On cholinergic mechanisms involved in ethanol reinforcement. A behavioral and neurochemical study in rodents

Abstract: Alcohol (ethanol) and smoking (nicotine) are commonly co-abused in human beings. Drugs of abuse interact with the brain mesolimbic dopamine system, an important part of the brain reward system. These dopaminergic neurons originate in the ventral tegmental area and project to e.g. the nucleus accumbens. Previous experiments in this research group have demonstrated that nicotinic acetylcholine receptors (nAChR), especially those located in the ventral tegmental area, are important in mediating the stimulating, dopamine enhancing and rewarding effects of ethanol in rodents. The overall aim of the present thesis was to further investigate the mode of action by which ethanol stimulates the mesoaccumal dopamine system. More specifically, the role of some nAChR subunits in mediating stimulatory, dopamine enhancing and rewarding effects was investigated. Furthermore, the possibility of an indirect effect of ethanol in stimulating the mesoaccumbal dopamine system was explored. Stimulatory effects of ethanol were measured by ethanol-induced locomotor activity, and the in vivo microdialysis technique was miniaturized from rats to mice to monitor ethanol-induced accumbal dopamine overflow. The rewarding effects of ethanol were assessed by means of a two-bottle (water and ethanol solution) free-choice paradigm in rodents. Additionally, a method to monitor acetylcholine levels in the ventral tegmental area concomitantly with extracellular dopamine levels in the nucleus accumbens in freely moving rats was developed. Obtained results indicate that the stimulatory and dopamine enhancing effects of ethanol are not mediated via alpha4beta2 or alpha7 containing nAChR, but that these receptors seem to be important in neurochemical effects of nicotine. Moreover, alpha-conotoxin MII, an alpha3beta2, beta3 and alpha6 nAChR antagonist, reduced the behavioral, neurochemical and rewarding effects of ethanol in rodents. In addition, with regard to a possible indirect ethanol-induced effect, voluntary ethanol intake in rats liberated endogenous ventral tegmental acetylcholine, almost time-locked with an overflow of dopamine in the nucleus accumbens. Collectively, the present thesis indicates that alpha-conotoxin MII sensitive receptors (possibly alpha3 subunit containing nAChR) could serve as pharmacological targets for treatment of alcoholism. The possibility of modulation of ventral tegmental acetylcholine should also be considered in the treatment of alcohol dependent individuals.