Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference: Possible Dependence on Dopamine Uptake Blockade

The involvement of the sigma1 receptor on the rewarding effects of cocaine was examined using the conditioned place preference (CPP) procedure in C57BL/6 mice. Acquisition or expression of cocaine (20 mg/kg i.p.)-induced CPP was significantly decreased by pre-treatment with the selective sigma1 receptor antagonists N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) or N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047), 1–10 mg/kg, i.p. The sigma1 receptor agonists igmesine or 2-(4-morpholinoethyl-1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) failed to induce CPP when injected alone. Moreover, the CPP induced by N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP), a selective dopamine reuptake inhibitor, was blocked by treatments with the sigma1 receptor antagonists as was similarly observed with cocaine. In addition, the repetitive treatment with cocaine during conditioning increased sigma1 receptor mRNA expression in the nucleus accumbens, but not in the caudate putamen, prefrontal cortex or cerebellum. These data show that the sigma1 receptor is not only necessary for acquisition of the cocaine-induced CPP, but that it is also implicated in its expression, confirming that activation of the sigma1 receptor is induced during cocaine's early effects. The sigma1 receptor is activated consequently to dopamine reuptake blockade and is not sufficient to induce CPP by itself. The mechanism of the sigma1 receptor involvement in CPP and the selectivity toward the CPP-inducing drug remains however to be determined. These results show that strategies targeting the sigma1 receptor with selective antagonists may allow effective attenuation of cocaine's rewarding properties and, in turn, offer new treatment strategies against drug addiction.