Development of β-adrenergic receptor subsensitivity by antidepressants

Abstract

CONSIDERABLE evidence exists that the tricyclic antidepressant drugs are selective inhibitors of monoamine uptake into monoaminergic nerve terminals^1,2. These drugs also potentiate pharmacological responses to the monoamines in both the peripheral and central nervous systems^3–6. These effects do not explain the discrepancy between the time-course of the biochemical and pharmacological responses which are elicited by these antidepressant drugs within minutes or hours and their clinical antidepressant action which requires treatment for weeks for efficacy to be reached. Furthermore, desipramine, an antidepressant drug, can potentiate neuronal responses to noradrenaline and dopamine in the caudate nucleus⁷, although it does not block the catecholamine uptake in this area of the brain^1,2. Finally the antidepressant iprindole does not influence noradrenaline turnover⁸ or metabolism^9,10 or its uptake into catecholaminergic neurones¹¹, but is effective in potentiating the responses of single cortical and caudate neurones to monoamines¹². Vetulani and his associates¹³ suggested that the therapeutic action of tricyclic antidepressants may be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events. The purpose of the experiments described here was to explore the molecular basis for antidepressant-induced noradrenergic subsensitivity by examining the kinetic properties of the β-adrenergic receptors in the microsomal suspension of rat brain by using a potent β-adrenergic receptor antagonist ³H-dihydroalprenolol as a radiolabelled ligand^14–19. Our results indicate that the main mechanism is a reduction in the number of receptors.