L-type calcium channel blockade on haloperidol-induced c-fos expression in the striatum

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 Ca2+ channels. In the current study, pretreatment with L-type Ca2+ 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 Ca2+ channel blocker compared with rats pretreated with vehicle alone. In addition, pretreatment prolonged the duration of halo peridol- induced catalepsy in rats. Infusions of L-type Ca2+ 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 D2 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 Ca2+ channels. Collectively, the results suggest that coadministration of L-type Ca2+ channel blockers affects haloperidol signaling in the lateral part of the neostriatum and may exacerbate the development of acute motor side effects. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.