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nor striatal D2 receptor up-regulation was observed in isofloxythepin-treated rats, even after the animals were withdrawn from the drug for an extended period of time.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.