Chronic effects of a monoamine oxidase-inhibiting antidepressant: decreases in functional alpha-adrenergic autoreceptors precede the decrease in norepinephrine-stimulated cyclic adenosine 3': 5'- monophosphate systems in rat brain

Abstract

Various antidepressant drugs (monoamine oxidase inhibitors and tricyclics) enhance norepinephrine availability and lead to adaptive changes in brain noradrenergic systems, namely, decreases in the number of beta receptors and in the responsiveness of adenylate cyclase to norepinephrine monamine oxidase inhibitor, but not after 3 days, there is an increase in norepinephrine release from rat brain microsacs in response to 43 mM KCl stimulation. Microsacs prepared from 21-day clorgyline-treated animals also show a marked decrease in the inhibition of norepinephrine release caused by the alpha 2-selective agonist clonidine. These functional changes in norepinephrine release mechanisms are accompanied by a 53% reduction in brainstem alpha 2 receptor density as measured by [3H]clonidine binding. At the same time, despite findings of a decrease in beta receptor number as determined by [3H]dihydroalprenolol binding data, no significant decrease in the responses of cyclic adenosine 3': 5'-monophosphate (cyclic AMP) systems to norepinephrine stimulation is observed. Decreases in the cyclic AMP response are observed by day 35 of clorgyline treatment. The results provide direct physiological support for a change in the norepinephrine release mechanism and an effect on autoreceptors, specifically, preceding postsynaptic adaptive changes in the instance of one antidepressant, clorgyline. Difficulties in observing such changes with other antidepressants may result from the multiple nature of alpha-adrenergic receptors, especially as measured by radioactive ligand techniques; the lack of a direct relationship between physiological changes and receptors as measured by radioligand techniques; the large doses of monoamine oxidase inhibitors used in some studies; and the possible multiplicity of antidepressant molecular mechanisms.

Desensitization of α₂-Adrenoceptors which Regulate Noradrenaline Synthesis and Release after Chronic Treatment with Clorgyline in the Rat Brain

“…Moreover, the few studies which have evaluated the modulation of the · 2 -adrenoceptors which regulate noradrenaline release following chronic treatment with this MAO-A inhibitor have provided conflicting results. In some studies no changes were found in the sensitivity of these adrenoceptors [14,15,22], whilst in others there was a reduction in the · 2 -adrenoceptor-mediated response in different brain regions [23,24].…”

Electrophysiologic Evidence for Desensitization of α2-Adrenoceptors on Serotonin Terminals Following Long-Term Treatment with Drugs Increasing Norepinephrine Synaptic Concentration

“…[Neuropsychopharmacology 10: [41][42][43][44][45][46][47][48][49][50][51]1994] Several studies have documented the possibility that presynaptic u2-adrenergic autoreceptors become desen sitized following long-term antidepressant treatments that increase the synaptic concentration of norepineph rine (NE) (Crews and Smith 1978;Svensson and Usdin 1978;McMillen et al 1980;Spyraky and Fibiger 1980;Cohen et al 1982;Finberg and Tal 1985;Lacroix et al 1991). Furthermore, the density of high-affinity state u2-adrenoceptors has been shown to be increased on platelets of depressed patients, a condition normalized by long-term treatment with antidepressant drugs (Garcia-Sevilla et al 1986Doyle et al 1985;Takeda et al 1989;Piletz et al 1991).…”

Epinephrine, the neglected catecholamine

“…In other words, there are a host of homeostatic mechanisms involved in neurotransmitter activity; these normally allow the organism to smooth out a variety of environmental parameters that ordinarily affect neurotransmitter pathways so as to constrain transitions between different states (Cohen & Campbell, in press). Antidepressant treatments act to allow an escape from these constraints, in some instances by enhancing norepinephrine or indoleamine levels in the synapse over a sustained period, as suggested by Stone and others (Cohen et al 1980;Cohen, Ebstein, Daly & Murphy 1982 and references therein). The constraints escaped in the .…”

“…The constraints escaped in the . former instance are probably those involving the inhibitory presynaptic noradrenergic system including alpha-2-adrenergic autoreceptors and other mechanisms of control of norepinephrine release (Cohen, Ebstein, Daly & Murphy 1982;Schoffelmeer & Mulder 1982). Evidence of such changes has been reported through physiological, biochemical, and behavioral measurements in a broad range of systems including thermoregulatory (Gorka & Zacny 1981), locomotor (Cohen, Aulakh, Campbell & Murphy 1982;Heal, Akagi, Bowdler & Green 1981 references therein), and reinforcement effects (Aulakh, Cohen, Pradhan & Murphy, in press) following electroconvulsive shock, monoamine oxidase, and tricyclic antidepressant treatments.…”