The interactions of noradnamine and imipramine-like antidepressant drugs.

1. The hypothesis of Roberts & Broadley (1965) that noradnamine formation in the brain is responsible for endogenous depression has been investigated in mice.2. Injections of noradnamine given directly into the lateral ventricles caused convulsions and profound hypothermia, but were without effect if given subcutaneously.3. The hypothermia, but not the convulsions, induced by noradnamine was reversed by imipramine-like antidepressant drugs given before or after the injection of noradnamine. The convulsions but not the hypothermia were abolished by phenobarbitone.4. Increasing doses of nortriptyline produced a parallel shift of the hypothermic log dose-response curve for intraventricular injections of noradnamine to the right.5 The minimal effective dose of nortriptyline required to reverse noradnamine hypothermia was the same whether the nortriptyline was injected directly into the lateral ventricle or subcutaneously.6. No evidence was found to substantiate the claim that reserpine hypothermia is mediated by noradnamine formation in the brain.7. Intraventricular, but not intraperitoneal, injection of noradnamine caused a depletion of brain noradrenaline and an increase in brain 5-hydroxytryptamine. These changes did not result from the convulsive activity and were not modified by pretreatment with nortriptyline. No effect on heart noradrenaline levels was recorded.8. Noradrenaline, given subcutaneously, also antagonized the hypothermic response to noradnamine.9. The reversal of noradnamine hypothermia by both noradrenaline given subcutaneously and nortriptyline was blocked by alpha and beta-adrenoceptive receptor blocking agents.10. It is considered that the mode of action of the antagonism of noradnamine hypothermia by imipramine-like antidepressant drugs is a peripheral and not a central mechanism and probably results from a potentiation of the effects of circulating noradrenaline released by noradnamine.