Differential effects of fluphenazine-N-mustard, on calmodulin activity and on D1 and D2 dopaminergic responses

Fluphenazine-N-mustard (FNM) has been shown to irreversibly block dopaminergic receptor sites and inhibit certain dopaminergically-mediated behaviors. In this study we measured whether FNM has any differential effects on D1 and D2 dopaminergic events. Accordingly, we examined the relative effects of FNM on rotational behavior induced by SKF 38393 (D1 agonist) and Ly 171555 (D2 agonist) in mice with unilateral, 6-hydroxydopamine-induced lesions of the striatum and the effects of FNM on the binding of [3H]Sch 23390 (D1 ligand) and [3H]spiroperidol (D2 ligand) to mouse striatal membranes. FNM inhibited rotational behavior induced by Ly 171555 at doses 10-fold lower than those required to block rotations induced by SKF 38393 (ID50 values: Ly 171555 = 1.8 mumole/kg, IP; SKF 38393 = 16 mumole/kg, IP). The inhibitory effect of high doses of FNM (20 mumole/kg) on rotational behavior was overcome by increasing the dose of SKF 38393 and apomorphine, a nonselective dopaminergic agonist. By contrast, the inhibitory effect of FNM was not overcome by Ly 171555, even when given in doses more than 100 times its ED50. Using striatal homogenates in vitro, FNM inhibited the specific binding of [3H]spiroperidol at concentrations about 10-fold lower than those required to inhibit the binding of [3H]Sch 23390 (IC50 values: [3H]spiroperidol = 90 nM; [3H]Sch 23390 = 840 nM). Considerably higher concentrations of FNM were needed to irreversibly inhibit calmodulin activity in striatal homogenates (IC50 = 10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)