Long-term effects of olanzapine, risperidone, and quetiapine on dopamine receptor types in regions of rat brain: implications for antipsychotic drug treatment.
Changes in members of the dopamine (DA) D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), D(4)) 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 D(2) binding 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 D(4) receptors in CPu (61%, 37%), NAc (65%, 32%), and HIP (61%, 37%). D(1)-like and D(3) 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 D(2) receptors in MPC, NAc, or HIP, and perhaps D(4) receptors in CPu, NAc, or HIP, but not in cerebral cortex. Selective up-regulation of D(2) 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.
Tarazi
F I
FI
Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts 02478, USA. ftarazi@hms.harvard.edu
Zhang
K
K
Baldessarini
R J
RJ
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D001569:Benzodiazepines; D001923:Brain Chemistry / Q000187:drug effects*; D003987:Dibenzothiazepines / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D008297:Male; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000069348:Quetiapine Fumarate; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050637:Receptors, Dopamine D3; D018967:Risperidone / Q000494:pharmacology*
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D010890:Pirenzepine; D018967:Risperidone; D000077152:Olanzapine