Prolonged inhibition of striatal dopamine receptor sites by isofloxythepin.
Using the [3H]spiperone binding technique to measure the residual drug effect of subcutaneously injected isofloxythepin (1 mg/kg, single dose) in the rat, we observed a significant blockade of [3H]spiperone-labeled, high affinity dopamine receptors (D2) in the striatum up to 4 days after drug administration. Higher doses of isofloxythepin (5 or 10 mg/kg) produced a receptor blockade and were associated with an inhibition of apomorphine-induced stereotypy which lasted more than a week. Neither dopaminergic behavior supersensitivity nor striatal D2 receptor up-regulation was observed in isofloxythepin-treated rats, even after the animals were withdrawn from the drug for an extended period of time. Isofloxythepin was shown to decrease the Bmax without altering the KD of [3H]spiperone binding (a non-competitive inhibition), and in vitro its binding was not readily dissociated even when the drug-receptor complex was washed repeatedly with large volumes of drug-free buffer. The IC50 of isofloxythepin for displacing [3H]spiperone binding was 0.8 nM. Isofloxythepin is therefore a potent dopamine receptor antagonist with prolonged pharmacological action and strong binding at D2 receptors.
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D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003988:Dibenzothiepins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D003988:Dibenzothiepins; D011954:Receptors, Dopamine; C022110:isofloxythepin; D013134:Spiperone; D001058:Apomorphine