Sex Steroid Hormone Receptor Content of Medial Preoptic Efferents to the Ventral Tegmental Area Is Sexually Dimorphic: Implications for Sex Differences in Mesolimbic Reward Processing.

INTRODUCTION: The medial preoptic area (mPOA) is an important regulator of natural and drug-induced reward. However, despite the mPOA being implicated in sexually dimorphic reward responses, sex differences in medial preoptic efferents to the ventral tegmental area (VTA) have not been fully investigated. METHODS: Two cohorts of male and female rats received unilateral injections of the tract-tracer Fluoro-Gold (FLG) into the VTA. Immunohistochemical staining was used to quantify co-labeled FLG-positive neurons with γ-aminobutyric acid (GABA), estrogen receptor α (ERα), and androgen receptors (AR). RESULTS: Results revealed a pattern of VTA innervation that was comparable between males and females; more efferents emerged from the rostrocentral portions of the mPOA than caudal portions. Results also indicated that males and females had the same percentage of GABAergic mPOA-VTA projections. Differences emerged when investigating the hormone receptor profile of projections to the VTA, where females had a greater percentage of efferents expressing ERα and males had a greater percentage of efferents expressing AR, in the central portion of the mPOA. Lastly, FLG-positive cells were colocalized with GABA and ERα in cohort 1 and GABA and AR in cohort 2. The majority of AR-expressing cells colocalized with GABAergic efferents to the VTA, but only a portion of ERα-expressing cells colocalized with GABAergic efferents to the VTA. CONCLUSION: Results indicate that sex differences are present in the sex-steroid hormone receptor content of mPOA-VTA projections, particularly among efferents arising from the central region of the mPOA. These sexually dimorphic connections may influence a wide range of sex differences in reward responses.

The medial preoptic area and acute cocaine's stimulant effects in rats: Potential influences of estradiol and biological sex.

The medial preoptic area (mPOA) in the hypothalamus is an important integrator of neuroendocrine signaling and a key regulator of both natural and drug-induced reward. Although the mPOA modulates sex differences in other behaviors, whether it also modulates sex differences in cocaine response remains unclear. To help us better understand the mPOA's role in sex differences associated with cocaine response, we examined cocaine-induced changes in locomotion and neural activity in the mPOA of male and female rats. In addition, neural activity in the striatum, a brain area known to be involved in cocaine response, was examined for comparison purposes. Fos, the protein product of the immediate early gene c-fos, was used as the marker of neural activity. Locomotion chambers were used to measure behavior, radioimmunoassays and vaginal lavages were used to determine hormonal status, and immunohistochemical assays were used to quantify Fos. To account for the effects of gonadal hormones, rats were left gonadally intact and categorized as either 'low-estradiol' or 'high-estradiol' based on their hormonal status on test day. Results indicate that high-estradiol females experienced greater cocaine-induced mPOA Fos-immunoreactivity (Fos-ir) and displayed greater cocaine-induced locomotion than low estradiol females. Conversely, high-estradiol males experienced less cocaine-induced mPOA Fos-ir and displayed less cocaine-induced locomotion than low-estradiol males. Cocaine-induced Fos-ir in the mPOA also correlated with cocaine-induced Fos-ir in areas of the striatum already associated with cocaine response. These findings further support the mPOA's role in the endocrine-mediated response to cocaine. It also identifies the mPOA as a contributor to sex differences in cocaine response and potential differences in vulnerability to developing cocaine use disorders.

Copulation induces expression of the immediate early gene Arc in mating-relevant brain regions of the male rat.

The medial amygdala (MeA), bed nucleus of the stria terminalis (BNST), and medial preoptic area (mPOA) are important for the regulation of male sexual behavior. Sexual experience facilitates sexual behaviors and influences activity in these regions. The goal of this study was to determine whether sexual experience or copulation induces plasticity in the MeA, BNST, or mPOA of male rats, as indicated by changes in levels of Arc, which is indicative of activity-dependent synaptic plasticity in the brain. To this end, sexually naïve or experienced males were placed in mating arenas either alone, with an inaccessible estrus female, or with an accessible estrus female. Arc protein levels were then quantified in these three regions using immunohistochemistry. As expected, sexual experience facilitated copulation, as evidenced by a reduction in latencies to mount, intromit, and ejaculate. Copulation also increased the number of Arc-positive cells in the MeA, anterior BNST, posterior BNST, and the posterior mPOA, but not in the central-rostral region of the mPOA. Surprisingly, prior sexual experience did not impact levels of Arc, suggesting that copulation-induced Arc occurs in both sexually naïve and experienced males.

Influence of preoptic estradiol on behavioral and neural response to cocaine in female Sprague-Dawley rats.

