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 o f mu opioid receptors in this area of the mesolimbic dopamine system in reg ulating cocaine reinforcement. Long-Evans rats were trained to self-adminis ter 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 decr ease in cocaine self-administration when delivered by microinfusion into th e VTA. At a dose of cocaine on the ascending limb of the self-administratio n dose-response curve, DAMGO microinfusions produced an increase in respond ing for the drug, The mu-selective antagonist CTOP produced small effects o n cocaine self-administration. A kappa-selective agonist and antagonist (U5 0,488 and norbinaltorphimine, respectively) produced either no effects or s mall effects that did not show consistent trends with dose, These experimen ts suggest that the mu agonist DAMGO is able to shift the dose-response cur ve for cocaine self-administration to the left. This effect appears to be s pecific for mu as compared to kappa agonists. These data are consistent wit h the known differential distribution of opioid receptor subtypes within th e VTA, and with the effects of opioid compounds in the VTA on dopa mine rel ease in the mesolimbic synaptic field. The data show that a mu opioid mecha nism in the somatodendritic region can alter reinforcement processes for co caine, which acts predominantly at the terminal field of dopamine cells.