5-HT1A agonists:: alcohol drinking in rats and squirrel monkeys

Rationale: Increased alcohol intake after administration of low doses of 5-HT1A agonists is thought to be due to a reduction in 5-HT impulse flow due to activation of 5-HT1A somatodendritic receptors, whereas decreased alcohol drinking found after administration of higher doses of 5-HT1A agonists may be mediated by action at postsynaptic 5-HT1A receptors. Objective: This study compares Long-Evans rats and squirrel monkeys to examine the hypothesis that low doses of the 5-HT1A selective agonists, 8-OH-DPAT and alnespirone, will preferentially increase, and at higher doses decrease alcohol drinking, and whether these effects can be antagonized by WAY 100635. Methods: Male Long-Evans rats were induced to drink from two bottles, one containing a solution of 10% ethanol and 1% sucrose (w/v), the other containing an equally preferred concentration of sucrose. Squirrel monkeys also drank from two bottles, one containing a solution of 2% ethanol and 15% sucrose (w/v), the other, water. Results: In rats, low doses of both 8-OH-DPAT (0.018-0.03 mg/kg) and alnespirone (0.3-3.0 mg/kg) increased alcohol drinking by ca. 100% without altering sucrose intake. The highest dose of 8-OH-DPAT (0.1 mg/kg) suppressed intake of both solutions without significant motor impairment. Pretreatment with WAY 100635 (0.1 mg/kg), shifted the entire dose-effect curve of 8-OH-DPAT to the right, and antagonized the effects of the 0.56 mg/kg dose of alnespirone. In the monkeys, administration of both agonists dose-dependently decreased alcohol intake and were behaviorally sedative. Conclusions: These results support the hypothesis that in rats, 5-HT1A receptor stimulation activates somatodendritic receptors at lower doses and postsynaptic receptors at higher doses, each with opposite effects on alcohol intake. The absence of such biphasic dose-effect curves in monkeys suggests a different. function of 5-HT1A somatodendritic receptors in rats and monkeys, at least with regard to alcohol drinking.