Chronic clorgyline induces selective down-regulation of alpha2-adrenoceptor agonist binding sites in rat brain.

Abstract

Inactivation of alpha2-adrenoceptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been shown to induce an increase in brain regulatory G alpha(i1/2) proteins, which was related to biphasic recovery of agonist binding sites. To investigate further the nature of this phenomenon, the chronic effects of clorgyline (a monoamine oxidase inhibitor antidepressant) on the recovery of alpha2-adrenoceptors after EEDQ and on EEDQ-induced up-regulation of G alpha(i1/2) proteins were assessed in rat brain. Clorgyline (1 mg kg(-1) for 7-35 days) induced a time-dependent down-regulation (20% to 55%) of the density of cortical alpha2-adrenoceptor agonist sites ([3H]UK 14304/bromoxidine binding) but not of antagonist sites ([3H]RX 821002/2-methoxy idazoxan binding). However, chronic clorgyline did not alter the immunoreactive levels of G alpha(i1/2), G alpha(i3), and G alpha(o) proteins in cortex. In clorgyline-treated rats, the turnover functions for agonist and antagonist binding sites (receptor recovery after EEDQ) were different and indicated that the reduced density of alpha2-adrenoceptor agonist sites induced by clorgyline was due to a greater rate of receptor disappearance. The recovery of [3H]UK 14304 binding in clorgyline-treated rats did not fit a biphasic recovery model and the turnover parameters were very similar to those obtained for the second phase of recovery (biphasic model) of agonist binding sites in naive rats. This suggested that clorgyline down-regulated only the alpha2-adrenoceptors of rapid turnover which is associated with the increases in the expression of G alpha(i1/2) proteins induced by EEDQ. In this context, clorgyline (1 mg kg(-1) for 7 days) fully prevented the up-regulation (50%) of brain G alpha(i1/2) proteins induced by EEDQ. The results indicate that one relevant mechanism involved in the in vivo desensitization of brain alpha2-adrenoceptors is an effective impairment of receptor-G protein coupling.