Pharmacological involvement of the calcium channel blocker flunarizine in dopamine transmission at the striatum

Single intrastriatal microinjections of 25, 50 and 100 nmol/mul of flunariz ine in normal rats produced a dose-dependent turning behavior toward the in jected side when they were challenged with apomorphine (I mg/kg, sx). This effect was seen at 1, 3 and 7 days following administration of the high dos e of flunarizine, but had subsided by 24 h after administration of the inte rmediate dose; the low dose was ineffective. However, intrastriatal injecti on of the high dose of flunarizine resulted in a local lesion and thereafte r this dose was not used. A similar dose-response relationship was determin ed for nifedipine, an L-type calcium channel antagonist. Injection of this antagonist did not result in apomorphine-elicited rotational behavior, refl ecting its lack of antidopaminergic action. Intrastriatal injections of hal operidol (5 mug/mul), an antagonist of dopamine D-2 receptors, or the sodiu m channel blocker lidocaine (40 mug/mul), were given in order to compare th eir effects to those observed with flunarizine. Intracerebral injection of haloperidol produced ipsilateral turning in response to systemic administra tion of apomorphine given 60 min after. The same response was obtained with the injection of apomorphine 10 min after the injection of intracerebral l idocaine. This effect was no longer apparent 24 h after the microinjection of haloperidol and 60 min after the injection of lidocaine. In rats rendere d hemiparkinsionian by lesioning the nigrostriatal pathway with 60HDA, intr astriatal microinjection of flunarizine (50 nmol/mul) significantly reduced apomorphine (0.2 mg/kg, s.c.)-elicited turning behavior towards the non-le sioned side. These results suggest an dntidopaminergic effect of flunarizin e mediated by antagonistic action of post-synaptic striatal dopamine recept ors. However, an action of the drug on sodium channels may not be ruled out . These studies offer additional supporting evidence for the induction or a ggravation of extrapyramidal side-effects in patients receiving flunarizine . (C) 2001 Elsevier Science Ltd. All rights reserved.