Endogenous neurotensin attenuates dopamine-dependent locomotion and stereotypy.
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.
Chartoff
Elena H
EH
Department of Psychiatry, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. echartoff@mclean.harvard.edu
Szczypka
Mark S
MS
Palmiter
Richard D
RD
Dorsa
Daniel M
DM
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D001552:Benzazepines / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D017403:In Situ Hybridization / Q000379:methods; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D012333:RNA, Messenger; D018028:Receptors, Neurotensin; C079087:SR 48692; D009496:Neurotensin; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D006220:Haloperidol; D002230:Carbidopa; D004298:Dopamine