σ1 receptor-related neuroactive steroids modulate cocaine-induced reward

The sigma(1) receptor is critically involved in the rewarding effect of cocaine, as measured using the conditioned place preference (CPP) procedure in mice. Neuroactive steroids exert rapid neuromodulatory effects in the brain by interacting with GABA(A), NMDA, and sigma(1) receptors. At the sigma(1) receptor level, 3beta-hydroxy-5-androsten-17-one [dehydroepiandrosterone (DHEA)] and 3beta-hydroxy-5-pregnen-20-one ( pregnenolone) act as agonists, whereas 4-pregnene-3,20-dione ( progesterone) is an efficient antagonist. The present study sought to investigate the action of neuroactive steroids in acquisition of cocaine-induced CPP in C57BL/6 mice. None of these steroids induced CPP alone. However, pretreatment with DHEA or pregnenolone ( 5 - 20 mg/kg, s.c.) during conditioning with cocaine ( 10 mg/kg, i.p.) increased the conditioned score. On the contrary, pretreatment with either progesterone ( 10 or 20 mg/kg, s.c.) or finasteride ( 25 mg/kg, twice a day), a 5alpha-reductase inhibitor, blocked acquisition of cocaine (20 mg/kg)-induced CPP. A crossed pharmacology was observed between steroids and sigma(1) ligands. The sigma(1) antagonist N-[2-(3,4-dichlorophenyl) ethyl]- N- methyl-2-(dimethylamino) ethylamine blocked cocaine-induced CPP and its potentiation by DHEA or pregnenolone. Progesterone blocked cocaine-induced CPP and its potentiation by the sigma(1) agonist igmesine. These results showed that neuroactive steroids play a role in cocaine-induced appetence, through their interaction with the sigma(1) receptor. Therefore, neuroendocrine control of cocaine addiction may not involve solely glucocorticoids. The importance of neuroactive steroids as factors of individual vulnerability to drug addiction should, thus, be considered.