release in males. In contrast, there was significantly more ES DA release from the DLS of female rats than male rats. This was true prior to and after treatment with methamphetamine. Furthermore, in castrated (CAST) males and ovariectomized (OVX) females, there were no sex differences in ES DA release from the DLS, demonstrating the hormone dependence of this sex difference. However, in the DLS of both intact and gonadectomized rats, DA reuptake was slower in females than in males. Finally, DA release following ES of the medial forebrain bundle at 60Hz was studied over four weeks. ES DA release increased over time for both CAST males and OVX females, demonstrating sensitization. Using this novel 16-channel chronic FSCV electrode, we found sex differences in the effects of social housing in the NAcS, sex differences in DA release from intact rats in DLS, sex differences in DA reuptake in DLS of intake and gonadectomized rats, and we report sensitization of ES-induced DA release in DLS in vivo . Significance Statement: Dopamine release is not uniform or fixed. In the nucleus accumbens, pair housing, compared with individual housing, is shown to differentially affect dopamine responsiveness to stimulation in a sex-dependent and region-specific way. There are also sex differences in stimulated dopamine release in the dorsolateral striatum of intact rats, which are not seen in gonadectomized rats, indicating the hormone dependence of this sex difference. However, reuptake of dopamine was slower in females than in males, independent of gonadal hormones. Importantly, the electrical stimulation-induced dopamine release in the dorsolateral striatum of gonadectomized rats demonstrated sensitization of dopamine release in vivo within animals for the first time. Thus, stimulated dopamine release exhibits sex-specific neuroplasticity that is modified in females by the housing conditions.

Immediate and Long-Term Effects of Tibial Nerve Stimulation on the Sexual Behavior of Female Rats.

OBJECTIVES: There are limited treatment options for female sexual dysfunction (FSD). Percutaneous tibial nerve stimulation (PTNS) has shown improvements in FSD symptoms in neuromodulation clinical studies, but the direct effects on sexual function are not understood. This study evaluated the immediate and long-term effects of PTNS on sexual motivation and receptivity in a rat model of menopausal women. Our primary hypothesis was that long-term PTNS would yield greater changes in sexual behavior than short-term stimulation. MATERIALS AND METHODS: In two experiments, after receiving treatment, we placed ovariectomized female rats in an operant chamber in which the female controls access to a male by nose poking. We used five treatment conditions, which were with or without PTNS and no, partial, or full hormone priming. In experiment 1, we rotated rats through each condition twice with behavioral testing immediately following treatment for ten weeks. In experiment 2, we committed rats to one condition for six weeks and tracked sexual behavior over time. We quantified sexual motivation and sexual receptivity with standard measures. RESULTS: No primary comparisons were significant in this study. In experiment 1, we observed increased sexual motivation but not receptivity immediately following PTNS with partial hormone priming, as compared with priming without PTNS (linear mixed effect models; initial latency [p = 0.34], inter-interval latency [p = 0.77], nose poke frequency [p = 0.084]; eight rats). In experiment 2, we observed trends of increased sexual receptivity (linear correlation for weekly group means; mounts [p = 0.094 for trendline], intromissions [p = 0.073], lordosis quotient [p = 0.58], percent time spent with a male [p = 0.39], decreased percent time alone [p = 0.024]; four rats per condition), and some sexual motivation metrics (linear correlation for weekly group means; nose pokes per interval [p = 0.050], nose poke frequency [p = 0.039], decreased initial latency [p = 0.11]; four rats per condition) when PTNS was applied long-term with partial hormone priming, as compared with hormone-primed rats without stimulation. CONCLUSIONS: PTNS combined with hormone priming shows potential for increasing sexual motivation in the short-term and sexual receptivity in the long-term in rats. Further studies are needed to examine variability in rat behavior and to investigate PTNS as a treatment for FSD in menopausal women.

Practical solutions for including sex as a biological variable (SABV) in preclinical neuropsychopharmacological research.

