Chronic clorgyline induces selective down-regulation of α2-adrenoceptor agonist binding sites in rat brain

Inactivation of al-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 alpha (2)-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 alpha (2)-adrenoceptor agonist sites ([H-3]UK 14304/bromoxidine binding) but not of antagonist sites ([H-3]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 alpha (2)-adrenoceptor agonist sites induced by clorgyline was due to a greater rate of receptor disappearance. The recovery of [H-3]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 alpha (2)-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 upregulation (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 alpha (2)-adrenoceptors is an effective impairment of receptor-G protein coupling.