Effects of Imidazoline Drugs on Early Response Gene Activity in Brain, Kidney and Adrenal Gland

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• 作者：Gundlach ; A.L. ; Burazin ; T.C.D. ; Louis ; W.J.
• 刊名：European Neuropsychopharmacology
• 出版年：1996
• 期刊代码：95_0924977x
• 类别：med
• 出版时间：June, 1996
• 卷：6
• 期：Supplement 3
• 页码：196
• 文件大小：127 K

摘要

I₂-Imidazoline receptor sites present in brain, kidney and adrenal gland are associated with the MAO enzymes or plasma membranes. Imidazolines increase GFAP production in cerebral cortex and cultured astrocytes; and activate gene expression in adrenal chromaffin cells. The imidazolines, 2-methoxyidazoxan (2-MI) and 2-(4,5-dihydroimidaz-2-yl)-quinoline (BU224) are ≥ 5000-fold selective for ^5;₂-adrenoceptors and I₂-receptor sites, respectively. To examine possible effects of occupying these sites in vivo, we examined effects of these drugs cf. clonidine (^5;₂-agonist/imidazoline) on the level of mRNAs encoding the early response genes (ERGs), c-fos, c-jun and NGFI-A in brain, kidney and adrenal gland. Sprague-Dawley rats (4/group) were injected with 2-MI, BU224 (1 or 10 mg/kg, i.p.); clonidine (0.1 or 0.5 mg/kg, i.p.); or vehicle, and killed after 1 h. Tissues were processed for in situ hybridization with specific [³⁵S]-labeled oligonucleotides and resultant x-ray film autoradiograms were analyzed by densitometry. 2-MI (^5;₂-antagonist) produced a marked increase of NGFI-A and c-fos mRNA in cerebral cortex (25-110%); BU224 a lesser increase (25-40%). High basal level of c-jun mRNA in brain was not altered. High doses of 2-MI and clonidine increased NGFI-A, c-fos and c-jun mRNA in the renal inner medulla. ERG expression in adrenal cortex and medulla was variable (probably stress-related), although 2-MI induced c-fos mRNA in the adrenal cortex. These results suggest differential net effects of ^5;₂-adrenoceptor activation/blockade on ERG expression in neuronal, renal and adrenal cells, which may be associated with direct central actions and a combination of direct and indirect effects in the periphery. Activity of BU224 in brainand kidney may reflect weak ^5;₂-adrenoceptor effects at high doses rather than I₂-receptor site activation, while its lack of activity in regions such as renal outer medulla and the adrenal gland may reflect the study of only rapid cellular responses and/or the enzymic location of I₂-receptor sites.