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

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 β receptors and in the responsiveness of adenylate cyclase to norepinephrine stimulation. After 21 days of treatment with 1 mg/kg/day of clorgyline, an A-type-selective monoamine 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 α₂-selective agonist clonidine. These functional changes in norepinephrine release mechanisms are accompanied by a 53% reduction in brainstem α₂ receptor density as measured by [³H]clonidine binding. At the same time, despite findings of a decrease in β 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 α-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.