The reversal of the central effects of noradrenaline by antidepressant drugs in mice

Abstract

1. Noradrenaline given directly into the lateral cerebral ventricles induced hypothermia in mice. This hypothermia was antagonized and eventually reversed to a hyperthermia by imipramine-like antidepressant drugs.2. The mechanism of action involved in this effect of antidepressant drugs has been studied using nortriptyline as a typical representative of antidepressant drugs.3. Nortriptyline pretreatment did not modify either the uptake, subcellular distribution, or the metabolism of (3)H-noradrenaline injected into the lateral cerebral ventricles.4. Nortriptyline had the same order of activity in reversing the hypothermia produced by the intraventricular injection of noradrenaline irrespective of whether it was given directly into the lateral cerebral ventricles or subcutaneously.5. Noradrenaline given subcutaneously caused hyperthermia in mice which antagonized and reversed the hypothermia induced by noradrenaline given directly into the lateral ventricles.6. The antagonism by both noradrenaline given subcutaneously and nortriptyline was reduced to the same degree by alpha- and beta-adrenoceptive receptor blocking agents.7. Nortriptyline, at dose levels required to antagonize and reverse the hypothermia induced by intraventricular injections of noradrenaline, potentiated the hyperthermia caused by noradrenaline given subcutaneously in conscious mice and the pressor responses to noradrenaline given either intravenously or into the lateral ventricles in anaesthetized mice.8. It is suggested that imipramine-like antidepressant drugs antagonize the hypothermia produced by intraventricular injections of noradrenaline by potentiating the hyperthermic effects of that part of the centrally administered noradrenaline that passes to the periphery rather than a direct central antagonism of the effects of noradrenaline.