Recently, many funding agencies have released guidelines on the importance of considering sex as a biological variable (SABV) as an experimental factor, aiming to address sex differences and avoid possible sex biases to enhance the reproducibility and translational relevance of preclinical research. In neuroscience and pharmacology, the female sex is often omitted from experimental designs, with researchers generalizing male-driven outcomes to both sexes, risking a biased or limited understanding of disease mechanisms and thus potentially ineffective therapeutics. Herein, we describe key methodological aspects that should be considered when sex is factored into in vitro and in vivo experiments and provide practical knowledge for researchers to incorporate SABV into preclinical research. Both age and sex significantly influence biological and behavioral processes due to critical changes at different timepoints of development for males and females and due to hormonal fluctuations across the rodent lifespan. We show that including both sexes does not require larger sample sizes, and even if sex is included as an independent variable in the study design, a moderate increase in sample size is sufficient. Moreover, the importance of tracking hormone levels in both sexes and the differentiation between sex differences and sex-related strategy in behaviors are explained. Finally, the lack of robust data on how biological sex influences the pharmacokinetic (PK), pharmacodynamic (PD), or toxicological effects of various preclinically administered drugs to animals due to the exclusion of female animals is discussed, and methodological strategies to enhance the rigor and translational relevance of preclinical research are proposed.

Neural Mechanisms Mediating Sex Differences in Motivation for Reward: Cognitive Bias, Food, Gambling, and Drugs of Abuse.

Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research.

Sex-specific and generational effects of alcohol and tobacco use on epigenetic age acceleration in the Michigan longitudinal study.

Background: Excessive alcohol and tobacco use are risk factors for poor health in both men and women, but use patterns and relationships with diseases and mortality differ between sexes. The impact of substance use on the epigenome, including DNA methylation profiles, may also differ by sex. It is also unknown whether parental substance use during childhood is associated with epigenetic changes that persist into adulthood. This study assessed the sex-specific effects of individuals' alcohol and tobacco use, as well as paternal alcohol and paternal/maternal tobacco use, on offspring's cellular aging as measured by epigenetic age acceleration. Methods: Four measures of epigenetic age acceleration (HorvathAA, HannumAA, PhenoAA, and GrimAA), the difference between chronological age and inferred age based on DNA methylation, were estimated from saliva samples. Linear mixed models tested associations between alcohol/tobacco use and epigenetic age acceleration in parents and offspring. Results: Current tobacco smoking was associated with a 4.61-year increase in GrimAA, and former tobacco smoking was associated with a 3.60-year increase in HannumAA after accounting for multiple testing (p < 0.0125). In males only, current tobacco smoking was nominally associated with a 2.19-year increase in HannumAA (p < 0.05), and this effect was significantly different than the female-specific effect (p < 0.0125). Paternal heavy alcohol use when the offspring was 12 or younger was associated with a 4.43-year increase in GrimAA among offspring (p < 0.0125). Conclusions: This study found evidence of sex-specific effects of alcohol and tobacco use, as well as paternal heavy alcohol use, on epigenetic age acceleration.

Activation of G protein-coupled estradiol receptor 1 in the dorsolateral striatum enhances motivation for cocaine and drug-induced reinstatement in female but not male rats.

BACKGROUND: Estradiol potentiates drug-taking behaviors, including motivation to self-administer cocaine and reinstatement of drug-seeking after extinction in females, but not males. The dorsolateral stratum (DLS) is a region of the brain implicated in mediating drug-seeking behaviors and, more specifically, is a target brain area to study how estradiol regulates these behaviors. The estradiol receptors α, ß, and G protein-coupled estradiol receptor 1 (GPER1) are all present in the DLS. In this study, the effects of activating GPER1 in the DLS on drug-seeking are investigated. METHODS: Gonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on a fixed-ratio 1 schedule of reinforcement. For 4 weeks, animals underwent testing on a progressive ratio schedule of reinforcement to determine their motivation to attain cocaine. Halfway through progressive ratio testing, a selective agonist targeting GPER1 (G1) was administered intra-DLS to determine the contribution of GPER1 activation on motivation for cocaine. The effects of intra-DLS GPER1 activation on drug-induced reinstatement after extinction were subsequently determined. RESULTS: Activation of GPER1, via intra-DLS G1 administration, potentiated females' motivation to self-administer cocaine. There was no effect of prior G1 treatment on extinction of cocaine-taking in females; however, G1 treatment resulted in greater drug-induced reinstatement (10 mg/kg cocaine, i.p.). There were no effects of intra-DLS GPER1 activation observed on motivation for cocaine or cocaine-induced reinstatement of responding in males. CONCLUSIONS: These results support the conclusion that activation of GPER1 in the DLS enhances cocaine-seeking behaviors for female, but not male rats.

Activation of G-protein coupled estradiol receptor 1 in the dorsolateral striatum attenuates preference for cocaine and saccharin in male but not female rats.

