The mu opioid agonist DAMGO alters the intravenous self-administration of cocaine in rats: mechanisms in the ventral tegmental area.

Microinfusions of the opioid subtype-selective agonist DAMGO and antagonist CTOP into the ventral tegmental area (VTA) were used to examine the role of mu opioid receptors in this area of the mesolimbic dopamine system in regulating cocaine reinforcement. Long-Evans rats were trained to self-administer cocaine intravenously and prepared with intracranial cannulae directed to the VTA. At doses of cocaine on the descending limb of the cocaine dose-response curve, the mu-selective agonist DAMGO produced a dose-related decrease in cocaine self-administration when delivered by microinfusion into the VTA. At a dose of cocaine on the ascending limb of the self-administration dose-response curve, DAMGO microinfusions produced an increase in responding for the drug. The mu-selective antagonist CTOP produced small effects on cocaine self-administration. A kappa-selective agonist and antagonist (U50,488 and norbinaltorphimine, respectively) produced either no effects or small effects that did not show consistent trends with dose. These experiments suggest that the mu agonist DAMGO is able to shift the dose-response curve for cocaine self-administration to the left. This effect appears to be specific for mu as compared to kappa agonists. These data are consistent with the known differential distribution of opioid receptor subtypes within the VTA, and with the effects of opioid compounds in the VTA on dopamine release in the mesolimbic synaptic field. The data show that a mu opioid mechanism in the somatodendritic region can alter reinforcement processes for cocaine, which acts predominantly at the terminal field of dopamine cells.