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

Abstract

Alcohol abuse i s 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 the reinforcing 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 doparnine release in the nucleus accumbens. Further, in behavioural studies, 5-HT3 receptor blockade decreases alcohol consumption in a free-choice paradigm. In humans, reinforcement i s 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.

Neuropharmacological treatments for alcoholism: scientific basis and clinical findings

“…Behavioral pharmacological studies show that many of alcohol's rewarding effects are mediated by interactions between DA and 5-HT 3 receptors in the midbrain and cortex (Wise and Bozarth 1987;Koob 1992;Johnson and Cowen 1993;Barnes and Sharp 1999;Hemby et al 1997b). 5-HT 3 receptors are densely distributed in the terminals of mesocorticolimbic DA-containing neurons where they regulate DA release in these brain regions (Kilpatrick et al 1987(Kilpatrick et al , 1996Oxford et al 1992).…”

“…Demonstration that 5-HT 3 receptor blockade reduces DA activity, and therefore the rewarding effects of abused drugs (including alcohol) comes from at least three different animal paradigms. 5-HT 3 receptor antagonists: a) attenuate hyperlocomotion in the rat induced by DA or ethanol injection into the nucleus accumbens (Bradbury et al 1985); b) inhibit DiMe-C7 (a neurokinin) induced hyperlocomotion which is also attenuated by the DA antagonist, fluphenazine (Eison et al 1982;Hagan et al 1990), and c) 5-HT 3 receptor antagonists decrease alcohol consumption in several animal models and across different species (Costall et al 1987;Fadda et al 1991;Sellers et al 1992;Hodge et al 1993;Johnson et al 1993;Meert 1993;Dyr and Kostowski 1995;Tomkins et al 1995;McBride and Li 1998;Rodd-Henricks et al 1999;Barnes and Sharp 1999;cf. Beardsley et al 1994).…”

“…In two separate studies, we were the first to show that ondansetron pretreatment attenuated low-dose alcohol-induced positive subjective effects (including the desire to drink) (Johnson and Cowen 1993;Johnson et al 1993). Swift and colleagues , using much higher alcohol and ondansetron doses, also found that ondansetron pre-treatment, compared with placebo, decreased alcohol preference.…”

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

“…Pharmacobehavioral studies show that many of alcohol's reinforcing effects are mediated by 5-HT 3 and dopamine interactions in the cortico-mesolimbic system [9,[213][214][215][216].…”

“…In two distinct experiments, Johnson and Cowen [214] and Johnson et al [224] showed that ondansetron pretreatment attenuated lowdose alcohol-induced positive subjective effects (including the desire to drink). Swift et al [230], using much higher alcohol and ondansetron doses, also discovered that ondansetron compared with placebo pretreatment reduced alcohol preference; however, a mixture of both stimulant and sedative interactions between ondansetron and alcohol also was observed.…”