Abstract
Changes in D2-like dopamine (DA) receptor binding in rat brain regions were compared by quantitative in vitro receptor autoradiography after 21-d treatment with a typical (fluphenazine), atypical (clozapine), or candidate atypical antipsychotic (S[+]-N-n-propylnorapomorphine, [+]-NPA). Fluphenazine treatment significantly increased binding of the D2,3,4 radioligands [3H]nemonapride and [3H]spiperone in caudate-putamen (CPu: 22%, 32%), nucleus accumbens (ACC: 67%, 52%), olfactory tubercle (OT: 53%, 43%), and medial prefrontal cerebral cortex (MPC: 46%, 47%) but not dorsolateral frontal cortex (DFC). D2-like binding in MPC was also increased by (+)-NPA (49%, 39%) and clozapine (60%, 40%), but not in DFC, CPu, ACC, or OT. Binding of D2,3-selective [3H]raclopride increased less after fluphenazine in ACC (27%) and CPu (16%) than with the nonselective radioligands, and not after clozapine or (+)-NPA. D3-selective binding of [3H]R(+)-7-OH-DPAT was not changed with any treatment or region including islands of Calleja. Binding of [3H]nemonapride or [3H]spiperone under D4-selective conditions (with 300 nM S[−]-raclopride and other masking agents, at sites occluded by D4 ligand L-745,870), was increased by fluphenazine, (+)-NPA, clozapine in ACC (120%, 76%, 70%, respectively), and CPu (54%, 37%, 35%), but not in OT, DFC or MPC. These results support the hypothesis that cerebrocortical D2-like and striatolimbic D4-like receptors contribute to antipsychotic actions of both typical and atypical drugs and encourage further consideration of S(+)aporphines as potential atypical antipsychotics.
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Acknowledgements
This work was supported by NIH grants MH-34006, and MH-47370, a grant from the Bruce J. Anderson Foundation, and awards from the Mailman Research Center Private Donors Neuropharmacology Research Fund (RJB), Training Grant MH-14275 (SKY), and provision of test materials from an NIMH-RBI Chemical Synthesis Program (Contract MH-30003). Drs. Peter Munson and David Rodbard of the NIH Biostatistical and Computing Center generously provided the program ALLFIT for the Macintosh microcomputer. Sandoz (clozapine) and McNeil Laboratories (haloperidol) generously donated drug substances.
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Tarazi, F., Yeghiayan, S., Baldessarini, R. et al. Long-Term Effects of S(+)N-n-Propylnorapomorphine Compared with Typical and Atypical Antipsychotics: Differential Increases of Cerebrocortical D2-Like and Striatolimbic D4-Like Dopamine Receptors. Neuropsychopharmacol 17, 186–196 (1997). https://doi.org/10.1016/S0893-133X(97)00046-8
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DOI: https://doi.org/10.1016/S0893-133X(97)00046-8
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