Antagonistic effects of isofloxythepin on dopamine D1 and D2 receptors and behaviors in rats.
1. In vitro, isofloxythepin competed for the binding of [3H]SCH 23390 to striatal D1 receptors and for the binding of [3H]spiperone to striatal D2 receptors with IC50 values of 6.1 (+/- 1.2) x 10(-10)M and 8.4 (+/- 2.6) x 10(-10)M, respectively. Isofloxythepin further inhibited the D1 receptor-mediated, dopamine-stimulated adenylate cyclase in the striatal tissue. 2. Fifteen hours after rats were injected with a single dose of isofloxythepin (1 mg/kg, SC), the ex vivo binding curve of [3H]spiperone to striatal D2 receptors was markedly inhibited, whereas the binding curve of [3H]SCH 23390 to striatal D1 receptors was unaffected. 3. Fifteen hours after isofloxythepin pretreatment, D1 agonist SKF 38393 (15 mg/kg, IP)-stimulated grooming behavior was not affected, whereas the D2 agonist quinpirole (3 mg/kg, IP)-stimulated stereotyped behavior was completely abolished. 4. On the basis of the findings from in vivo studies, we conclude that, although isofloxythepin is found to have high affinity for both D1 and D2 receptors in vitro, it lacks D1 antagonistic potency in vivo.
Lau
Y S
YS
Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City 64108, USA. YSLAU@CCTR.UMKC.EDU
Fung
Y K
YK
Anderson
T M
TM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines; D003988:Dibenzothiepins / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006120:Grooming / Q000187:drug effects; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013134:Spiperone; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D001552:Benzazepines; D003988:Dibenzothiepins; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C022110:isofloxythepin; D013134:Spiperone; D000262:Adenylyl Cyclases