Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

Abstract

Preclinical and clinical studies indicate that females are more vulnerable to relapse than males, and the neurobiological effects of estrogen are thought to mediate, in part, the sex differences in cocaine-taking behavior. The goal of the present study was to investigate the involvement of estrogen receptor a (ERa) and b (ERb) in estrogen-mediated increases in cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized (OVX) female rats. Rats were initially trained to self-administer cocaine (0.4 mg/kg/inf, i.v.) under a fixed-ratio 1 (FR 1) schedule of reinforcement during daily 2-h sessions. After a 10-day maintenance period, cocaine solutions were replaced with saline, and self-administration was extinguished over a 14-day period. OVX rats were then treated with either the mixed ERa/b agonist estradiol benzoate (EB), the ERa-selective agonist, propyl-pyrazole-triol (PPT), the ERb-selective agonist, diarylpropionitrile (DPN), or a vehicle control (dimethyl sulfoxide, DMSO). Treatment lasted a total of 9 days, and during this time, rats were assessed for nonreinforced reinstatement of extinguished cocaine-seeking behavior after priming injections of saline or cocaine (5, 10, or 15 mg/kg, i.p.). OVX rats showed no differences in self-administration during maintenance or extinction. OVX rats treated with EB exhibited greater responding for cocaine during reinstatement compared to OVX + DMSO controls. Selective activation of ERb with DPN also increased cocaine-induced reinstatement responding, whereas selective activation of ERa with PPT did not affect cocaineseeking behavior. These results indicate that estrogen influences the propensity for reinstatement of extinguished cocaine-seeking behavior, and that estrogen-mediated enhancement of cocaine-induced reinstatement responding involves the activation of ERb.

Increasing Progesterone Levels Are Associated With Smoking Abstinence Among Free-Cycling Women Smokers Who Receive Brief Pharmacotherapy

“…The results of the present study were not consistent with the tentatively hypothesized negative relationship between estradiol level and abstinence, which was based primarily on preclinical research suggesting estradiol may have a facilitative effect on cocaine related sensitization, self-administration and relapse/reinstatement. [51][52][53][54][55][56][57] Since there is no preclinical research examining the effects of estradiol in nicotinereinforced behavior (e.g., self-administration), the lack of association between estradiol and abstinence observed here is consistent with the possibility that estradiol may not have uniform effects across different substances of abuse.…”

Sex differences in drug abuse

“…In a similar experiment, Carroll and colleagues found that acute or chronic estradiol enhanced reinstatement of responding for cocaine [73]. In another experiment, an agonist for estrogen receptor-ß (ERß), but not an agonist for estrogen receptor-α (ERα), was effective at reinstatement of responding when primed with 5 mg/kg cocaine [72]. Only one dose of the agonists were used, so it is possible that higher doses of the ERα agonist might have also been effective.…”

“…Only one dose of the agonists were used, so it is possible that higher doses of the ERα agonist might have also been effective. Interestingly, at higher doses of cocaine, responding was re-initiated whether or not the animals were treated the ERß agonist [72]. Thus, estradiol rapidly enhances the subjective effects of cocaine to reinstate responding for access to cocaine, but estradiol does not reinstate responding on its own.…”

1H-NMR and HPLC–MS/MS-based global/targeted metabolomic evaluation of Hypericum perforatum L. intervention for menopause

“…Body weights were recorded daily. OVX was performed according to a previous study (Larson & Carroll, 2007), and the experimental protocols followed the guidelines of the Guide for the Care and Use of Laboratory Animals and were approved by the Laboratory Animal Care and Use Committee of the Beijing Institute of Radiation Medicine.…”