α₂-Adrenoceptor Antagonists as Antidepressants: The Search for Selectivity

Abstract

Tricyclic antidepressants and monoamine oxidase inhibitors are presumed to act rapidly to elevate synaptic levels of norepinephrine (NE) and serotonin (5-HT) by inhibiting uptake and metabolism, respectively. Synaptic levels of NE, how-ever, are not controlled entirely by reuptake and metabolic processes, but are under the additional influence of a negative feedback inhibition mediated by an agonist action of NE itself upon α₂-adrenoceptors located presynaptically on the noradrenergic nerve terminal (Timmermans and van Zwieten 1982). Antagonism of these so-called autoreceptors leads to enhancement of the release of NE from its storage sites in the nerve terminal and thereby to a situation akin to that following uptake inhibition. α₂-Autoreceptors have been demonstrated to exist at almost all noradrenergic axons where postsynaptic α-adrenoceptors are known to occur, and they are widely distributed in the brain, particularly in the cortex. The possibility that α₂-autoreceptor antagonism might lead to antidepressant properties has stimulated the development of a number of putative therapeutic agents, which vary widely in their potency and selectivity (Pinder 1985 a, b).