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

Rationale and Objectives: The present study was designed to assess possible abuse-related effects of the endogenous neuroactive steroid pregnanolone ( 3 alpha-hydroxy-5 beta-pregnan-20-one) and the orally bioavailable, water-s oluble neuroactive steroid pro-drug Co 8-7071 (3 alpha,21-dihydroxy-3 beta- trifluoromethyl-5 beta-pregnan-20-one, 21-hemisuccinate). Methods: Four rhe sus monkeys were prepared with chronic intravenous (IV) catheters and train ed to press a lever under a ten-response fixed-ratio (FR) schedule of metho hexital injection (0.1 mg/kg per injection). Three rhesus monkeys were trai ned to discriminate intragastric infusions of pentobarbital (10 mg/kg) from saline infusions under a FR5 schedule of stimulus-shock termination. Resul ts: At least two doses of pregnanolone (0.003-0.1 mg/kg per injection) main tained injections per session above saline levels in the four monkeys teste d, whereas Co 8-7071 (0.01-1.0 mg/kg per injection) maintained injections p er session above saline levels in two of four monkeys at relatively low lev els of injections per session. In rhesus monkeys trained to discriminate pe ntobarbital, IV pregnanolone injections (0.1-1.7 mg/kg, 5-min presession) d ose-dependently reproduced the discriminative stimulus effects of pentobarb ital in all monkeys tested. Intravenous administration of Co 8-7071 (1-10 m g/kg, 5-min presession) resulted in a dose-dependent increase to >80% pento barbital-appropriate responding in two of three monkeys tested. Following i ntragastric infusions of Co 8-7071 (1.0-30 mg/kg), greater than or equal to 80% pentobarbital-appropriate responding occurred in one out of three monk eys at 10 mg/kg when administered 60 min before the session. When administe red 120 min before the session, however, 10-30 mg/kg Co 8-7071 reproduced t he discriminative stimulus effects of pentobarbital in each of the three mo nkeys tested. Conclusions: These data demonstrate barbiturate-like abuse-re lated effects that differed between two pregnane steroids. Whereas pregnano lone functioned as a reinforcer, suggesting that this compound has abuse po tential, Co 8-7071 did not, despite having pentobarbital-like discriminativ e effects.