Brain α2‐adrenoceptors in monoamine‐depleted rats: increased receptor density, G coupling proteins, receptor turnover and receptor mRNA

• Published in: British journal of pharmacology 2001-04, Vol.132 (7), p.1467-1476
• Main Authors: Ribas, Catalina, Miralles, Antonio, Busquets, Xavier, García‐Sevilla, Jesús A
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; agonist and antagonist binding sites; Biological and medical sciences; Depression; Drug toxicity and drugs side effects treatment; G coupling proteins; Medical sciences; monoamine depletion; Mood disorders; Pharmacology. Drug treatments; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; rat brain; receptor turnover; reserpine; Toxicity: nervous system and muscle; α2a‐adrenoceptor mRNA; α2‐Adrenoceptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703963

This study was designed to assess the molecular and cellular events involved in the up‐regulation (and receptor supersensitivity) of brain α2‐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 (Bmax values) of cortical α2‐adrenoceptor agonist sites (34 – 48% for [3H]‐UK14304, 22 – 32% for [3H]‐clonidine) but not that of antagonist sites (11 – 18% for [3H]‐RX821002). Competition of [3H]‐RX821002 binding by (−)‐adrenaline further indicated that chronic reserpine was associated with up‐regulation of the high‐affinity state of α2‐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 (Gαi1/2, Gαi3, Gαo and Gαs) were increased (25 – 34%). Because the high‐affinity conformation of the α2‐adrenoceptor is most probably related to the complex with Gαi2 proteins, these results suggested an increase in signal transduction through α2‐adrenoceptors (and other monoamine receptors) induced by chronic reserpine. After α2‐adrenoceptor alkylation, the analysis of receptor recovery (Bmax for [3H]‐UK14304) indicated that the increased density of cortical α2‐adrenoceptors in reserpine‐treated rats was probably due to a higher appearance rate constant of the receptor (Δr=57%) and not to a decreased disappearance rate constant (Δk=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 α2a‐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 α2‐adrenoceptors. British Journal of Pharmacology (2001) 132, 1467–1476; doi:10.1038/sj.bjp.0703963