Specific tricyclic antidepressant binding sites in rat brain

Abstract

The discovery of high-affinity binding sites for psychoactive drugs such as benzodiazepines^1,2, opiates³ and neuroleptics⁴ has opened up new approaches to the study of these drugs and their mechanisms of action. Although most tricyclic antidepressants inhibit neuronal uptake of noradrenaline and serotonin⁵, their mechanism of action remains unclear. Changes in the sensitivity of the β-receptor after chronic tricyclic antidepressant treatment^6,7 suggest that they modulate noradrenergic neuro-transmission. Tricyclic antidepressants also act directly on cholinergic⁸, histaminergic⁹, α-adrenergic¹⁰ and serotonergic¹¹ receptors. It is not clear, however, which, if any, of these effects are related to the primary antidepressant effect or whether they are simply responsible for some of the side effects. We have thus investigated the possibility that specific binding sites for tricyclic antidepressants exist in the central nervous system. So far, binding studies using ³H-labelled tricyclic antidepressant drugs have only detected binding to histaminergic H₂ and cholinergic muscarinic receptors¹² and low-affinity binding¹³. We demonstrate here a population of specific high-affinity binding sites for ³H-imipramine on brain membranes which may be responsible for the antidepressant effects of these drugs.