Rationale: There is evidence that central mu opioid receptors (MORs) are implicated in several aspects of cocaine addiction, and that MOR expression is elevated by cocaine in vitro and in the nucleus accumbens (NAc) when administered in vivo.
Objective: To understand the cellular mechanisms involved in regulating MOR expression, this study explored whether neuronal nitric oxide synthase (nNOS) modulates the neurochemical and behavioral effects of acute and repeated cocaine administration.
Methods: Male Sprague-Dawley rats received a single cocaine injection (20 mg/kg, i.p.) in combination with the selective nNOS inhibitor 7-nitroindazole (7-NI) (0, 25, or 50 mg/kg, i.p.), and the expression of MOR and nNOS messenger RNA (mRNA) and protein levels in the NAc were measured. In a separate conditioned place preference (CPP) experiment, 7-NI (0, 25, or 50 mg/kg, i.p.) was administered prior to cocaine (0 or 20 mg/kg, i.p.) conditioning sessions, and levels of MOR and nNOS mRNA and protein in the NAc were measured following CPP test.
Results: Acute cocaine administration significantly enhanced nNOS and MOR mRNA and protein expression in the NAc, and this increase in MOR expression was blocked by 7-NI. Furthermore, in 7-NI pre-treated rats, cocaine-induced CPP was not statistically significant and the increase in MOR mRNA expression in the NAc in these animals was attenuated.
Conclusions: These findings suggest that nNOS modulates MOR expression following acute cocaine administration, and that cocaine CPP and associated upregulation of MOR expression involve both nNOS-dependent and independent mechanisms. Elucidation of these molecular events may identify useful therapeutic target for cocaine addiction.
Keywords: 7-Nitroindazole; Cocaine; Conditioned place preference; Mu opioid receptor; Neuronal nitric oxide synthase; Nucleus accumbens.