5-HT receptor ligands differentially affect operant oral self-administration of ethanol in the rat

The present study evaluated the effects of the selective serotonin (5-hydroxyhyptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT_1B receptor agonist, tetrahydro-4-pyridyl[3,2-b]pyridine, CP-94,253 the preferential 5-HT_2A receptor agonist, 1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane, DOI and the mixed 5-HT_2C/1B receptor agonist, 1-(3-chlorophenyl)piperazine, mCPP, on oral ethanol (10% v/v) self-administration in a two-lever, fixed-ratio:1, water vs. ethanol choice procedure in the rat. All compounds affected operant behavior, with varying degrees of specificity, that is, the extent to which a reduction of ethanol-reinforced lever pressing coincided with a reduction of ethanol preference, and selectivity, that is, the extent to which a reduction of ethanol-reinforced lever pressing could be dissociated from an effect on total responding on both levers. Fluoxetine (5–20 mg/kg, i.p.) and CP-94,253 (1–10 mg/kg, i.p.) induced a nonselective disruption of operant behavior; the profile being weakly specific for CP-94,253. DOI (0.1–0.3 mg/kg, i.p.) and mCPP (0.3–1 mg/kg, i.p.) induced a specific effect; the profile being more selective for DOI. These findings suggest that operant ethanol self-administration can be suppressed in a specific manner by activation of 5-HT_2A and, possibly, 5-HT_2C receptors, and in a nonselective manner by activation of 5-HT_1B receptors. As fluoxetine indirectly stimulates these receptors and its behavioral profile resembles more that of a 5-HT_1B receptor agonist, activation of 5-HT_1B receptors may underlie its effects on operant ethanol self-administration.