There are sex differences in the response to psychomotor stimulants, where females exhibit a greater response than males, due to the presence of the gonadal hormone estradiol (E2). Extensive research has shown that E2 enhances drug-seeking and the rewarding properties of cocaine for females. The role of E2 in male drug-seeking, however, is not well understood. The current study investigated pharmacological manipulation of E2 receptors in the dorsolateral striatum (DLS) on preference for cocaine in gonad-intact male and female rats. In males, activation of G-protein coupled E2 receptor 1 (GPER1), via administration of ICI 182,780 or G1, attenuated conditioned place preference for 10 mg/kg cocaine, while inhibition of GPER1, via G15, enhanced preference at a 5 mg/kg cocaine dose. Similarly, GPER1 activation, via G1, prevented males from forming a preference for 0.1% saccharin (SACC) versus plain water. Surprisingly, activation of GPER1 did not alter preference for cocaine or SACC in females. These studies also examined the quantity of E2 receptor mRNA in the dorsal striatum, using qPCR. No sex differences in relative mRNA expression of ERα, ERß, and GPER1 were observed. However, there was greater GPER1 mRNA, relative to ERα and ERß, in both males and females. The results presented here indicate that E2, acting via GPER1, may be protective against drug preference in male rats.

Sex differences in vulnerability to addiction.

This article reviews evidence for sex differences in vulnerability to addiction with an emphasis on the neural mechanisms underlying these differences. Sex differences in the way that the gonadal hormone, estradiol, interacts with the ascending telencephalic dopamine system results in sex differences in motivated behaviors, including drug-seeking. In rodents, repeated psychostimulant exposure enhances incentive sensitization to a greater extent in females than males. Estradiol increases females' motivation to attain psychostimulants and enhances the value of drug related cues, which ultimately increases their susceptibility towards spontaneous relapse. This, along with females' dampened ability to alter decisions regarding risky behaviors, enhances their vulnerability for escalation of drug use. In males, recent evidence suggests that estradiol may be protective against susceptibility towards drug-preference. Sex differences in the actions of estradiol are reviewed to provide a foundation for understanding how future research might enhance understanding of the mechanisms of sex differences in addiction-related behaviors, which are dependent on estradiol receptor (ER) subtype and the region of the brain they are acting in. A comprehensive review of the distribution of ERα, ERß, and GPER1 throughout the rodent brain are provided along with a discussion of the possible ways in which these patterns differentially regulate drug-taking between the sexes. The article concludes with a brief discussion of the actions of gonadal hormones on the circuitry of the stress system, including the hypothalamic pituitary adrenal axis and regulation of corticotropin-releasing factor. Sex differences in the stress system can also contribute to females' enhanced vulnerability towards addiction.

Women, opioid use and addiction.

In the midst of the current coronavirus pandemic, the United States continues to struggle with an ongoing opioid epidemic, initially fueled by widespread prescribing of opioid medications during the 1990s. The primary reason for prescribing opioids is to treat pain. Women have more acute and chronic pain and have been prescribed these drugs in significantly greater numbers than men. Comparison of women and men with chronic pain also shows that women receive the majority of prescription opioids, and the use of these prescribed medications became the major pathway to misuse and addiction for women. Yet, recognition of the extent of women's exposure to opioids and the attendant consequences has been limited. Attempts to stem the overall tide of the epidemic focused on reducing the availability of prescription opioids. However, as these medications became more difficult to obtain and treatment opportunities were limited, many turned to other synthetic opioids, such as heroin and fentanyl. Thus, the public health crisis of opioid addiction has endured. This paper highlights the importance of understanding differences among women and men in opioid use and its biological and psychosocial effects to advance the gender-based treatment approaches and effective public health policy.

High density carbon fiber arrays for chronic electrophysiology, fast scan cyclic voltammetry, and correlative anatomy.

OBJECTIVE: Multimodal measurements at the neuronal level allow for detailed insight into local circuit function. However, most behavioral studies focus on one or two modalities and are generally limited by the available technology. APPROACH: Here, we show a combined approach of electrophysiology recordings, chemical sensing, and histological localization of the electrode tips within tissue. The key enabling technology is the underlying use of carbon fiber electrodes, which are small, electrically conductive, and sensitive to dopamine. The carbon fibers were functionalized by coating with Parylene C, a thin insulator with a high dielectric constant, coupled with selective re-exposure of the carbon surface using laser ablation. MAIN RESULTS: We demonstrate the use of this technology by implanting 16 channel arrays in the rat nucleus accumbens. Chronic electrophysiology and dopamine signals were detected 1 month post implant. Additionally, electrodes were left in the tissue, sliced in place during histology, and showed minimal tissue damage. SIGNIFICANCE: Our results validate our new technology and methods, which will enable a more comprehensive circuit level understanding of the brain.

