Inhibition of Uptake of Tritiated-noradrenaline in the Intact Rat Brain by Imipramine and Structurally Related Compounds

Abstract

IMIPRAMINE is one of the most effective drugs for the alleviation of mental depression. There is little information concerning the mechanism of action of this drug at the biochemical level. An impressive body of evidence has been accumulating over the past few years indicating that noradrenaline is involved in behaviour. Although other antidepressant drugs such as monoamine oxidase inhibitors¹, and amphetamine², affect cerebral noradrenaline concentration, imipramine was found to have no measurable effect on the level of the neurohumour in the brain³.It has been shown that imipramine blocks the uptake of noradrenaline in peripheral tissues⁴ and brain slices⁵; however, many other drugs including the tran-uillizer chlorpromazine have the same action^5,6. Because noradrenaline cannot cross the blood-brain barrier, it was virtually impossible to examine directly the action of imipramine or other drugs on the uptake of noradrenaline by the intact brain. We have recently described a procedure which made it possible to introduce tritiated-noradrenaline of high specific activity into the rat brain by an intraventricular injection. The tritiated-noradrenaline is taken up and retained by nerve endings in the brain and then shows the essentially same biochemical behaviour as the endogenous neurohumour⁷. This technique enabled us to investigate the effect of imipramine on the uptake of tritiated-noradrenaline by the intact rat brain. It will be shown that imipramine and structurally related antidepressant drugs but not chlorpromazine block the uptake of tritiated-noradrenaline in the brain.