Recent evidence suggests that thyrotropin releasing hormone (TRH) may be a potential antidepressant in humans. The mechanisms underlying its antidepressant actions are unknown. Elucidating the mechanisms of action of TRH may provide new insights for the development of novel pharmacotherapeutic agents in the treatment of depression. Although systemically administered TRH produced a constellation of motoric effects in rats, no alterations were found in forebrain dopamine release with in vivo microdialysis procedures. Forebrain serotonergic pathways are also not involved in mediating such behavioral effects, as revealed by selective lesioning studies. Decreases in some of the behavioral effects of TRH were, however, found following 5'7-DHT lesions of the raphe nucleus, suggesting that descending serotonergic systems may mediate at least some of the pharmacological actions of TRH. Vagotomy was not found to alter any of the behavioral effects of TRH over a wide range of doses, while decreasing the depressant effects of CCK-8. Deafferentation also had little effect on the behavioral actions of TRH, suggesting that peripheral actions of this peptide are not critical for determining its behavioral profile. In situ hybridization techniques revealed considerable induction of c-fos mRNA in the pontine nuclei, deep layers of the cerebellum, and thalamic nuclei following systemic injections. Activation of these central nervous system components may have relevance for understanding the mechanisms through which this compound produces its antidepressant effects. Extensive studies using the forced-swim test, which has been used to screen for clinically effective antidepressants, have revealed that TRH has little effect on passive behaviors in this test. It is possible, however, that it may potentiate clinical antidepressants in this behavioral paradigm.