SEROTONIN MECHANISMS IN ALCOHOL-DRINKING BEHAVIOR

Rat lines selectively bred for disparate alcohol-drinking behaviors exhibit innate differences in the contents of serotonin (5-HT) in several CNS limbic regions, e.g., nucleus accumbens (ACB), frontal cortex, hypothalamus, and olfactory tubercles. In these regions, the selectively bred alcohol-preferring (P) line has levels approximately 20% (P < 0.05) lower than values obtained for the alcohol-nonpreferring (NP) line. In addition, in some limbic regions, the densities of (1) 5-HT1A receptors are higher by approximately 30% and (2) 5-HT1B and 5-HT2 receptors are lower (by 25-40%) in the P than in the NP line. Systemic administration of agents that increase synaptic levels of 5-HT, such as fluoxetine (a 5-HT uptake inhibitor), d-fenfluramine (a 5-HT releaser) and D, L-5-hydroxytryptophan (an immediate precursor of 5-HT), significantly decreased alcohol consumption of the P line of rats. Systemic (1.0 and 2.0 g/kp ip) administration or local perfusion (100 mM) of ethanol significantly increased the extracellular levels of 5-HT in the ACB of unselected Wistar rats. An interaction of the dorsal raphe nucleus (DRN) 5-HT system with the ventral tegmental area (VTA) dopamine (DA) pathway projecting to the ACB was indicated by the findings that DA release in the ACB increased and decreased following stimulation and inhibition, respectively, of DRN 5-HT neurons. Moreover, an involvement of 5-HT in mediating alcohol-stimulated DA release in the ACB is indicated by the observation that local application of a 5-HT3 antagonist can attenuate this stimulated release. Overall, the data suggest that an innate 5-HT deficiency in certain limbic structures of the P rat may be a major neurobiological factor underlying their high alcohol drinking characteristics. (C) 1993 Wiley-Liss, Inc.