title: Pharmacological involvement of the calcium channel blocker flunarizine in dopamine transmission at the striatum.
abstract: Single intrastriatal microinjections of 25, 50 and 100nmol/microl of flunarizine in normal rats produced a dose-dependent turning behavior toward the injected side when they were challenged with apomorphine (1mg/kg, s.c). This effect was seen at 1, 3 and 7 days following administration of the high dose of flunarizine, but had subsided by 24h 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 (5microg/microl), an antagonist of dopamine D(2) receptors, or the sodium channel blocker lidocaine (40microg/microl), 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 60min after. The same response was obtained with the injection of apomorphine 10min after the injection of intracerebral lidocaine. This effect was no longer apparent 24h after the microinjection of haloperidol and 60min after the injection of lidocaine. In rats rendered hemiparkinsionian by lesioning the nigrostriatal pathway with 6OHDA, intrastriatal microinjection of flunarizine (50nmol/microl) significantly reduced apomorphine (0.2mg/kg, s.c.)-elicited turning behavior towards the non-lesioned side. These results suggest an antidopaminergic 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.
authors.affiliation: Laboratorio de Neurofisiología, Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
authors.forename: J E
authors.initials: JE
authors.lastname: Belforte
authors.forename: C
authors.initials: C
authors.lastname: Magariños-Azcone
authors.forename: I
authors.initials: I
authors.lastname: Armando
authors.forename: W
authors.initials: W
authors.lastname: Buño
authors.forename: J H
authors.initials: JH
authors.lastname: Pazo
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005444:Flunarizine / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D009543:Nifedipine; D006220:Haloperidol; D001058:Apomorphine; D005444:Flunarizine; D004298:Dopamine