The effect of the novel anxiolytic, buspirone, administered systemically was determined in Sprague-Dawley rats induced to drink ethyl alcohol chronically by repeated microinjections of 25 ng/microliter tetrahydropapaveroline HBr (THP) into brain-stem monoaminergic pathways. Self-selection of alcohol in concentrations from 3% to 30% was determined for each rat in a free-choice drinking situation with water available as the alternative fluid. After stereotaxic implantation of guide tubes, THP was microinjected repeatedly into striatal lemniscal and preoptic sites which were found to mediate significant increases in alcohol preference. After the baseline level of intake of a single, maximally preferred alcohol concentration was established, each rat was treated with either saline vehicle or buspirone given intramuscularly b.i.d. in doses of 5.0 mg/kg or 20 mg/kg. Overall, the repeated administration of either dose of buspirone produced a significant decrease in the voluntary alcohol intake of the rats as measured by the proportion measure and absolute g of alcohol ingested. However, the alteration in drinking varied from animal to animal with respect to both magnitude and duration of the anxiolytic's effect. The response to buspirone seemed to be dependent in part on the individual site in each animal at which THP had been infused to evoke alcohol intake. Post-mortem histological analysis revealed that buspirone-treated rats reduced alcohol consumption by 83% if THP had been microinjected into substantia nigra; by 60% if given in the nucleus accumbens-preoptic area; and by 34% when injected into the medial lemniscus-zona incerta. These results suggest, therefore, that buspirone can exert a specific effect in attenuating the consumption of alcohol of the rat in a free-choice situation. In relation to the differential actions of the anxiolytic, it is envisaged that on an anatomical basis the antagonism of alcohol drinking may be mediated by a pharmacological alteration of circumscribed pathways associated with dopaminergic or serotonergic neurons.