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Molecular Switch from L-Type Cav1.3 to Cav1.2 Ca2+ Channel Signaling Underlies Long-Term Psychostimulant-Induced Behavioral and Molecular Plasticity

T. Giordano,Thomas F. Tropea,Shirish S. Satpute,M. Sinnegger-Brauns,J. Striessnig,B. Kosofsky,A. Rajadhyaksha

Published 2010 in Journal of Neuroscience

ABSTRACT

L-type Ca2+ channel (LTCC)-activated signaling cascades contribute significantly to psychostimulant-induced locomotor sensitization; however, the precise contribution of the two brain-specific subunits Cav1.2 and Cav1.3 remains mostly unknown. In this study, by using amphetamine and cocaine locomotor sensitization in mutant mice expressing dihydropyridine (DHP)-insensitive Cav1.2 LTCCs (Cav1.2DHP−/−), we find that, as opposed to a previously identified role of the Cav1.3 subunit of LTCCs in development of sensitization, the Cav1.2 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 Cav1.2 versus Cav1.3 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 Cav1.3 channels and via a dopamine D1-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 Cav1.2 LTCCs are blocked. This Cav1.2-dependent blunting of CREB activation that underlies expression of locomotor sensitization occurs only after extended drug-free periods and involves recruitment of D1 receptors and the ERK pathway. Thus, our results demonstrate that specific LTCC subunits are required for the development (Cav1.3) versus expression (Cav1.2) of psychostimulant sensitization and that subunit-specific signaling pathways recruited by psychostimulants underlies long-term drug-induced behavioral responses.

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