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. Findings from studies which utilized neuropharmacological and behavioral techniques suggest that dopaminergic and serotonergic forebrain projections are not mediators of the behavioral responses elicited by systemically administered TRH. Vagal and other afferent systems also do not appear to be involved. There was some indication the descending serotonergic projections may mediate some of the behavioral actions of TRH. Behaviorally effective doses of TRH were also found to activate c-fos (a marker for neuronal activity) in the granular layer of the cerebellum, pontine nuclei, and various thalamic regions 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. Studies using the forced-swim test, which has been used to screen for clinically effective antidepressants, have revealed that TRH seems to attenuate passive behaviors in this paradigm, which is consistent with its clinical effectiveness as an antidepressant. TRH was also found to dose-dependently decrease the acoustic startle response following i.p. administration, but had no effect on pre-pulse inhibition. Finally, TRH potentiated cocaine-induced locomotor activity. In thyroidectomized rats, the effects of i.p. TRH on startle and cocaine-induced hyperactivity were abolished, suggesting peripheral, i.e., thyroid hormone mediation of these effects of TRH. However, acute thyroid hormone (T3) injections did not affect cocaine-induced hyperactivity, and chronic T3 replacement in thyroidectomized animals did not reinitiate TRH's behavioral effects.