Abstract
Changes in members of the dopamine (DA) D1-like (D1, D5) and D2-like (D2, D3, D4) receptor families in rat forebrain regions were compared by quantitative in vitro receptor autoradiography after prolonged treatment (28 days) with the atypical antipsychotics olanzapine, risperidone, and quetiapine. Olanzapine and risperidone, but not quetiapine, significantly increased D2binding in medial prefrontal cortex (MPC; 67% and 34%), caudate-putamen (CPu; average 42%, 25%), nucleus accumbens (NAc; 37%, 28%), and hippocampus (HIP; 53%, 30%). Olanzapine and risperidone, but not quetiapine, produced even greater up-regulation of D4 receptors in CPu (61%, 37%), NAc (65%, 32%), and HIP (61%, 37%). D1-like and D3 receptors in all regions were unaltered by any treatment, suggesting their minimal role in mediating actions of these antipsychotics. The findings support the hypothesis that antipsychotic effects of olanzapine and risperidone are partly mediated by D2 receptors in MPC, NAc, or HIP, and perhaps D4 receptors in CPu, NAc, or HIP, but not in cerebral cortex. Selective up-regulation of D2 receptors by olanzapine and risperidone in CPu may reflect their ability to induce some extrapyramidal effects. Inability of quetiapine to alter DA receptors suggests that nondopaminergic mechanisms contribute to its antipsychotic effects.
Footnotes
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Send reprint requests to: Dr. Frank I. Tarazi, Mailman Research Center, McLean Hospital, Harvard Medical School, 115 Mill St., Belmont, MA 02478. E-mail: ftarazi{at}hms.harvard.edu
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This work was supported by National Alliance for Research on Schizophrenia and Depression Young Investigator Award, The Grable Foundation, and a research award from Eli Lilly Corporation (F.I.T.), National Institutes of Health Grants MH-34006 and MH-47370, a grant from the Bruce J. Anderson Foundation, and funds of the McLean Private Donors Neuropharmacology Research Fund (R.J.B.).
- Abbreviations:
- DA
- dopamine
- CPu
- caudate-putamen
- DFC
- dorsolateral-frontal cerebral cortex
- EC
- entorhinal cortex
- HIP
- hippocampus
- MPC
- mesioprefrontal cortex
- NAc
- nucleus accumbens septi (core and shell subdivisions)
- EPS
- extrapyramidal signs
- 7-OH-DPAT
- R(+)-[2,3-3H]7-hydroxy-N,N-di-n-propyl-2-amino-1,2,3,4-tetrahydronaphthalene
- DTG
- 1,3-ditolylguanidine
- RT
- room temperature
- SCH-23390
- R(+)-[N-methyl-3H]7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- Received September 29, 2000.
- Accepted January 31, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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