The rodent vaginal microbiome across the estrous cycle and the effect of genital nerve electrical stimulation.

Treatment options are limited for the approximately 40% of postmenopausal women worldwide who suffer from female sexual dysfunction (FSD). Neural stimulation has shown potential as a treatment for genital arousal FSD, however the mechanisms for its improvement are unknown. One potential cause of some cases of genital arousal FSD are changes to the composition of the vaginal microbiota, which is associated with vulvovaginal atrophy. The primary hypothesis of this study was that neural stimulation may induce healthy changes in the vaginal microbiome, thereby improving genital arousal FSD symptoms. In this study we used healthy rats, which are a common animal model for sexual function, however the rat vaginal microbiome is understudied. Thus this study also sought to examine the composition of the rat vaginal microbiota. Treatment rats (n = 5) received 30 minutes of cutaneous electrical stimulation targeting the genital branch of the pudendal nerve, and Control animals (n = 4) had 30-minute sessions without stimulation. Vaginal lavage samples were taken during a 14-day baseline period including multiple estrous periods and after twice-weekly 30-minute sessions across a six-week trial period. Analysis of 16S rRNA gene sequences was used to characterize the rat vaginal microbiota in baseline samples and determine the effect of stimulation. We found that the rat vaginal microbiota is dominated by Proteobacteria, Firmicutes, and Actinobacteria, which changed in relative abundance during the estrous cycle and in relationship to each other. While the overall stimulation effects were unclear in these healthy rats, some Treatment animals had less alteration in microbiota composition between sequential samples than Control animals, suggesting that stimulation may help stabilize the vaginal microbiome. Future studies may consider additional physiological parameters, in addition to the microbiome composition, to further examine vaginal health and the effects of stimulation.

Ovarian Hormones Mediate Changes in Adaptive Choice and Motivation in Female Rats.

In female rodents, sexual receptivity is coordinated with cyclic changes in the release of gonadal hormones. Increases in estradiol (E) and progesterone (P) during proestrus and estrus not only induce ovulation but also modulate behaviors that increase the likelihood that the female will find a mate and reproduce. This includes changes in receptive behaviors, such as lordosis, as well as changes in appetitive or proceptive behaviors, including motivation. Interestingly, the direction of these changes in motivation is dependent on the type of reward that is being pursued. While induction of sexual receptivity by E and P increases motivation for access to a male, motivation for a palatable food reward is decreased. These concurrent changes may facilitate adaptive choice across the estrous cycle; females bias their choice for sex when fertilization is most likely to occur, but for food when copulation is unlikely to result in impregnation. In order to test this hypothesis, we developed a novel paradigm to measure the motivated choice between a palatable food reward and access to a male conspecific. Ovariectomized, hormone primed females were trained to operantly respond for both food and sex on a fixed interval (FI) schedule. After training, unprimed and primed females were tested in a chamber that allows them to choose between food and sex while still requiring responding on the FI schedule for reach reward. From this we can not only determine the impact of hormone priming on female choice for food or sex, but also how this is reflected by changes in motivation for each specific reward, as measured by the average number of responses made during each fixed interval. Induction of sexual receptivity by hormone priming biases choice toward sex over food and this change is accompanied by an increase in motivation for sex but a decrease in motivation for food. This work provides evidence in support of a novel framework for understanding how the release of ovarian hormones over the course of the estrous cycle modulates adaptive behavioral choice in females by directly assessing motivation via operant responding when multiple rewards are available.

Estradiol-Induced Potentiation of Dopamine Release in Dorsal Striatum Following Amphetamine Administration Requires Estradiol Receptors and mGlu5.

