Effects of allopregnanolone on the reinstatement of cocaine-seeking behavior in male and female rats

Rationale Previous research indicates that progesterone (PROG) decreased cocaine-seeking behavior in female rats. This effect of PROG may be in part due to its metabolite allopregnanolone (ALLO), which has been shown to decrease the sensitizing effects of cocaine and reduce lethality associated with cocaine overdose in mice. Objective The purpose of the present study was to examine the effects of ALLO on the reinstatement of cocaine-seeking behavior in female and male rats. Methods Rats were trained to lever press for i.v. infusions of cocaine (0.4 mg/kg per infusion) during 2-h sessions, and once acquisition criteria were met, cocaine self-administration continued for 14 days. Cocaine was then replaced with saline, and lever pressing was allowed to extinguish over 21 days. After the extinction phase, rats received s.c. ALLO (15 or 30 mg/kg), PROG (0.5 mg/kg), PROG (0.5 mg/kg) plus the 5-alpha reductase inhibitor finasteride (25 mg/kg), or vehicle pretreatment for 3 days. Rats were then tested during reinstatement with three doses of cocaine (5, 10, and 15 mg/kg, i.p. in mixed order). Results PROG, and to a greater extent ALLO, decreased cocaine-primed reinstatement in females, while finasteride blocked the attenuating effects of PROG on reinstatement. ALLO had no effect on cocaine-primed reinstatement in males. Conclusion These findings suggest that ALLO may explain part of PROG’s inhibitory effect on cocaine-primed reinstatement, and it may serve as a novel approach for preventing relapse in female cocaine abusers.