Endogenous neurotensin attenuates dopamine-dependent locomotion and stereotypy

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• 作者：Chartoff ; Elena H. ; Szczypka ; Mark S. ; Palmiter ; Richard D. ; Dorsa ; Daniel M.
• 关键词：Neural basis of behavior ; Neuropeptides and behavior ; Striatum ; Microinjection ; Neuropeptide ; Dopamine-deficient mouse ; l-DOPA ; SR 48692
• 刊名：Brain Research
• 出版年：2004
• 出版时间：October 1, 2004
• 年：2004
• 卷：1022
• 期：1-2
• 页码：71-80
• 全文大小：444 K

文摘

The neuropeptide neurotensin (NT) is highly sensitive to changes in dopaminergic signaling in the striatum, and is thought to modulate dopamine-mediated behaviors. To explore the interaction of NT with the dopamine system, we utilized mice with a targeted deletion of dopamine synthesis specifically in dopaminergic neurons. Dopamine levels in dopamine-deficient (DD) mice are less than 1 % of control mice, and they require daily administration of the dopamine precursor l-dihydroxyphenylalanine (l-DOPA) for survival. DD mice are supersensitive to the effects of dopamine, becoming hyperactive relative to control mice in the presence of l-DOPA. We show that 24 h after l-DOPA treatment, when DD mice are in a aaadopamine-depletedaaa state, Nt mRNA levels in the striatum of DD mice are similar to those in control mice. Administration of l-DOPA or l-DOPA plus the l-amino acid decarboxylase inhibitor, carbidopa, (C/l-DOPA) induced Nt expression in the striatum of DD mice. The dopamine D1 receptor antagonist, SCH23390, blocked C/l-DOPA-induced Nt. To test the hypothesis that this striatal Nt expression modulated dopamine-mediated behavior in DD mice, we administered SR 48692, an antagonist of the high affinity NT receptor, together with l-DOPA or C/l-DOPA. l-DOPA-induced hyperlocomotion and C/l-DOPA-induced stereotypy were potentiated by peripheral administration of SR 48692. Furthermore, intrastriatal microinjections of SR 48692 augmented l-DOPA-induced hyperlocomotion. These results demonstrate a dynamic regulation of striatal Nt expression by dopamine via D1 receptors in DD mice, and point to a physiological role for endogenous striatal NT in counteracting motor behaviors induced by an overactive dopamine system.