Serotonergic mediation of DRL 72s behavior: Receptor subtype involvement in a behavioral screen for antidepressant drugs

Background: The functioning of the brain serotonin system has been implicat ed in the action of antidepressant drugs. The behavior of rats performing t he Differential Reinforcement of Low Rate-72 sec (DRL 72s) has been used as a screen for drugs with antidepressant activity. Many antidepressant drugs alter serotonergic function. Hence, experiments were designed to investiga te the role of the brain serotonin system in the performance of DRL 72s beh avior. Methods: Rats were trained to perform a DRL 72s, and then depleted (LESION) of brain serotonin (5-HT) using intracerebroventricular 5,7-dihydroxytrypt amine (5,7-DHT). Control rats (SHAM) were injected with the 5,7-DHT vehicle . Results: The 5,7-DHT-treated rats showed a higher response rate, a decrease in the number of reinforcements, and a shift in the interresponse time (IR T) distribution reward shorter IRTs when compared to SHAM and prelesion per formance. The behavioral deficit in the 5,7-DHT rats persisted for 17 weeks . Postmortem assays indicated extensive depletion of 5-HT in all the assaye d brain regions of the LESION rats. The effects of the serotonergic agonist s 8-hydroxy-2-di-N-propylaminotetralin (8-OH-DPAT), 5-methoxy-dimethyltrypt amine (5-MeODMT), buspirone, and 5-hydroxytryptophan (5-HTP) were assessed. 5-MeODMT and 8-OH-DPAT resulted in greater improvement of DRL 72s performa nce in the LESION rats than in the SHAM rats. Buspirone failed to ameliorat e the behavioral deficit in the LESION rats and produced a behavioral defic it in the SHAM rats. 5-HTP improved performance in the SHAM rats and in the LESION rats. Conclusions: These results support the contention that the brain 5-HT syste m is involved in the mediation of antidepressant drug effects. (C) 1999 Soc iety of Biological Psychiatry.