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 flunarizine in normal rats produced a dose-dependent turning behavior toward the injected 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 dose of flunarizine, but had subsided by 24 h after administration of the intermediate dose; the low dose was ineffective. However, intrastriatal injection of the high dose of flunarizine resulted in a local lesion and thereafter this dose was not used. A similar dose-response relationship was determined for nifedipine, an L-type calcium channel antagonist. Injection of this antagonist did not result in apomorphine-elicited rotational behavior, reflecting its lack of antidopaminergic action. Intrastriatal injections of haloperidol (5 mug/mul), an antagonist of dopamine D-2 receptors, or the sodium channel blocker lidocaine (40 mug/mul), were given in order to compare their effects to those observed with flunarizine. Intracerebral injection of haloperidol produced ipsilateral turning in response to systemic administration of apomorphine given 60 min after. The same response was obtained with the injection of apomorphine 10 min after the injection of intracerebral lidocaine. This effect was no longer apparent 24 h after the microinjection of haloperidol and 60 min after the injection of lidocaine. In rats rendered hemiparkinsionian by lesioning the nigrostriatal pathway with 60HDA, intrastriatal microinjection of flunarizine (50 nmol/mul) significantly reduced apomorphine (0.2 mg/kg, s.c.)-elicited turning behavior towards the non-lesioned side. These results suggest an dntidopaminergic effect of flunarizine mediated by antagonistic action of post-synaptic striatal dopamine receptors. However, an action of the drug on sodium channels may not be ruled out. These studies offer additional supporting evidence for the induction or aggravation of extrapyramidal side-effects in patients receiving flunarizine. (C) 2001 Elsevier Science Ltd. All rights reserved.