The effect of highly selective inhibitors of the uptake of noradrenaline or 5-hydroxytryptamine on TRH-induced hyperthermia in mice.

Well established as supposed antidepressant drugs, desipramine (1.25-5 mg/kg), nisoxetine (0.625-2.5 mg/kg) and clomipramine (1.25-5 mg/kg) but not fluoxetine (2.5-40 mg/kg) or citalopram (2.5-40 mg/kg) dose-dependently potentiated TRH (40 mg/kg)-induced hyperthermia in mice. Alpha-adrenergic blocking agents, phenoxybenzamine (20 mg/kg) and prazosin (5 mg/kg), which when given alone lowered body temperature, did not prevent the thermogenic effect of TRH but completely abolished the potentiating effect of clomipramine and almost completely antagonized the same effect of desipramine. The potentiating effect of desipramine on TRH-induced hyperthermia was also attenuated by 4 mg/kg l-propranolol but not by the same dose of d-propranolol. l-Propranolol (4 mg/kg) did not affect the potentiating effect of clomipramine. Cyproheptadine (5 mg/kg), an antagonist of 5-hydroxytryptamine receptors (which, like the alpha-adrenoceptor antagonist, produced hypothermia in normal mice) did not prevent the effects of clomipramine or desipramine. We conclude that a noradrenergic rather than a 5-hydroxytryptaminergic mechanism is involved in the potentiating effect of antidepressant drugs on TRH-induced hyperthermia. Hence, screening tests for antidepressants, which are based on the potentiation of the TRH-induced hyperthermia will always result in false negatives for antidepressants, such as citalopram, which are highly selective inhibitors of the uptake of 5-hydroxytryptamine.