title: Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice.
abstract: Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors, NTS1 and NTS2. The functional-anatomical interactions between NT, the mesotelencephalic dopamine system, and structures targeted by dopaminergic projections have been studied. The present study was conducted to determine the effects of NT receptor subtypes on dopaminergic function with the use of mice lacking either NTS1 (NTS1(-/-)) or NTS2 (NTS2(-/-)). Basal and amphetamine-stimulated locomotor activity was determined. In vivo microdialysis in freely moving mice, coupled with HPLC-ECD, was used to detect basal and d-amphetamine-stimulated striatal extracellular dopamine levels. In vitro radioligand binding and synaptosomal uptake assays for the dopamine transporters were conducted to test for the expression and function of the striatal pre-synaptic dopamine transporter. NTS1(-/-) and NTS2(-/-) mice had higher baseline locomotor activity and higher basal extracellular dopamine levels in striatum. NTS1(-/-) mice showed higher locomotor activity and exaggerated dopamine release in response to d-amphetamine. Both NTS1(-/-) and NTS2(-/-) mice exhibited lower dopamine D(1) receptor mRNA expression in the striatum relative to wild type mice. Dopamine transporter binding and dopamine reuptake in striatum were not altered. Therefore, lack of either NTS1 or NTS2 alters the dopaminergic system. The possibility that the dysregulation of dopamine transmission might stem from a deficiency in glutamate neurotransmission is discussed. The data strengthen the hypothesis that NT receptors are involved in the pathogenesis of schizophrenia and provide a potential model for the biochemical changes of the disease.
authors.affiliation: Neuropsychopharmacology Laboratory, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Liang
authors.forename: Mona
authors.initials: M
authors.lastname: Boules
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Li
authors.forename: Katrina
authors.initials: K
authors.lastname: Williams
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Miura
authors.forename: Alfredo
authors.initials: A
authors.lastname: Oliveros
authors.forename: Elliott
authors.initials: E
authors.lastname: Richelson
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000235:genetics* / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; C490984:Ntsr2 protein, mouse; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D003913:Dextroamphetamine; D004298:Dopamine