TY - JOUR
T1 - Neuroimaging and physiological evidence for involvement of glutamatergic transmission in regulation of the striatal dopaminergic system
AU - Tokunaga, Masaki
AU - Seneca, Nicholas
AU - Shin, Ryong Moon
AU - Maeda, Jun
AU - Obayashi, Shigeru
AU - Okauchi, Takashi
AU - Nagai, Yuji
AU - Zhang, Ming Rong
AU - Nakao, Ryuji
AU - Ito, Hiroshi
AU - Innis, Robert B.
AU - Halldin, Christer
AU - Suzuki, Kazutoshi
AU - Higuchi, Makoto
AU - Suhara, Tetsuya
PY - 2009/2/11
Y1 - 2009/2/11
N2 - 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, [ 11C]MNPA [(R)-2- 11CH 3O-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 neurochemical 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 extrastriatallocalization 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.
AB - 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, [ 11C]MNPA [(R)-2- 11CH 3O-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 neurochemical 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 extrastriatallocalization 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.
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U2 - 10.1523/JNEUROSCI.2559-08.2009
DO - 10.1523/JNEUROSCI.2559-08.2009
M3 - Article
C2 - 19211895
AN - SCOPUS:60849098734
SN - 0270-6474
VL - 29
SP - 1887
EP - 1896
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 6
ER -