Rationale The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration. Objective to examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine. Methods Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward, BSR). Mice received cocaine (n=11, 3.0 – 30.0 mg/kg, i.p.) or the neuroactive steroid allopregnanolone (n=11, 3.0 – 17.0 mg/kg, i.p.). BSR thresholds (θ0) and maximum operant response rates (MAX) after drug treatments were compared to those after vehicle injections. Results Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 minutes following the 30 mg/kg dose, while allopregnanolone was maximally effective (30% reduction) 15-45 minutes after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates. Conclusions The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol suggesting that positive modulation of GABAA receptors can facilitate reward-related behaviors in C57BL/6J mice.

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