Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition.
Recent evidence suggests that the dopamine D4 receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1-5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D4-selective compounds, CP-293,019 (5.6-17.8 mg/kg), U-101,387 (3-30 mg/kg) and L-745,870 (1-10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D4 dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D2 receptor antagonists.
Mansbach
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RS
Department of Neuroscience, Pfizer Inc., Groton, CT 06340, USA. mansbach@pfizer.com
Brooks
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EW
Sanner
M A
MA
Zorn
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SH
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D002460:Cell Line; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D013216:Reflex, Startle / Q000187:drug effects*; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001058:Apomorphine; D018492:Dopamine Antagonists; D010879:Piperazines; D011719:Pyrazines; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D013449:Sulfonamides; C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; C111732:CP 293019; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; C100448:sonepiprazole; D000096926:Benzenesulfonamides