Rewarding effect of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one in mice

The GABAA-receptor agonist neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) has anxiolytic and locomotor stimulant effects and shares some subjective properties with benzodiazepines, barbiturates and ethanol, but there have been no studies of its reinforcing or rewarding effects. The present study examined the rewarding properties of 3 alpha,5 alpha-P using the conditioned place preference paradigm. Male DBA/2J mice received four pairings of a distinctive floor stimulus with 3 alpha,5 alpha-P (3.2, 10 or 17 mg/kg, IP) in an unbiased conditioning procedure. On alternate days a different distinctive floor was paired with vehicle. At the lowest dose (3.2 mg/kg), there was no difference between conditioning subgroups in preference for the drug-paired floor type, indicating an absence of place conditioning. However, a dose-dependent conditioned preference was evident at the higher doses as shown by the greater amount of time spent on the floor paired with 3 alpha,5 alpha-P. In addition, 3 alpha,5 alpha-P produced a dose-dependent increase in locomotor activity, which was significant following the 17 mg/kg dose. A control study showed no effect of the beta-cyclodextrin vehicle on place conditioning in the absence of neurosteroid. These results provide the first demonstration that 3 alpha,5 alpha-P, an endogenous modulator of GABAA receptor function, possesses rewarding properties using the conditioned place preference paradigm.