Reinforcing and discriminative stimulus effects of the neuroactive steroids pregnanolone and Co 8-7071 in rhesus monkeys

Abstract

Rationale and objectives: The present study was designed to assess possible abuse-related effects of the endogenous neuroactive steroid pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and the orally bioavailable, water-soluble neuroactive steroid pro-drug Co 8-7071 (3alpha,21-dihydroxy-3beta-trifluoromethyl-5beta-pregnan-20- one, 21-hemisuccinate).

Methods: Four rhesus monkeys were prepared with chronic intravenous (i.v.) catheters and trained to press a lever under a ten-response fixed-ratio (FR) schedule of methohexital injection (0.1 mg/kg per injection). Three rhesus monkeys were trained to discriminate intragastric infusions of pentobarbital (10 mg/kg) from saline infusions under a FR5 schedule of stimulus-shock termination.

Results: At least two doses of pregnanolone (0.003-0.1 mg/kg per injection) maintained injections per session above saline levels in the four monkeys tested, whereas Co 8-7071 (0.01-1.0 mg/kg per injection) maintained injections per session above saline levels in two of four monkeys at relatively low levels of injections per session. In rhesus monkeys trained to discriminate pentobarbital, i.v. pregnanolone injections (0.1-1.7 mg/kg, 5-min presession) dose-dependently reproduced the discriminative stimulus effects of pentobarbital in all monkeys tested. Intravenous administration of Co 8-7071 (1-10 mg/kg, 5-min presession) resulted in a dose-dependent increase to >80% pentobarbital-appropriate responding in two of three monkeys tested. Following intragastric infusions of Co 8-7071 (1.0-30 mg/kg), > or =80% pentobarbital-appropriate responding occurred in one out of three monkeys at 10 mg/kg when administered 60 min before the session. When administered 120 min before the session, however, 10-30 mg/kg Co 8-7071 reproduced the discriminative stimulus effects of pentobarbital in each of the three monkeys tested.

Conclusions: These data demonstrate barbiturate-like abuse-related effects that differed between two pregnane steroids. Whereas pregnanolone functioned as a reinforcer, suggesting that this compound has abuse potential, Co 8-7071 did not, despite having pentobarbital-like discriminative effects.