title: Striatal dopamine receptor plasticity in neurotensin deficient mice.
abstract: Schizophrenia is thought to be caused, at least in part, by dysfunction in striatal dopamine neurotransmission. Both clinical studies and animal research have implicated the dopamine neuromodulator neurotensin (NT) in the pathophysiology of schizophrenia. Utilizing male mice lacking the NT gene (NT(-/-)), these studies examined the consequences of NT deficiency on dopaminergic tone and function, investigating (1) dopamine concentrations and dopamine receptor and transporter expression and binding in dopaminergic terminal regions, and (2) the behavioral effects of selective dopamine receptor agonists on locomotion and sensorimotor gating in adult NT(-/-) mice compared to wildtype (NT(+/+)) mice. NT(-/-) mice did not differ from NT(+/+) mice in concentrations of dopamine or its metabolite DOPAC in any brain region examined. However, NT(-/-) mice showed significantly increased D1 receptor, D2 receptor, and dopamine transporter (DAT) mRNA in the caudate putamen compared to NT(+/+) controls. NT(-/-) mice also showed elevated D2 receptor binding densities in both the caudate putamen and nucleus accumbens shell compared to NT(+/+) mice. In addition, some of the behavioral effects of the D1-type receptor agonist SKF-82958 and the D2-type receptor agonist quinpirole on locomotion, startle amplitude, and prepulse inhibition were dose-dependently altered in NT(-/-) mice, showing altered D1-type and D2-type receptor sensitivity to stimulation by agonists in the absence of NT. The results indicate that NT deficiency alters striatal dopamine receptor expression, binding, and function. This suggests a critical role for the NT system in the maintenance of striatal DA system homeostasis and implicates NT deficiency in the etiology of dopamine-associated disorders such as schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: lgc51@scarletmail.rutgers.edu.
authors.forename: Lucy G
authors.initials: LG
authors.lastname: Chastain
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Chase H
authors.initials: CH
authors.lastname: Bourke
authors.affiliation: Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Iuvone
authors.affiliation: Department of Microbiology and Physiological Systems, Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Dobner
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Becky
authors.initials: B
authors.lastname: Kinkead
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009496:Neurotensin / Q000172:deficiency* / Q000235:genetics; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D019257:Quinpirole; D009496:Neurotensin; C071262:SK&F 82958; D004298:Dopamine
keywords: Dopamine; Dopamine receptor; Neurotensin; Schizophrenia; Striatum