Response of nicotine self-administration in the rat to manipulations of mu-opioid and gamma-aminobutyric acid receptors in the ventral tegmental area

Rationale: The mesolimbic dopamine system has been implicated in the reinfo rcing effects of nicotine, a drug which appears to act at least in part thr ough the ventral tegmental area (VTA). Other neuronal elements in the VTA a re important in drug reward. In particular, mu opioid receptors in the VTA have been shown to influence cocaine reinforcement. Objective: The aim of t his study was to test whether the mu opioid receptors in the VTA also regul ate the intake of nicotine. Methods. This research was carried out with ani mals trained to self-administer nicotine or cocaine, or to respond for food . Mu receptors were targeted with the selective agonist [D-Ala2,N-Me-Phe4,G ly-ol5]-enkephalin (DAMGO) and gamma-aminobutyric acid (GABA) receptors wit h the selective agonists baclofen and muscimol; each of these compounds was delivered by microinfusion into the VTA. Results: The mu-selective agonist DAMGO, tested over a dose range of 0.005-0.05 mu g, had an effect at the h ighest dose only, where it produced a reduction in self-administration main tained by doses of either 10 mu g/kg or 30 mu g/kg per infusion of nicotine . Intra-VTA microinfusions of DAMGO did not reinstate extinguished respondi ng previously established for nicotine, nor did they have prominent effects on operant behavior maintained by food. In contrast to the overall limited effects of DAMGO on nicotine self-administration, the GABA agonists muscim ol and baclofen each reduced nicotine self-administration substantially whe n delivered into the VTA, whereas they were less effective against cocaine self-administration. Conclusions: The lesser effect of DAMGO microinfusions in the VTA on nicotine than cocaine self-administration is associated with the opposite efficacy of GABA agonists. These findings suggest that nicoti ne and cocaine differentially activate circuitry in which mu receptors are situated, especially GABA-ergic elements.