Abstract
Levels of ionotropic glutamate (Glu) N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainic acid (KA) receptors in rat forebrain regions were compared by quantitative in vitro receptor autoradiography after continuous treatment for 28 days with the atypical antipsychotics olanzapine, risperidone, and quetiapine, or vehicle controls. All three treatments significantly decreased NMDA binding in caudate-putamen (CPu; by 30, 34, and 26%, respectively) but increased AMPA receptor levels in same region (by 22, 30, and 28%). Olanzapine and risperidone, but not quetiapine, also reduced NMDA receptor labeling in hippocampal CA1 (21 and 19%) and CA3 (23 and 22%) regions. KA receptors were unaltered by any treatment in the brain regions examined. These findings suggest that the antipsychotic effects of olanzapine and risperidone may be mediated in part by NMDA receptors in hippocampus, and perhaps AMPA receptors in CPu. The findings also support the hypothesis that down-regulation of NMDA receptors by atypical antipsychotic agents in CPu contributes to their low risk of extra-pyramidal side effects. Inability of olanzapine, risperidone, and quetiapine to alter KA receptors suggests their minimal role in mediating the central nervous system actions of these drugs.
Footnotes
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This study was supported by Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression Young Investigator Award, and research awards from Eli Lilly & Co. and Janssen Pharmaceuticals (to F.I.T.); Adam Corneel Award (to K.Z.); and a grant from the Bruce J. Anderson Foundation and funds of the McLean Hospital Private Donors Neuropharmacology Research Fund (to R.J.B.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.052597.
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ABBREVIATIONS: Glu, glutamate; NMDA, N-methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; KA, kainic acid; NMDAR, N-methyl-d-aspartate receptor; PCP, phencyclidine; APD, antipsychotic drug; EPS, extrapyramidal side effect; CNQX, 6-cyano-7-nitroquinoxaline; KSCN, potassium thiocyanate; CPu, caudate-putamen; NAc, nucleus accumbens; DFC, dorsolateral-frontal cerebral cortex; MPC, mesioprefrontal cortex; EC, entorhinal cortex; T, room temperature; O.D., optical density; ANOVA, analysis of variance; 5-HT, 5-hydroxytryptamine (serotonin); DA, dopamine.
- Received April 7, 2003.
- Accepted June 6, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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