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.
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.
Tarazi
F I
FI
Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA 02178, USA.
Yeghiayan
S K
SK
Baldessarini
R J
RJ
Kula
N S
NS
Neumeyer
J L
JL
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001345:Autoradiography; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D015195:Drug Design; D005476:Fluphenazine / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; C493601:Drd4 protein, rat; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; C009074:N-n-propylnorapomorphine; D003024:Clozapine; D001058:Apomorphine; D005476:Fluphenazine