Sex differences in the effects of allopregnanolone on yohimbine-induced reinstatement of cocaine seeking in rats

Drug Alcohol Depend. 2010 Mar 1;107(2-3):264-7. doi: 10.1016/j.drugalcdep.2009.11.002. Epub 2009 Dec 14.


Sex differences exist in several aspects of cocaine abuse, and recent research suggests that this may be due, in part, to differential sensitivity to stress. Women, compared to men, exhibit greater stress-induced cocaine craving and responses to both cocaine and stress fluctuate during phases of the hormonal cycle. The goal of the present study was to compare male and female rats on the maintenance and extinction of cocaine seeking and on an animal model of stress-induced relapse by administering the pharmacological stressor yohimbine. An additional goal was to examine possible sex-specific treatment effects of the progesterone metabolite, allopregnanolone, on yohimbine-induced reinstatement. Male and female rats were trained to lever press for i.v. infusions of cocaine (0.4 mg/kg). Following a 14-day maintenance period, cocaine solutions were replaced with saline, and rats were allowed to extinguish lever pressing. Subsequently, rats were administered saline, yohimbine (2.5mg/kg), or allopregnanolone (15 mg/kg)+yohimbine (2.5mg/kg) priming injections on separate days using a within-subjects reinstatement procedure. The results indicated that females were more resistant to extinction than male rats and that both groups reinstated cocaine seeking following injections of yohimbine; however, female rats responded more than males to yohimbine-priming injections. Additionally, allopregnanolone blocked yohimbine's potentiating effect on responding in females but not males. These results suggest that females may be more sensitive than males to stress-induced reinstatement of cocaine-seeking behavior, and the progesterone metabolite, allopregnanolone, offers protection against this vulnerability.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic alpha-Antagonists / pharmacology
  • Analysis of Variance
  • Anesthetics / pharmacology
  • Animals
  • Behavior, Addictive / chemically induced
  • Behavior, Addictive / drug therapy*
  • Behavior, Animal / drug effects
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Conditioning, Operant / drug effects*
  • Disease Models, Animal
  • Extinction, Psychological / drug effects*
  • Female
  • Male
  • Pregnanolone / administration & dosage
  • Pregnanolone / pharmacology*
  • Rats
  • Rats, Wistar
  • Secondary Prevention
  • Self Administration
  • Sex Factors
  • Yohimbine / administration & dosage
  • Yohimbine / pharmacology*


  • Adrenergic alpha-Antagonists
  • Anesthetics
  • Yohimbine
  • Pregnanolone
  • Cocaine