Dopamine D₄ receptor signaling in the rat paraventricular hypothalamic nucleus: Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase ph

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• 作者：Robert S. Bitner ; Arthur L. Nikkel ; Stephani Otte ; Brenda Martino ; Eve H. Barlow ; Pramila Bhatia ; Andrew O. Stewart ; Jorge D. Brioni ; Michael W. Decker and Robert B. Moreland
• 关键词：Dopamine D₄ receptor ; PVN ; PD168077 ; A-381391 ; c-Fos ; ERK1/2
• 刊名：Neuropharmacology
• 出版年：2006
• 出版时间：April 2006
• 年：2006
• 卷：50
• 期：5
• 页码：521-531
• 全文大小：992 K

文摘

The dopamine D₄ receptor has been investigated for its potential role in several CNS disorders, notably schizophrenia and more recently, erectile dysfunction. Whereas studies have investigated dopamine D₄ receptor-mediated signaling in vitro, there have been few, if any, attempts to identify dopamine D₄ receptor signal transduction pathways in vivo. In the present studies, the selective dopamine D₄ agonist PD168077 induces c-Fos expression and extracellular signal regulated kinase (ERK) phosphorylation in the hypothalamic paraventricular nucleus (PVN), a site known to regulate proerectile activity. The selective dopamine D₄ receptor antagonist A-381393 blocked both c-Fos expression and ERK1/2 phosphorylation produced by PD168077. In addition, PD168077-induced ERK1/2 phosphorylation was prevented by SL327, an inhibitor of ERK1/2 phosphorylation. Interestingly, treatment with A-381393 alone significantly reduced the amount of Fos immunoreactivity as compared to basal expression observed in vehicle-treated controls. Dopamine D₄ receptor and c-Fos coexpression in the PVN was observed using double immunohistochemical labeling, suggesting that PD168077-induced signaling may result from direct dopamine D₄ receptor activation. Our results demonstrate functional dopamine D₄ receptor expression and natural coupling in the PVN linked to signal transduction pathways that include immediate early gene and MAP kinase activation. Further, the ability of the selective dopamine D₄ antagonist A-381393 alone to reduce c-Fos expression below control levels may imply the presence of a tonic dopamine D₄ receptor activation under basal conditions in vivo. These findings provide additional evidence that the PVN may be a site of dopamine D₄ receptor-mediated proerectile activity.