Potentiation by TRH of the effect of imipramine on the forced-swimming test.

Discovery of the potentiation of thyrotropin releasing hormone (TRH)-induced hyperthermia in mice by antidepressants which activate alpha-adrenergic systems instigated investigation of other relations between TRH and antidepressants. For this study the forced-swimming test using mice was chosen since this test is more sensitive for selection of antidepressants which modify catecholaminergic systems than for those affecting 5-hydroxytryptaminergic systems. The effects of imipramine were potentiated by TRH. The involvement of alpha-adrenergic systems was then investigated in this effect since it is already known that these systems are directly implicated in the potentiation of TRH-induced hyperthermia by some antidepressants. Then the involvement of opiate systems was investigated since endogenous opiates are implicated in the action of some antidepressants, and some interactions between TRH and opiate systems are known to exist. TRH made effective a completely inactive dose of imipramine as small as 2 mg kg-1 (i.p.) or 1 microgram per mouse (i.c.v.). Pretreatment by both alpha 1- and alpha 2-adrenoceptor antagonists (phenoxybenzamine, 8 mg kg-1 i.p.; phentolamine, 4 mg kg-1 i.p.) or by a alpha 1-adrenoceptor antagonist (prazosin, 2 mg kg-1 i.p.) did not prevent this potentiation. In contrast the alpha 2-adrenoceptor antagonist (Yohimbine, 2 mg kg-1 i.p.) blocked the TRH effect. The imipramine potentiation by TRH was blocked by pretreatment with an opiate antagonist (naloxone, 1 mg kg-1 i.p.) and the potentiation was decreased in morphine-tolerant mice. 5 These data indicate that potentiation of the effects of imipramine on the forced-swimming test does not seem to be associated with an increase of effective levels of noradrenaline in the synaptic clefts and suggest an interaction between TRH and the opiate systems.