Background Females exhibit more rapid escalation of cocaine use and enhanced cocaine-taking behavior as compared to males. While ovarian hormones likely play a role in this increased vulnerability, research has yet to examine the role of estradiol in affecting the behavioral and neurological response to cocaine in a brain region- and sex-specific way. Methods First, we examined stereotypy and locomotor sensitization after repeated cocaine administration (10 mg/kg i.p.) in intact (SHAM) and castrated (CAST) males, and ovariectomized (OVX) females treated with 5 μg estradiol benzoate (EB) or vehicle (OIL). Next, we used in vivo microdialysis to examine the effects of acute EB treatment on cocaine-induced DA in the regions mediating the display of these behaviors (i.e., the dorsolateral striatum, DLS; and the nucleus accumbens, NAc; respectively). Results We find that EB enhances sensitization of cocaine-induced stereotypy in OVX females after 12 days of cocaine treatment, and after a 10-day withdrawal. Similarly, the OVX/EB females show enhanced locomotor sensitization compared to the other three groups on the same days. Using in vivo microdialysis to assess the neurochemical response, we find that EB rapidly enhances cocaine-induced DA in DLS dialysate of OVX females but not CAST males, and has no effect in NAc of either sex. Conclusions With these experiments, we show that there are sex differences in the effects of estradiol to preferentially enhance the response to cocaine in the DLS over the NAc in females, which may contribute to the preferential sensitization of stereotypy in females.

BACKGROUND Incidence of ovulatory disorders is common in obese animal models. The mechanism behind this effect is not clear. We hypothesized that high fat (HF) diet induces alterations in neuroendocrine mechanisms resulting in anovulation in diet-induced obese (DIO) animals. METHODS Adult female DIO and diet-resistant (DR) rats were fed either chow or HF diet (45% calories from fat) for 6 weeks. Oestrous cyclicity and body weight were monitored regularly. At the end of treatment, rats were implanted with a jugular catheter to monitor luteinising hormone (LH) levels on the day of prooestrous. Rats were sacrificed on the following prooestrous, their brains and ovaries were collected. Plasma from trunk blood was analyzed for oestradiol and leptin concentrations. Ovaries were fixed and sectioned for histological analysis. Brains were removed, frozen and sectioned and norepinephrine (NE) concentrations in discrete hypothalamic areas were measured using HPLC-EC. RESULTS HF diet affected oestrous cyclicity in both DIO and DR rats with the effect being more pronounced in DIO animals. HF diet increased leptin levels in both DIO and DR rats. Oestradiol levels were low in the DIO-HF group. NE levels in the hypothalamus were unaffected by HF diet or genotype. A normal LH surge was observed in DR-Chow rats and LH levels were low in the rest of the groups. CONCLUSION DIO rats have an inherently reduced reproductive capacity and exposure to a HF diet decreases it further. A reduction in oestradiol and LH surge levels could contribute to this effect, however the underlying mechanisms need to be studied further.

Cocaine dependence is characterized by compulsive drug taking and reduced involvement in social, occupational, or recreational activities. Unraveling the diverse mechanisms contributing to the loss-of-interest in these 'non-drug' pursuits is essential for understanding the neurobiology of addiction and could provide additional targets for treating addiction. The study objectives were to examine changes in cocaine-induced dopamine (DA) overflow in the nucleus accumbens (NAc) over the course of self-administration and determine the roles of α1-and β-adrenergic receptors (AR) in the loss-of-interest in food rewards following the development of an addicted phenotype in male and female rats. Subjects were given access to cocaine and palatable food pellets in a choice self-administration paradigm to identify 'addicted' cocaine-preferring (CP) individuals and resistant pellet-preferring (PP) individuals based on their patterns of self-administration over 7 weeks. Cocaine-induced DA overflow in the NAc was examined with microdialysis early and late during self-administration (weeks 2 and 7). Subjects were treated in counter-balanced order with propranolol (β-AR antagonist), terazosin (α1-AR antagonist), or vehicle for an additional 3 weeks of self-administration. CP rats displayed increased motivation for cocaine and attenuated motivation for pellets following the development of cocaine preferences. In females, the estrous cycle affected pellet, but not cocaine, self-administration. CP rats displayed attenuated cocaine-induced DA overflow in the NAc. Propranolol enhanced cocaine reinforcement and reduced pellet intake, whereas terazosin enhanced motivation for pellets and reversed preferences in a subset of CP rats. The implications of these results for the treatment of addiction are discussed.

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.

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.

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Obesity is known to interfere with HPG functions, but the mechanisms involved are not clear. We hypothesized that a high fat (HF) diet would affect norepinephrine (NE) levels in the hypothalamus to impact luteinizing hormone (LH) release and ovulation in obesity. To test this, adult female diet‐induced obese (DIO) and diet resistant (DR) rats were fed chow or HF diet for 6 wks. Estrous cyclicity was monitored and hourly blood samples were collected from 1000–1900h for LH measurement on the day of proestrous. Animals were sacrificed on proestrous and plasma was processed for estradiol and leptin concentrations. Ovarian sections were subjected to morphological analysis. The medial preoptic area (MPA) and suprachiasmatic nucleus (SCN) of the hypothalamus that regulate LH secretion, were analyzed for NE levels. Leptin levels increased while estradiol levels were significantly reduced in the HF‐fed DIO group. NE levels (Mean±SE; pg/μg of protein) in the SCN dropped significantly in DIO HF (14.8±1.8) vs. chow‐fed DR rats (26.1±3.7; p<0.05). LH surge levels (ng/ml) in DIO HF was significantly lower compared to DR chow group (0.82±0.2 vs. 8.4±3.5; p<0.05). Ovaries from DIO HF animals had degenerating cystic follicles and no corpora lutea indicating anovulation. These results indicate that HF feeding inhibits the HPG axis in DIO rats possibly by increasing leptin levels to decrease ovarian estradiol synthesis. This leads to reduced NE levels in the hypothalamus causing suppression of the LH surge and anovulation.

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