Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement

Rationale The use of animal models to study existing medications for smoking cessation can elucidate the mechanism(s) of action of cessation agents and further validate the models for medication development. Objective The objective of the study was to evaluate the response of nicotine self-administration (NSA) to pharmacological agents related to the smoking cessation medication bupropion and to nicotine dosing mimicking nicotine replacement on fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. Materials and methods NSA was maintained at a nicotine dose of 30 μg/kg/infusion i.v. in rats trained on FR5 and PR40% schedules. Pharmacological manipulations related to bupropion were examined by treating animals with a dopamine reuptake inhibitor [GBR 12909 (GBR)], a norepinephrine reuptake inhibitor [nisoxetine (NIS)], and a nicotinic antagonist [dihydro-β-erythroidine (DHβE)]. The effect of nicotine replacement was examined on the PR schedule by chronic dosing with osmotic minipumps. Results Significant treatment effects occurred with NIS and combinations of NIS–DHβE and with GBR on response rates. Chronic nicotine dosing reduced self-administration. The two schedules yielded different results with some treatments. Conclusions Noradrenergic–nicotinic cholinergic interactions and enhanced responding consequent to dopamine reuptake inhibition may be part of the complex behavioral pharmacology of bupropion-like compounds. Observation of differential results with the two schedules has implication for the use of self-administration techniques to elaborate the mechanisms of dependence as well as drug discovery.