Comparison of the effects of fluphenazine-N-mustard on dopamine binding sites and on behavior induced by apomorphine in supersensitive mice.

PMID 3120028


The effects of fluphenazine-N-mustard (FNM) on the binding of [3H]spiroperidol both in vitro and in vivo and on behavior produced by apomorphine were examined in mice. In vitro, FNM inhibited the binding of [3H]spiroperidol to membranes from the striatum in the mouse, with an IC50 of approximately 100 nM. In vivo administration of FNM resulted in a dose-dependent inhibition of the subsequent binding of [3H]spiroperidol with an ED50 of approximately 20 mumol/kg, (i.p.). To examine whether or not this interaction was irreversible, FNM was preincubated with striatal homogenates in vitro or administered in vivo; the striata were subsequently homogenized, washed extensively to remove reversibly bound FNM and then assayed by measuring the binding of [3H]spiroperidol to these washed membranes. The results showed that FNM caused a 50-60% blockade of the binding sites, suggesting that FNM irreversibly inhibits binding sites for spiroperidol. Studies of the effects of FNM on the function of dopamine showed that prior administration of FNM blocked the apomorphine-induced rotational behavior in mice with unilateral lesions of the striatum produced by 6-hydroxydopamine; the ED50 was 0.8 mumol/kg, (i.p.), a dose which was about 100-fold less than that found to inhibit the binding of [3H]spiroperidol by 50%. Half-maximum recovery of behavior occurred 4 days after the injection of FNM (20 mumol/kg, i.p.). Under similar circumstances, full recovery of the binding of [3H]spiroperidol occurred within 1 day. These data suggest that FNM interacts irreversibly with binding sites for [3H]spiroperidol, but the magnitude of this interaction was not predictive of its behavioral efficacy.