Sex differences in the effects of estradiol in the nucleus accumbens and striatum on the response to cocaine: Neurochemistry and behavior

Abstract

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.

The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc)

“…However, given the prevalence of morbid obesity being higher in women than men [32–34] and that sex related differences in dopaminergic function are believed to play an important role in the observed sex differences in the vulnerability to eating disorders [32,33,35], it will be important in the future to consider the effect of sCT on DA release in females. Estradiol, the main type of estrogen, is a major regulator of both physiological and pathophysiological aspects of eating [32].…”

“…Estradiol, the main type of estrogen, is a major regulator of both physiological and pathophysiological aspects of eating [32]. Estradiol has also been demonstrated to have significant modulatory effects on DA systems in females but has not been shown to enhance striatal DA release in males [35,36]. Two rat studies investigating the estrogenic modulation of amylin’s eating-inhibitory effects have produced contradictory results.…”

“…Estrogen’s effect on the suppression of food intake by sCT has yet to be investigated. However, given that sCT activates the same signaling pathway as amylin and estrogen enhances striatal DA release, it is possible that estrogen may modulate the suppression effect of sCT on both food intake and DA release [18,35]. It is clear there is a need to investigate sex differences in amylin sensitivity in feeding and reward-related eating behavior.…”

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

“…Estradiol induces dopamine release in the striatum via disinhibition of local dopaminergic terminals (Becker, 1990; Thompson and Moss, 1994; Hedges et al, 2010), an effect that is mediated by classic estrogen receptors (Xiao et al, 2003) and mimicked by activation of group I mGluRs (Bruton et al, 1999). The effects of estradiol on dopamine release specifically within the NAc can be fairly rapid and transient (Thompson and Moss, 1994) and may not always be observed when dopamine is sampled along longer time frames (Cummings et al, 2014). One mechanism that may link ERα/mGluR5 signaling to changes in dopamine release is the endogenous endocannabinoid system.…”

Stress-induced alterations in estradiol sensitivity increase risk for obesity in women

“…Translational data from rodent models indicate that E2 stimulates striatal DA release [168, 169] and transiently decreases D2R availability [170–172]. This effect of E2 on the dopaminergic system in females is linked to an increased propensity to self-administer cocaine [173, 174]. While these data from translational rodent work suggest that E2 may increase motivation to ingest CDDs similar to its enhancing motivational effects of E2 on cocaine abuse in women, it remains to be determined whether exposure to chronic stress exacerbates the effects of E2 on reward pathways to drive stress-induced intake of CDDs in females.…”