Estradiol potentiates behavioral sensitization to cocaine as well as self-administration of cocaine and other drugs of abuse in female rodents. Furthermore, stimulated dopamine (DA) in the dorsolateral striatum (DLS) is rapidly enhanced by estradiol, and it is hypothesized that this enhanced DA release mediates the more rapid escalation of drug taking seen in females, compared with males. The mechanisms mediating the effect of estradiol to enhance stimulated DA release were investigated in this study. Using in vivo microdialysis and high performance liquid chromatography coupled with electrochemical detection, we first examined the effect of estradiol on amphetamine-induced DA increase in the DLS of ovariectomized rats. We then tested whether the potentiation of this DA increase could be blocked by the estradiol receptor antagonist, ICI 182,780 (ICI), or an antagonist to the metabotropic glutamate receptor subtype 5 (mGlu5), 2-methyl-6-(phenylethynyl)pyridine (MPEP). There is evidence that estradiol receptors collaborate with mGlu5 within caveoli in DLS and mGlu5 is hypothesized to mediate many of the effects of estradiol in the addiction processes in females. Our data show that estradiol enhances the DA response to amphetamine. Either ICI or MPEP prevented the effect of estradiol to enhance DA release. Importantly, our results also showed that neither ICI or MPEP alone is able to influence the DA response to amphetamine when estradiol is not administrated, suggesting that ICI and MPEP act via estradiol receptors. Together, our findings demonstrate that estradiol potentiates amphetamine-stimulated DA release in the DLS and this effect requires both estradiol receptors and mGlu5.

The federal plan for health science and technology's response to the opioid crisis: understanding sex and gender differences as part of the solution is overlooked.

The Fast-Track Action Committee on (the) Health Science and Technology Response to the Opioid Crisis recently released their draft report for public comment. This report provides the "roadmap" for a coordinated federal research and development response to the opioid crisis. Other than noting the important concerns regarding maternal and neonatal exposure to opioids, the report overlooks the laboratory, clinical, and epidemiological data that inform the need for further research on sex and gender differences in opioid addiction that have critical gender-based treatment and prevention implications. As we embark on research and development, investigations into the neurobiology of pain, opioid use, and addiction must include both females and males in model systems and, similarly, psychological and sociocultural investigations must study women and men. All data should be reported by sex and gender so that gender-specific treatment and prevention strategies derived from this research are provided to practitioners and the public. We encourage biomedical researchers and clinical care providers, as well as the public, to insist that a successful response to the opioid crisis should highlight the importance of understanding sex and gender differences in the current opioid epidemic.

Sex differences in prenatal stress effects on cocaine pursuit in rats.

Disruption of early-life ontogeny has severe and persistent consequences for the health of the developing organism. Both clinical and preclinical findings indicate that such interference can be caused by maternal stress during the gestation period (prenatal stress [PS]). In rats, PS facilitates the rewarding and neurochemical-stimulating effects of drugs, suggesting that PS may represent a risk factor for drug abuse in humans. Very little, however, is known about its effects in females, even though sex differences in drug susceptibility have been well documented in no PS (NPS) controls. Thus, we tested for independent effects and interactions between maternal restraint stress during the last week of gestation and sex on drug use with an extended regimen of drug self-administration. Male and female rats were provided daily access to a large but controlled amount of cocaine for seven weeks. Drug pursuit during the final week was used to indicate susceptibility to developing an addiction-like phenotype, based on reports that drug use becomes increasingly compulsive-like after weeks of testing. Overall, females satisfied more addiction-like criteria than males, and the same was true for PS rats when compared to NPS controls. In addition, sex and PS interacted to disproportionately promote drug pursuit of females with a history of PS. These results indicate that sex differences in drug susceptibility persist with continued drug exposure, and that PS widens this difference by more severely affecting females. In all, PS may be a risk factor for drug addiction in humans, and to a greater extent in women vs. men.

Effect of social housing and oxytocin on the motivation to self-administer methamphetamine in female rats.

Social housing has been shown to attenuate the motivation for cocaine in female, but not male rats. Here we investigate the potential mechanisms mediating the effect of social housing on the response to methamphetamine (METH). Female rats were individually or socially (pair) housed. The dopamine (DA) response to an acute METH infusion (0.3mg/kg, i.v.) was investigated using in vivo microdialysis in the nucleus accumbens with or without oxytocin (OT; 0.3mg/kg, i.p.) 30min prior to METH. The effects of social housing and OT on self-administered METH (0.06mg/kg/inf) was investigated. The METH-induced DA response was higher in individually housed compared to socially-housed females. On the other hand, individually housed females had a significantly higher breaking point (BP) than socially-housed females. Two weeks of OT treatment reduced BP in both groups. Reinstatement to METH was more pronounced in isolates compared to socially-housed females. More of the socially-housed females had very low BP than did the individually housed females. OT was most effective in reducing BP in females with moderate to high BP, irrespective of housing conditions. These data show that social housing attenuates escalation of METH intake and reinstatement of METH seeking in female rats, and that chronic OT treatment can reduce motivation for METH.

