Nomifensine alters sex differences in striatal dopaminergic function

Abstract

A series of three experiments are presented in which the acute effects of the catecholamine reuptake inhibitor, nomifensine, upon striatal dopaminergic function are compared in female and male mice. In Experiment 1, treatment with nomifensine (5 mg kg⁻¹), at 30 min prior to injection of methamphetamine (40 mg kg⁻¹) significantly decreased the amount of striatal dopamine depletion in male, but not female, mice, thereby abolishing the sex difference in methamphetamine-induced neurotoxicity (males > females). In Experiment 2, the methamphetamine-evoked sex differences in dopamine and DOPAC output from superfused striatal tissue (males > females) were abolished in mice treated with nomifensine at 30 min prior to tissue removal. In Experiment 3, the potassium chloride-evoked sex differences in dopamine and DOPAC output from superfused striatal tissue (females > males) were reversed in mice treated with nomifensine at 30 min prior to tissue removal. Taken together these results demonstrate the critical role played by catecholamine transporters in sex differences of dopaminergic function and suggest that this may involve the dopamine transporter, due to its high concentrations within the striatum. Such findings highlight the need for gender-specific considerations in use of treatments that target reuptake transporters function.