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.
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.
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DOI：
10.1523/jneurosci.2255-10.2010
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发表时间：
2010-12-15
期刊：
影响因子：
--
通讯作者：
Rajadhyaksha AM
中科院分区：
文献类型：
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作者：
Giordano TP;Tropea TF;Satpute SS;Sinnegger-Brauns MJ;Striessnig J;Kosofsky BE;Rajadhyaksha AM
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 largely unknown. In this study by utilizing 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 following a fourteen day 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 naïve versus drug pre-exposed mice examined fourteen days later revealed that an acute amphetamine and cocaine challenge in drug naïve mice increases Ser 133 CREB phosphorylation in the NAc via Cav1.3 channels and via a dopamine D1-dependent mechanism, independent of the ERK pathway, an important mediator of psychostimulant-induced plasticity. In contrast, in amphetamine and cocaine pre-exposed 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 following 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.
