J. Neurochem. (2011) 118, 1056–1066.
Abstract
The present study investigated regulation of histone acetylation by L‐type voltage‐dependent calcium channels (VDCCs), one of the machineries to provide Ca2+ signals. Acetylation of histone through the phosphorylation of protein kinase Cγ (PKCγ) in the development of methamphetamine (METH)‐induced place preference was demonstrated in the limbic forebrain predominantly but also in the nucleus accumbens of α1C subunit knockout mice. Chronic administration of METH produced a significant place preference in mice, which was dose‐dependently inhibited by both chelerythrine (a PKC inhibitor) and nifedipine (an L‐type VDCC blocker). Protein levels of acetylated histone H3 and p‐PKCγ significantly increased in the limbic forebrain of mice showing METH‐induced place preference, and it was also significantly attenuated by pre‐treatment with chelerythrine or nifedipine. METH‐induced place preference was also significantly attenuated by deletion of half the α1C gene, which is one of the subunits forming Ca2+ channels. Furthermore, increased acetylation of histone H3 was found in specific gene‐promoter regions related to synaptic plasticity, such as Nrxn, Syp, Dlg4, Gria1, Grin2a, Grin2b, Camk2a, Creb, and cyclin‐dependent kinase 5, in wild‐type mice showing METH‐induced place preference, while such enhancement of multiple synaptic plasticity genes was significantly attenuated by a deletion of half the α1C gene. These findings suggest that L‐type VDCCs play an important role in the development of METH‐induced place preference by facilitating acetylation of histone H3 in association with enhanced expression of synaptic plasticity genes via PKCγ phosphorylation following an increase in the intracellular Ca2+ concentration.