Endogenous neurotensin attenuates dopamine-dependent locomotion and stereotypy

Elena H. Chartoff, Mark S. Szczypka, Richard D. Palmiter, Daniel Dorsa

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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 "dopamine-depleted" 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.

Original languageEnglish (US)
Pages (from-to)71-80
Number of pages10
JournalBrain Research
Volume1022
Issue number1-2
DOIs
Publication statusPublished - Oct 1 2004

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Keywords

  • Dopamine-deficient mouse
  • l-DOPA
  • Microinjection
  • Neuropeptide
  • SR 48692
  • Striatum

ASJC Scopus subject areas

  • Neuroscience(all)

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