The serotonin-1A receptor antagonist WAY-100635 modifies fluoxetine's antidepressant-like profile on the differential reinforcement of low rates 72-s schedule in rats

Rationale: Recent preclinical and clinical data suggest that co-administration of a serotonin-1A (5-HT-1A) receptor antagonist with an antidepressant drug has greater therapeutic efficacy than when the antidepressant drug is administered alone. Objective: The purpose of the present experiment was to determine whether pretreatment with the selective 5-HT-1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide (WAY-100635; 0.003, 0.03, 0.3 mg/kg, s.c.) would alter the effects of the antidepressant fluoxetine (2.5– 10 mg/kg, i.p.) on the differential reinforcement of low-rate 72-s (DRL 72-s) schedule. The DRL 72-s schedule is a behavioral screen selective and sensitive to antidepressant drugs. Results: WAY-100635 had no behavioral effects on its own. The lower doses of fluoxetine (2.5 mg/kg and 5 mg/kg) had no effects, but 10 mg/kg increased reinforcement rate without affecting response rate. The increase in reinforcement rate was blocked by pretreatment with 0.03 mg/kg and 0.3 mg/kg WAY-100635, although the combination of fluoxetine and WAY-100635 also significantly reduced response rate. Interestingly, 0.003 mg/kg or 0.03 mg/kg WAY-100635 administered with 5.0 mg/kg fluoxetine increased reinforcement rate, even though this dose of fluoxetine had no effect on performance. Conclusion: These data demonstrate that the behavioral effects of fluoxetine are modified by 5-HT-1A receptor blockade.