The cholinergic system in drug dependence

Drug dependence represents a serious health problem to our societies. Improving treatment efficacy has remained a considerable therapeutic challenge. The Austrian host research group was the first to show that the acquisition (i.e., learning) of drug (but not food)-seeking behavior critically depends on the activation of nicotinic and muscarinic acetylcholine receptors in the core region of the nucleus accumbens. In contrast, after chronic drug use, activation of the cholinergic system by acetylcholinesterase inhibitors causes a decrease in the reinforcing effects of drugs of abuse. Our aim is to investigate the neurobiological basis of this "cholinergic switch", i.e., opposite effects of the activation of the cholinergic system during the initial vs chronic stage of drug abuse. We propose to investigate if the contribution of the nucleus accumbens core cholinergic system becomes less and less important with increasing duration of cocaine self-administration in three different operant conditioning paradigms (Skinner box, T-maze, straight runway) coupled with in vivo microdialysis and LC/MS/MS. We also aim to investigate if the acetylcholinesterase inhibitor donepezil can enhance reallocation of behavior directed at a non-drug reinforcer (i.e., food) in chronically cocaine-self-administering animals, i.e., if donepezil can enhance (re-)learning of non-drug- associated behavior. Finally, we intend to explore molecular mechanisms underlying the cholinergic switch. In summary, the proposed project will investigate the changing role of the cholinergic system during the course of drug dependence (the "cholinergic switch") and possibly lead to novel therapies.