Cocaine self-administration and locomotor activity are altered in Lewis and F344 inbred rats by RTI 336, a 3-phenyltropane analog that binds to the dopamine transporter

Abstract

Lewis and Fischer 344 (F344) rats differ in responses to cocaine and characteristics of the mesolimbic dopamine system. Compared to F344 rats, Lewis rats have lower D 2 receptor and dopamine transporter (DAT) levels in nucleus accumbens (NAc). We showed previously that altering D 1 and D 2 receptor levels pharmacologically had strain-dependent effects on cocaine self-administration. This study tests whether the phenyltropane analog, 3β-(4-Chlorophenyl) tropane-2β-[3-(4′-methylphenyl) isoxazol-5-yl] Hydrochloride (RTI 336), a potent and selective DAT inhibitor, differentially alters reinforcing, discriminative, and locomotor effects of cocaine in these strains. The effects of RTI 336 pretreatment on cocaine self-administration were assessed under a fixed-ratio (FR) schedule of reinforcement. Its effects on cocaine discrimination were conducted using a two-lever food-reinforced task. Finally, the effects of RTI 336 pretreatment on cocaine-induced locomotor activity were examined. RTI 336 increased cocaine self-administration in F344 rats, while Lewis rats showed reduced intake under the FR schedule. RTI 336 reduced cocaine-induced locomotor activity in Lewis rats but not in F344 rats. RTI 336 did not substitute for or antagonize cocaine's discriminative stimulus effects in either strain. Results show that a DAT inhibitor alters cocaine-induced behaviors in a strain-dependent manner. These effects may relate to inherent differences in NAc DAT levels between Lewis and F344 rats.