Alcohol-induced reinforcement: Dopamine and 5-HT3 receptor interactions in animals and humans

Abstract

Alcohol abuse is a major health problem worldwide. Whatever the treatment goal, be it abstinence or 'controlled' drinking, the outcome from both pharmacological and nonbiological treatments remains disappointing. Behavioural experiments in animals have suggested that the reinforcing properties of alcohol, like other drugs of abuse, are critical to drug-seeking behaviour. Dopaminergic fibres running from the ventral tegmental area to the nucleus accumbens may play a central role in mediating there inforcing effects of drugs of abuse including alcohol. Thus, alcohol increases extracellular levels of dopamine in the nucleus accumbens and dopamine receptor antagonists decrease alcohol consumption in a number of behavioural paradigms. A recently described subtype of serotonin (5-HT) receptor, the 5-HT3 receptor, appears to modulate the effects of alcohol on dopamine release in the nucleus accumbens. In rodents, 5-HT3 receptor antagonists inhibit alcohol-induced dopamine release in the nucleus accumbens. Further, in behavioural studies, 5-HT3 receptor blockade decreases alcohol consumption in a free-choice paradigm. In humans, reinforcement is difficult to measure directly. Nevertheless, the pleasurable subjective effects of alcohol are important behavioural correlates of the reinforcement process. Our preliminary findings in humans suggest that the 5-HT3 receptor antagonist, ondansetron, can attenuate some of the pleasurable effects of a small dose of alcohol including the subjective desire to drink. We speculate, although we have no direct evidence for this at present, that in humans this effect could also be due to a blockade of alcohol-induced dopamine release in the nucleus accumbens as has been demonstrated in animals. Further studies with clinical populations are required to assess the effects of 5-HT3 receptor antagonists on drinking behaviour and to explore their potential in the management of alcohol abuse.