Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism

Acute or chronic consumption of alcohol interferes differentially with transmission processes in the CNS, affecting many--if not all--of the known neurotransmitter systems. Conversely, selective pharmacological manipulations of some of these neurotransmitter systems have been shown to reduce ethanol intake and preference as well as the severity of the ethanol withdrawal syndrome in animal models, certain compounds having even been employed successfully in the clinic. This review examines the studies which have attempted to elucidate the roles of these neurotransmitter systems in the mechanisms involved in the various aspects of alcohol abuse and alcoholism, with an emphasis on recent developments. The brain's major amino acid transmitter systems--inhibitory gamma-aminobutyric acid (GABA) and excitatory glutamate--have been widely studied over the past decade, with the general consensus that acute ethanol facilitates GABAergic transmission (by enhancing chloride conductance through the GABAA receptor) and inhibits glutamatergic function (by decreasing cationic conductance through the NMDA receptor). Conversely, the development of tolerance associated with chronic ethanol consumption leads to a reduced GABAergic and increased glutamatergic function. Interactions between ethanol and the monoaminergic transmitter systems are complex. Dopaminergic and noradrenergic mechanisms, along with the endogenous opioid systems of the brain, seem to be implicated in the rewarding effects of ethanol via activation of positive reinforcement pathways, while the serotonergic system mediates negative reinforcement. A number of ligands of the dopaminergic, serotonergic and opioidergic receptors involved in ethanol consumption-related behaviors have been recognized for their effects in reducing ethanol preference and/or alleviating symptoms of the ethanol withdrawal syndrome in various animal models. Several of these substances are being used with success clinically. Studies of the central cholinergic system in alcoholics have provided clues to the mechanisms underlying the deleterious effects of ethanol on learning and memory, and evidence of a reduced central cholinergic activity has been reported in alcohol-dependent patients. Interestingly, acetylcholine-rich grafts and cholinomimetic drugs have been found to ameliorate ethanol-induced behavioral deficits in alcoholized rats. More generally, basic studies on alcohol's effects on central neurotransmission certainly hold the key to the development of new strategies for the treatment of alcoholism.