Nucleus accumbens acetylcholine in drug addiction

Substance abuse and dependence are mental disorders of very high prevalence that exact great costs on society. Among the brain regions determining an addict`s deleterious preference for drug seeking and consumption over other behaviors, the nucleus accumbens, a ventral striatal structure, holds a central role. When we determined the neurotransmitter release in the nucleus accumbens core during the acquisition of the reinforcing effect of remifentanil, a mu opioid agonist, in an operant runway procedure using in vivo microdialysis followed by simultaneous tandem mass spectrometric (LC/MS/MS) analysis of dopamine, acetylcholine, and remifentanil, we found that the acquisition of remifentanil`s reinforcing effect was paralleled by an increase in acetylcholine overflow in the NAcore, whereas the overflow of dopamine, the expected prime neurotransmitter candidate for conditioning in drug reinforcement, did not change. Our results require a substantial modification of the "dopamine theory of reward", at least for the initial phase during which a drug of abuse gains control over an individual`s behavior, and have opened a new field of investigation. By local intra-accumbens manipulation nicotinic and muscarinic acetylcholine receptors, we propose to delineate the role of acetylcholine vs dopamine, both in the core and the shell region of the accumbens, during the acquisition and, finally, during the expression of drug vs food reinforcement, both for the drug stimulus itself as well as for the conditioning of drug-associated stimuli, with the aim of obtaining new therapeutic targets in the treatment of drug dependence. Details of our testable hypotheses are given below.

The road to recovery from drug abuse is a rough one for most drug-dependent individuals. Helping the substance- dependent individuals reorient their behavior toward non-drug alternative activities has remained one of the greatest challenges in the therapy of substance dependence and requires massive relearning from the individual. We discovered that acetylcholine, a brain neurotransmitter instrumental for attention, learning, and memory, is also necessary for the acquisition of drug seeking. Surprisingly, it was acetylcholine and not dopamine, the prime neurotransmitter most commonly involved in drug abuse and dependence, that was elevated in the nucleus accumbens core, a central area in the so-called brain "reward circuit", when rats learned to find drugs of abuse attractive. This effect could be blocked by locally administering antagonists of muscarinic and nicotinic receptors into the nucleus accumbens core. Of high therapeutic relevance, our intervention spared the attractiveness of natural reinforcers such as palatable food, indicating that drugs targeting the accumbal cholinergic system may leave the individual`s ability to perceive alternative natural stimuli as reinforcing intact. During the ensuing and continuing close scientific exchange with several basic and clinical researchers from all over the world, it became apparent that the contribution of the cholinergic system reverses during the progression of the addictive process. This "cholinergic switch" is currently being investigated in our laboratory.