l-152804 and Cocaine-Related-Disorders

Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined.. To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.. The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular dopamine with microdialysis as well as dopamine transporter-mediated uptake of dopamine in vitro. Immunocytochemistry was used to determine whether dopamine neurons express Y5-like immunoreactivity.. In self-administration, L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose-response curve for cocaine downward. Y5-KO mice also showed modestly attenuated self-administration. Cocaine-induced hyperactivity was attenuated by L-152,804 and in Y5-KO mice. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L-152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behaviour by regulating dopamine. Consistent with this concept, dopamine neurons in the ventral tegmental area appeared to contain Y5 receptors. In contrast, neither L-152,804 nor NPY influenced dopamine transporter-mediated dopamine uptake.. The present data indicate that Y5 antagonism may attenuate cocaine-induced behavioural effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction.

Topics: Animals; Animals, Outbred Strains; Cocaine; Cocaine-Related Disorders; Corpus Striatum; Cyclohexanes; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Drug Interactions; Female; Hyperkinesis; Male; Mice; Mice, Knockout; Nucleus Accumbens; Receptors, Neuropeptide Y; Reinforcement, Psychology; Self Administration; Xanthenes