Sigma 1 receptor-related neuroactive steroids modulate cocaine-induced reward

Abstract

The sigma1 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 sigma1 receptors. At the sigma1 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 sigma1 ligands. The sigma1 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 sigma1 agonist igmesine. These results showed that neuroactive steroids play a role in cocaine-induced appetence, through their interaction with the sigma1 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.

Fig. 1.

Effects of neuroactive steroids on acquisition of cocaine-induced CPP: coadministration of DHEA (a) or pregnenolone (b). Steroids were administered subcutaneously 10 min before cocaine, which was given immediately before placement in the compartment during conditioning. Conditioned scores represent the difference in time spent in the drug-paired compartment between the postconditioning and preconditioning sessions. Mice per group: n = 12–16 (a) and n = 8–12 (b). V, Vehicle. *p < 0.05 and **p < 0.01 versus the V+V-treated group;^#p < 0.05 versus the cocaine+V-treated group.

Fig. 2.

Effects of neuroactive steroids on acquisition of cocaine-induced CPP: coadministration of progesterone (a) or effect of the 5α-reductase inhibitor finasteride (b). Progesterone was administered subcutaneously 10 min before cocaine, given immediately before placement in the compartment during conditioning. Finasteride (25 mg/kg) was administered subcutaneously, every 12 hr during 6 d, starting 1 d before preconditioning. Conditioned scores represent the difference in time spent in the drug-paired compartment between the postconditioning and preconditioning sessions. Mice per group:n = 12–19 (a) andn = 10–19 (b). V, Vehicle. *p < 0.05 and **p < 0.01 versus the V+V-treated group; ^#p < 0.05 versus the cocaine+V-treated group.

Fig. 3.

Involvement of the σ₁ receptor in the modulation of cocaine-induced CPP by neuroactive steroids: blockade by the σ₁ antagonist BD1047 of the potentiating effects of DHEA (a) or pregnenolone (b). BD1047 was administered intraperitoneally simultaneously with the steroid, given subcutaneously 10 min before cocaine, injected immediately before placement in the compartment during conditioning. Mice per group: n = 12–25 (a) and n = 12–26 (b). V, Vehicle. *p < 0.05 and **p < 0.01 versus the V+V-treated group;^#p < 0.05 versus the cocaine+V-treated group.

Fig. 4.

Involvement of the σ₁ receptor in the modulation of cocaine-induced CPP by neuroactive steroids: coadministration of the σ₁ agonist igmesine before cocaine (a) and blockade of its effect by progesterone (b). Progesterone was administered subcutaneously simultaneously with igmesine, given intraperitoneally 10 min before cocaine, injected immediately before placement in the compartment during conditioning. Mice per group: n= 11–19 (a) and n = 10–20 (b). V, Vehicle. *p < 0.05 and **p < 0.01 versus the V+V-treated group;^#p < 0.05 and^##p < 0.01 versus the cocaine+V-treated group.