RATIONALE: Systemic estradiol (E2) increases the behavioral and neural response to cocaine. Where in the brain E2 acts to modulate cocaine response is not entirely clear. Evidence supports a role in this modulation for several candidate regions, including the medial preoptic area (mPOA). OBJECTIVES: This study examined whether manipulation of E2 in the mPOA modulates differing behavioral responses to cocaine and whether this is reflected in differing levels of c-Fos in the NAc following cocaine administration. METHODS: Female rats received ovariectomies and bilateral cannulations of the mPOA. They then received either artificial cerebrospinal fluid (aCSF) or E2 microinjections into the mPOA the day before receiving systemic injections of saline or cocaine (5 or 10 mg/kg). Conditioned-place preference (CPP) to cocaine and locomotor activation were then obtained. RESULTS: Animals receiving 10 mg/kg, but not 5 mg/kg, cocaine developed significant CPP, and those receiving E2 into the mPOA expressed greater CPP than those receiving microinjections of only aCSF at both doses (p < 0.05, d > 0.80). Cocaine also caused significant psychomotor activation, but this was not dependent on microinjection of E2 in the mPOA. Finally, animals that received cocaine had increased NAc core and shell c-Fos relative to animals that received saline, with animals receiving both E2 microinjections and systemic cocaine expressing the highest activation in the caudal NAc, compared to rats receiving aCSF microinjections and systemic cocaine (p = 0.05, d = 0.70). CONCLUSIONS: These results indicate that E2 in the mPOA facilitates the behavioral response and neural activation that follows cocaine administration. Furthermore, they confirm the close relationship between the mPOA and cocaine response.

Colocalization of Mating-Induced Fos and D2-Like Dopamine Receptors in the Medial Preoptic Area: Influence of Sexual Experience.

Dopamine in the medial preoptic area (mPOA) stimulates sexual activity in males. This is evidenced by microdialysis and microinjection experiments revealing that dopamine receptor antagonists in the mPOA inhibit sexual activity, whereas agonists facilitate behavior. Microdialysis experiments similarly show a facilitative role for dopamine, as levels of dopamine in the mPOA increase with mating. While the majority of evidence suggests an important role for dopamine receptors in the mPOA in the regulation of male sexual behaviors, whether sexual activity or sexual experience influence dopamine receptor function in the mPOA has not been previously shown. Here we used immunohistochemical assays to determine whether varying levels of sexual activity or experience influence the number of cells containing Fos or D2 receptor immunoreactivity. Results show that sexual experience facilitated subsequent behavior, namely experience decreased latencies. Moreover, the number of cells with immunoreactivity for Fos or D2 correlated with levels of sexual experience and sexual activity. Sexual activity increased Fos immunoreactivity. Sexually experienced animals also had significantly more D2-positive cells. Sexually inexperienced animals copulating for the first time had a larger percentage of D2-positive cells containing Fos, when compared to sexually experienced animals. Finally, regardless of experience, animals that had sex prior to sacrifice had significantly more D2-positive cells that contained Fos, vs. animals that did not copulate. These findings are noteworthy because sexually experienced animals display increased sexual efficiency. The differences in activation of D2 and changes in receptor density may play a role in this efficiency and other behavioral changes across sexual experience.

The medial preoptic area modulates cocaine-induced locomotion in male rats.

Cocaine-induced locomotion is mediated by dopamine in the nucleus accumbens (NAc). Recent evidence indicates that the medial preoptic area (mPOA), a region in the rostral hypothalamus, modulates cocaine-induced dopamine in the NAc. Specifically, rats with lesions of the mPOA experienced a greater increase in dopamine following cocaine administration than rats with sham lesions. Whether the mPOA similarly influences cocaine-induced locomotion is not known. Here we examined whether radiofrequency or neurotoxic lesions of the mPOA in male rats influence changes in locomotion that follow cocaine administration. Locomotion was measured following cocaine administration in male rats with neurotoxic, radiofrequency, or sham lesions of the mPOA. Results indicate that bilateral lesions of the mPOA facilitated cocaine-induced locomotion. This facilitation was independent of lesion type, as increased locomotion was observed with either approach. These findings support a role for the mPOA as an integral region in the processing of cocaine-induced behavioral response, in this case locomotor activity.

Estradiol in the Preoptic Area Regulates the Dopaminergic Response to Cocaine in the Nucleus Accumbens.

The sex-steroid hormone estradiol (E2) enhances the psychoactive effects of cocaine, as evidenced by clinical and preclinical studies. The medial preoptic area (mPOA), a region in the hypothalamus, is a primary neural locus for neuroendocrine integration, containing one of the richest concentrations of estrogen receptors in the CNS and also has a key role in the regulation of naturally rewarding behaviors. However, whether estradiol enhances the neurochemical response to cocaine by acting in the mPOA is still unclear. Using neurotoxic lesions and microdialysis, we examined whether the mPOA modulates cocaine-induced neurochemical activity in the nucleus accumbens. Tract tracing and immunohistochemical staining were used to determine whether projections from the mPOA to the ventral tegmental area (VTA) are sensitive to estrogen signaling. Finally, estradiol microinjections followed by microdialysis were used to determine whether estrogenic signaling in the mPOA modulates cocaine-induced changes of dopamine in the nucleus accumbens. Results showed that lesions of the mPOA or microinjections of estradiol directly into the mPOA increased cocaine-induced release of dopamine in the nucleus accumbens. Immunohistochemical analyses revealed that the mPOA modulates cocaine responsiveness via projections to both dopaminergic and GABAergic neurons in the VTA, and that these projections are sensitive to estrogenic stimulation. Taken together, these findings point to a novel estradiol-dependent pathway that modulates cocaine-induced neurochemical activity in the mesolimbic system.