Single prolonged stress decreases sign-tracking and cue-induced reinstatement of cocaine-seeking.

Exposure to prolonged, uncontrollable stress reduces reward-seeking behavior, resulting in anhedonia in neuropsychiatric disorders, such as posttraumatic stress disorder. However, it is unclear to what degree stressed subjects lose interest in rewards themselves or in reward-related cues that instigate reward-seeking behavior. In the present study, we investigated the effects of single prolonged stress (SPS) on cue-directed behavior in two different procedures: Pavlovian conditioned approach (PCA) and cue-induced reinstatement of cocaine-seeking. In Experiment 1, rats were exposed to SPS and tested for the acquisition of sign-tracking (cue-directed) and goal-tracking (reward-directed) behaviors during a PCA procedure. In Experiment 2, rats were exposed to SPS and tested for the expression of sign- and goal-tracking as well as cue-induced reinstatement of cocaine-seeking. Because dopaminergic activity in the nucleus accumbens is known to play a central role in many cue-directed behaviors, including both sign-tracking and cue-induced reinstatement, Experiment 3 used in vivo microdialysis to measure the effect of SPS on baseline and evoked dopamine levels in the nucleus accumbens. SPS decreased sign-tracking and increased goal-tracking during the acquisition of PCA behavior without affecting reward consumption. In addition, SPS decreased cue-induced reinstatement without affecting cocaine self-administration. Finally, SPS decreased evoked but not baseline levels of dopamine in the nucleus accumbens. These results suggest that SPS decreases the motivational, but not consummatory, aspects of reward-seeking behavior, which may result from long-term, SPS-induced reductions in dopamine release in the nucleus accumbens.

Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes.

BACKGROUND AND PURPOSE: Females are more sensitive than males to both the acute and prolonged effects of psychomotor stimulants. In females, this is regulated by oestradiol, which enhances dopamine release in the dorsal striatum. In this study, we tested the acute effect of oestradiol on dopamine release in the nucleus accumbens (NAc) shell after cocaine administration and investigated which oestradiol receptors (ERs) contribute to sex differences in the response to cocaine. EXPERIMENTAL APPROACH: The ability of oestradiol benzoate (EB) to acutely modulate the effect of cocaine on phasic dopamine release in the NAc shell was measured by fast-scan cyclic voltammetry in anaesthetized male and female rats. The roles of ER subtypes, ERα and ERß, was determined with selective agonists. KEY RESULTS: EB acutely enhanced the effect of cocaine on stimulated dopamine release from the NAc shell in females but not in male rats only at levels of stimulation expected to optimally saturate dopamine transporters. Enhanced dopamine release after cocaine administration was also observed in females after selective activation of ERß but not ERα. EB attenuated the effect of cocaine on NAc shell dopamine reuptake in males but not in females. CONCLUSIONS AND IMPLICATIONS: Oestradiol acutely and rapidly regulates dopamine release in females and dopamine reuptake in males. In females, oestradiol rapidly enhances the effect of cocaine on dopamine release, likely via activation of ERß. The effect of oestradiol in males is not seen with selective receptor subtype activation, a topic deserving of further study. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

Sex differences in neural mechanisms mediating reward and addiction.

There is increasing evidence in humans and laboratory animals for biologically based sex differences in every phase of drug addiction: acute reinforcing effects, transition from occasional to compulsive use, withdrawal-associated negative affective states, craving, and relapse. There is also evidence that many qualitative aspects of the addiction phases do not differ significantly between males and females, but one sex may be more likely to exhibit a trait than the other, resulting in population differences. The conceptual framework of this review is to focus on hormonal, chromosomal, and epigenetic organizational and contingent, sex-dependent mechanisms of four neural systems that are known-primarily in males-to be key players in addiction: dopamine, mu-opioid receptors (MOR), kappa opioid receptors (KOR), and brain-derived neurotrophic factor (BDNF). We highlight data demonstrating sex differences in development, expression, and function of these neural systems as they relate-directly or indirectly-to processes of reward and addictive behavior, with a focus on psychostimulants and opioids. We identify gaps in knowledge about how these neural systems interact with sex to influence addictive behavior, emphasizing throughout that the impact of sex can be highly nuanced and male/female data should be reported regardless of the outcome.