Ca_v1.3 L-type Ca²⁺ channel-activated CaMKII/ERK2 pathway in the ventral tegmental area is required for cocaine conditioned place preference

We have previously demonstrated that pharmacological blockade of ventral tegmental area (VTA) Ca_v1.3 L-type calcium channels (LTCCs) using Ca_v1.2 dihydropyridine insensitive (Ca_v1.2DHP^-/-) mutant mice attenuates cocaine conditioned place preference (CPP). However, the molecular mechanisms by which Ca_v1.3 channels mediate the effects of cocaine in the VTA remain largely unknown. In this study using Ca_v1.2DHP^-/- male mice, we find that cocaine place preference increases CaM kinase IIα, ERK2, and CREB phosphorylation in the VTA, proteins strongly linked to cocaine behaviors. To further explore the causal role of these intracellular signaling proteins in cocaine preference, the CaM kinase II inhibitor, KN93 was directly injected into the VTA of male mice before each cocaine conditioning session. We found that KN93 attenuates conditioned preference for cocaine compared to vehicle treated mice and decreased VTA ERK2 and CREB phosphorylation. Additionally, blockade of the ERK pathway with the MEK inhibitor, U0126 or knockdown of ERK2 using siRNA, attenuated cocaine preference and VTA CREB phosphorylation but not CaMKIIα phosphorylation, suggesting that ERK is activated downstream of CaMKIIα. Examination of postsynaptic density (PSD) GluA1 subunit of AMPA receptors in the nucleus accumbens (NAc) that we have previously shown to be upregulated following long withdrawal periods, was blunted by KN93, U0126 and ERK2 siRNA when examined 30 days following cocaine CPP. Taken together, these findings demonstrate that Ca_v1.3 channels in the VTA are required for cocaine reward behavior and activation of the CaMKIIα/ERK/CREB signaling pathway in the VTA is necessary for long-lasting changes in the NAc. This article is part of the Special Issue on 'L-type calcium channel mechanisms in neuropsychiatric disorders'.