Beschreibung:
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<jats:list-item><jats:p>This study was designed to assess the molecular and cellular events involved in the up‐regulation (and receptor supersensitivity) of brain α<jats:sub>2</jats:sub>‐adrenoceptors as a result of chronic depletion of noradrenaline (and other monoamines) by reserpine.</jats:p></jats:list-item>
<jats:list-item><jats:p>Chronic reserpine (0.25 mg kg<jats:sup>−1</jats:sup> s.c., every 48 h for 6 – 14 days) increased significantly the density (B<jats:sub>max</jats:sub> values) of cortical α<jats:sub>2</jats:sub>‐adrenoceptor agonist sites (34 – 48% for [<jats:sup>3</jats:sup>H]‐UK14304, 22 – 32% for [<jats:sup>3</jats:sup>H]‐clonidine) but not that of antagonist sites (11 – 18% for [<jats:sup>3</jats:sup>H]‐RX821002). Competition of [<jats:sup>3</jats:sup>H]‐RX821002 binding by (−)‐adrenaline further indicated that chronic reserpine was associated with up‐regulation of the high‐affinity state of α<jats:sub>2</jats:sub>‐adrenoceptors.</jats:p></jats:list-item>
<jats:list-item><jats:p>In cortical membranes of reserpine‐treated rats (0.25 mg kg<jats:sup>−1</jats:sup> s.c., every 48 h for 20 days), the immunoreactivities of various G proteins (Gαi<jats:sub>1/2</jats:sub>, Gαi<jats:sub>3</jats:sub>, Gαo and Gαs) were increased (25 – 34%). Because the high‐affinity conformation of the α<jats:sub>2</jats:sub>‐adrenoceptor is most probably related to the complex with Gαi<jats:sub>2</jats:sub> proteins, these results suggested an increase in signal transduction through α<jats:sub>2</jats:sub>‐adrenoceptors (and other monoamine receptors) induced by chronic reserpine.</jats:p></jats:list-item>
<jats:list-item><jats:p>After α<jats:sub>2</jats:sub>‐adrenoceptor alkylation, the analysis of receptor recovery (<jats:italic>B</jats:italic><jats:sub>max</jats:sub> for [<jats:sup>3</jats:sup>H]‐UK14304) indicated that the increased density of cortical α<jats:sub>2</jats:sub>‐adrenoceptors in reserpine‐treated rats was probably due to a higher appearance rate constant of the receptor (Δ<jats:italic>r</jats:italic>=57%) and not to a decreased disappearance rate constant (Δ<jats:italic>k</jats:italic>=7%).</jats:p></jats:list-item>
<jats:list-item><jats:p>Northern‐ and dot‐blot analyses of RNA extracted from the cerebral cortex of saline‐ and reserpine‐treated rats (0.25 mg kg<jats:sup>−1</jats:sup>, s.c., every 48 h for 20 days) revealed that reserpine markedly increased the expression of α<jats:sub>2a</jats:sub>‐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<jats:sub>2</jats:sub>‐adrenoceptors.</jats:p></jats:list-item>
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</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2001) <jats:bold>132</jats:bold>, 1467–1476; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0703963">10.1038/sj.bjp.0703963</jats:ext-link></jats:p>