Molecular switch from L-type Ca v 1.3 to Ca v 1.2 Ca2+ channel signaling underlies long-term psychostimulant-induced behavioral and molecular plasticity.

L-type Ca(2+) channel (LTCC)-activated signaling cascades contribute significantly to psychostimulant-induced locomotor sensitization; however, the precise contribution of the two brain-specific subunits Ca(v)1.2 and Ca(v)1.3 remains mostly unknown. In this study, by using amphetamine and cocaine locomotor sensitization in mutant mice expressing dihydropyridine (DHP)-insensitive Ca(v)1.2 LTCCs (Ca(v)1.2DHP(-/-)), we find that, as opposed to a previously identified role of the Ca(v)1.3 subunit of LTCCs in development of sensitization, the Ca(v)1.2 subunit mediates expression of amphetamine and cocaine sensitization when examined after a 14 d drug-free period. Molecular studies to further elucidate the role of Ca(v)1.2 versus Ca(v)1.3 LTCCs in activating signaling pathways in the nucleus accumbens (NAc) of drug-naive versus drug-preexposed mice examined 14 d later revealed that an acute amphetamine and cocaine challenge in drug-naive mice increases Ser133 cAMP response element-binding protein (CREB) phosphorylation in the NAc via Ca(v)1.3 channels and via a dopamine D(1)-dependent mechanism, independent of the extracellular signal-regulated kinase (ERK) pathway, an important mediator of psychostimulant-induced plasticity. In contrast, in amphetamine- and cocaine-preexposed mice, an amphetamine or cocaine challenge no longer activates CREB unless Ca(v)1.2 LTCCs are blocked. This Ca(v)1.2-dependent blunting of CREB activation that underlies expression of locomotor sensitization occurs only after extended drug-free periods and involves recruitment of D(1) receptors and the ERK pathway. Thus, our results demonstrate that specific LTCC subunits are required for the development (Ca(v)1.3) versus expression (Ca(v)1.2) of psychostimulant sensitization and that subunit-specific signaling pathways recruited by psychostimulants underlies long-term drug-induced behavioral responses.