Individual differences in cocaine-induced locomotor sensitization in low and high cocaine locomotor-responding rats are associated with differential inhibition of dopamine clearance in nucleus accumbens.

Abstract

Behavioral sensitization to cocaine reflects neuroadaptive changes that intensify drug effects. However, repeated cocaine administration does not induce behavioral sensitization in all male Sprague-Dawley rats. Because cocaine inhibits the dopamine (DA) transporter (DAT), we investigated whether altered DAT function contributes to these individual differences. Freely moving rats had electrochemical microelectrode/microcannulae assemblies chronically implanted in the nucleus accumbens so that exogenous DA clearance signals were recorded simultaneous with behavior. The peak DA signal amplitude (A(max)) and efficiency of clearance (k) were used as indices of in vivo DAT function. Low and high cocaine responders (LCRs and HCRs, respectively) were identified based on their locomotor responsiveness to an initial injection of cocaine (10 mg/kg i.p.). Consistent with DAT inhibition, cocaine elevated A(max) and reduced k in HCRs, but not in LCRs. The same dose of cocaine was administered for six additional days and after a 7-day withdrawal. Baseline behavioral and dopamine clearance indices were unaltered by repeated cocaine or after withdrawal. Only LCRs expressed cocaine-induced sensitized locomotor activation, and this was accompanied by cocaine-induced elevations in A(max) and reductions in k. These sensitized responses to cocaine persisted in LCRs after withdrawal. In contrast, neither locomotor nor electrochemical responses were altered by repeated saline administration or a saline challenge after repeated cocaine administration, suggesting that conditioning did not significantly contribute. Our results suggest that increased DAT inhibition by cocaine is associated with locomotor sensitization and that DAT serves as a common substrate for mediating both the initial and sensitized locomotor responsiveness to cocaine.