Central Cholinergic Mechanisms in Cocaine Reinforcement

Mark, Gregory

Abstract

Cocaine is a potent psychostimulant with high abuse liability in humans. The substantial health risk posed by chronic cocaine use has prompted a serious research effort to identify the neurobiological substrates that underlie the motivational aspects of drug seeking. Research in this area has concentrated anatomically on a ventromedial nucleus of the basal ganglia called the nucleus accumbens (NAc), which is considered to be an integral component in the link between motivation and action. Recent neurochemical investigations have suggested the importance of several neurotransmitter systems (e.g. dopamine, serotonin, glutamate) localized within the NAc in modulating drug reinforcement. Despite this substantial progress, our understanding of the neurochemical mechanisms involved in the motivational/behavioral aspects of drug seeking remains incomplete. In particular, the NAc is known to contain a population of cholinergic interneurons whose activity may have important motivational consequences. Therefore, a primary goal of the proposed studies is to characterize the extent to which ACh modulates drug self-administration in rats. Sprague- Dawley rats will be implanted with intravenous catheters and trained to lever-press for infusions of cocaine on a progressive ratio schedule of reinforcement. After a steady level of baseline responding is established, micro-infusions of ACh agonists, oxotremorine and methylcarbamylcholine or cholinergic antagonists (atropine and mecamylamine) will be delivered into the lateral ventricle or bilaterally into the NAc prior to drug availability. Responding on both a drug-active and an inactive lever will be measured for five hours following each infusion. Selective increases in responding on the drug-active lever should indicate an increase in the motivation to obtain cocaine while decreases in responding would signal a suppression of cocaine's reinforcing effects. It is hoped that the results of these studies will contribute to an understanding of the neurochemical substrates which underlie drug-seeking and potentially contribute to the development of clinically efficacious treatments for drug craving and relapse.