title: L-type calcium channel blockade on haloperidol-induced c-Fos expression in the striatum.
abstract: Haloperidol-induced c-Fos expression in the lateral part of the neostriatum has been correlated with motor side effects while c-Fos induction in the medial part of the neostriatum and the nucleus accumbens is thought to be associated with the therapeutic effects of the drug. Induction of c-Fos in the striatum by haloperidol involves dopamine D(2) (DA D(2)) receptor antagonism and is dependent on activation of N-methyl-d-aspartate (NMDA) receptors and L-type Ca(2+) channels. In the current study, pretreatment with L-type Ca(2+) channel blockers suppressed haloperidol-induced c-Fos throughout the neostriatum and the nucleus accumbens at 2 h postinjection. However, elevated c-Fos protein expression was observed only in the lateral part of the neostriatum at 5 h postinjection of haloperidol following pretreatment of L-type Ca(2+) channel blocker compared with rats pretreated with vehicle alone. In addition, pretreatment prolonged the duration of haloperidol-induced catalepsy in rats. Infusions of L-type Ca(2+) channel blockers directly into the neostriatum mimicked similar patterns of changes in haloperidol-induced c-Fos expression. Prolonged expression of c-Fos was not observed following coadministration of nifedipine and a dopamine D(1) (DA D(1)) receptor agonist, SKF 81297, but could be mimicked by the DA D(2/3) receptor antagonist raclopride, suggesting that the phenomenon is likely related to DA D(2) receptor antagonism. Moreover, the expression levels of haloperidol-induced zif 268 and haloperidol-induced phosphorylated CREB and phosphorylated Elk-1 were also substantially elevated for a prolonged period of time in the lateral, but not the medial part of the neostriatum, following blockade of L-type Ca(2+) channels. Collectively, the results suggest that coadministration of L-type Ca(2+) channel blockers affects haloperidol signaling in the lateral part of the neostriatum and may exacerbate the development of acute motor side effects.
authors.affiliation: Department of Anatomy & Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: W J
authors.initials: WJ
authors.lastname: Rushlow
authors.forename: N
authors.initials: N
authors.lastname: Rajakumar
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects* / Q000235:genetics*; D006220:Haloperidol / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D050807:ets-Domain Protein Elk-1 / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D050807:ets-Domain Protein Elk-1; D020891:Raclopride; D009553:Nimodipine; C067113:SK&F 81297; D009543:Nifedipine; D006220:Haloperidol