Brain α 2 ‐adrenoceptors in monoamine‐depleted rats: increased receptor density, G coupling proteins, receptor turnover and receptor mRNA

This study was designed to assess the molecular and cellular events involved in the up‐regulation (and receptor supersensitivity) of brain α 2 ‐adrenoceptors as a result of chronic depletion of noradrenaline (and other monoamines) by reserpine. Chronic reserpine (0.25 mg kg −1 s.c., every 48 h for 6 – 14 days) increased significantly the density (B max values) of cortical α 2 ‐adrenoceptor agonist sites (34 – 48% for [ 3 H]‐UK14304, 22 – 32% for [ 3 H]‐clonidine) but not that of antagonist sites (11 – 18% for [ 3 H]‐RX821002). Competition of [ 3 H]‐RX821002 binding by (−)‐adrenaline further indicated that chronic reserpine was associated with up‐regulation of the high‐affinity state of α 2 ‐adrenoceptors. In cortical membranes of reserpine‐treated rats (0.25 mg kg −1 s.c., every 48 h for 20 days), the immunoreactivities of various G proteins (Gαi 1/2 , Gαi 3 , Gαo and Gαs) were increased (25 – 34%). Because the high‐affinity conformation of the α 2 ‐adrenoceptor is most probably related to the complex with Gαi 2 proteins, these results suggested an increase in signal transduction through α 2 ‐adrenoceptors (and other monoamine receptors) induced by chronic reserpine. After α 2 ‐adrenoceptor alkylation, the analysis of receptor recovery ( B max for [ 3 H]‐UK14304) indicated that the increased density of cortical α 2 ‐adrenoceptors in reserpine‐treated rats was probably due to a higher appearance rate constant of the receptor (Δ r =57%) and not to a decreased disappearance rate constant (Δ k =7%). Northern‐ and dot‐blot analyses of RNA extracted from the cerebral cortex of saline‐ and reserpine‐treated rats (0.25 mg kg −1 , s.c., every 48 h for 20 days) revealed that reserpine markedly increased the expression of α 2a ‐adrenoceptor mRNA in the brain (125%). This transcriptional activation of the receptor gene expression appears to be the cellular mechanism by which reserpine induces up‐regulation in the density of brain α 2 ‐adrenoceptors.British Journal of Pharmacology (2001) 132 , 1467–1476; doi: 10.1038/sj.bjp.0703963