LACK OF POTENTIATION OF THE ANTIALCOHOL EFFECTS OF FLUOXETINE BY PINDOLOL IN ALCOHOL-PREFERRING CAA RATS

1. Recent clinical evidence suggests that the nonselective 5-HT1A rece ptor antagonist pindolol may enhance the antidepressive efficacy of se lective serotonin reuptake inhibitors (SSRIs); an effect generally asc ribed to a presumed blockade of somatodendritic 5-HT1A receptors by pi ndolol. 2. The present study investigated whether blockade of 5-HT1A r eceptors similarly potentiates the previously reported anti-alcohol ef fects of the SSRI fluoxetine. 3. Pindolol and the selective 5-HT1A rec eptor antagonist WAY-100635 were tested alone and in combination with fluoxetine in cAA rats, a genetic model of alcoholism. However, as pin dolol has also a high affinity to 5-HT1B receptors, the effects of sel ective 5-HT1B receptor agonists and antagonists were evaluated as well . 4. Neither pindolol (3-30 mg/kg, IP), nor WAY-100635 (1-10 mg/kg, IF ) affected alcohol intake when tested alone. In contrast, the 5-HT1B r eceptor agonists CP-94,253 and TFMPP (both 1-10 mg/kg, IP), and antago nists metergoline (1-10 mg/kg, IP) and GR 127935 (3-30 mg/kg, IP) were found to reduce alcohol intake with different degrees of selectivity (that is, the extent to which reductions in ethanol intake could be se parated from reductions in food- and/or total fluid intake) and specif icity (that is, the degree to which effects on ethanol intake coincide d with effects on ethanol preference). 5. Because the behavioral profi le of pindolol resembles that of WAY-100635, and not that of the 5-HT1 B receptors ligands, combination experiments with fluoxetine were only performed with the former two compounds. Neither pindolol (30 mg/kg), nor WAY-100635 (3 mg/kg) potentiated the anti-alcohol effects of fluo xetine (10 mg/kg, IP). Moreover, WAY-100635 tended to shift the anti-a lcohol effect of fluoxetine towards a less selective and specific prof ile. It is concluded that acute blockade of 5-HT1A receptors does not potentiate the anti-alcohol effects of fluoxetine. In addition, it is suggested that different mechanisms underly the antidepressive and ant i-alcohol effects of SSRIs.