Short-term effects of the nociceptin receptor antagonist Compound B on the development of methamphetamine sensitization in mice: a behavioral and c-fos expression mapping study.

The nociceptin antagonist Compound B (CompB) stimulates mesolimbic dopamine release and induces a conditioned place preference but has little effect on locomotion. As behavioral sensitization often occurs as an epiphenomenon to mesolimbic activation and reward, we studied the effect of CompB on behavioral sensitization to methamphetamine. Locomotor responses of C57BL6 mice to repeated methamphetamine (2 mg/kg s.c.) administration alone or immediately following CompB (10 mg/kg s.c.) were recorded for 3 alternating days. Six days later, methamphetamine (1 mg/kg s.c.) was administered and locomotor activity monitored again before determining neural activity by analysis of c-fos expression. Methamphetamine treatment induced a progressive locomotor (behavioral) sensitization, with CompB pretreatment enhancing the locomotor response to methamphetamine during the early stages only. Previous CompB administration little affected methamphetamine-sensitized or acute methamphetamine-induced locomotion on the challenge day. Analysis of c-fos expression supported these results as of the 36 neuroanatomical regions quantified; very few showed CompB-dependent responses. However, numerous regions differentially responsive to either acute (e.g. ventromedial, ventrolateral and central caudate putamen), chronic (e.g. central amygdala, lateral habenula, dorsomedial caudate putamen) or sensitized (e.g. medial nucleus accumbens core, central amygdala, lateral habenula) methamphetamine treatment were identified, thereby providing a comprehensive map of the short and long-term effects of methamphetamine on mouse brain activity per se. Thus, despite its mesolimbic activating and rewarding properties, CompB has little long-term influence on neural activity, suggesting CompB is able to induce short-term increases in hedonic state in the absence of locomotion or major long-term effects.