title: Neuroimaging and physiological evidence for involvement of glutamatergic transmission in regulation of the striatal dopaminergic system.
abstract: Aberrant neurotransmissions via glutamate and dopamine receptors have been the focus of biomedical research on the molecular basis of psychiatric disorders, but the mode of their interaction is yet to be uncovered. In this study, we demonstrated the pharmacological reversal of methamphetamine-stimulated dopaminergic overflow by suppression of group I metabotropic glutamate (mGlu) receptor in living primates and rodents. In vivo positron emission tomography (PET) was conducted on cynomolgus monkeys and rats using a full agonistic tracer for dopamine D(2/3) receptor, [(11)C]MNPA [(R)-2-(11)CH(3)O-N-n-propylnorapomorphine], and fluctuation of kinetic data resulting from anesthesia was avoided by scanning awake subjects. Excessive release of dopamine induced by methamphetamine and abolishment of this alteration by treatment with an antagonist of group I mGlu receptors, 2-methyl-6-(phenylethynyl)pyridine (MPEP), were measured in both species as decreased binding potential because of increased dopamine and its recovery to baseline levels, respectively. Counteraction of MPEP to the methamphetamine-induced dopamine spillover was also supported neurochemically by microdialysis of unanesthetized rat striatum. Moreover, patch-clamp electrophysiological assays using acute brain slices prepared from rats indicated that direct targets of MPEP mechanistically involved in the effects of methamphetamine are present locally within the striatum. Because MPEP alone did not markedly alter the baseline dopaminergic neurotransmission according to our PET and electrophysiological data, the present findings collectively extend the insights on dopamine-glutamate cross talk from extrastriatal localization of responsible mGlu receptors to intrastriatal synergy and support therapeutic interventions in case of disordered striatal dopaminergic status using group I mGlu receptor antagonists assessable by in vivo imaging techniques.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Ryong-Moon
authors.initials: RM
authors.lastname: Shin
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Shigeru
authors.initials: S
authors.lastname: Obayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagai
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology*; D008251:Macaca; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D018698:Glutamic Acid; D004298:Dopamine