L-type Ca2+ channels mediate adaptation of extracellular signal-regulated kinase 1/2 phosphorylation in the ventral tegmental area after chronic amphetamine treatment
L-type Ca2+ channels mediate adaptation of extracellular signal-regulated kinase 1/2 phosphorylation in the ventral tegmental area after chronic amphetamine treatment
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DOI：
10.1523/jneurosci.0612-04.2004
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发表时间：
2004-08-25
影响因子：
5.3
通讯作者：
Kosofsky, BE
中科院分区：
文献类型：
--
作者：
Rajadhyaksha, A;Husson, I;Kosofsky, BE
L型钙通道（LTCCs）在慢性精神兴奋药诱导的行为中起重要作用。然而，钙离子第二信使途径激活LTCCs后，急性和反复精神兴奋剂管理，有助于药物诱导的分子适应知之甚少。使用慢性安非他明治疗模式在大鼠中，我们已经研究了LTCCs在激活腹侧被盖区（VTA）的促分裂原活化蛋白（MAP）激酶通路中的作用，这是精神兴奋剂强化特性的主要目标。使用免疫印迹和免疫组化分析，我们发现，在慢性盐水治疗的大鼠挑战注射安非他明增加磷酸化的MAP[细胞外信号调节激酶1/2（ERK 1/2）]激酶在VTA是独立的LTCCs。然而，在慢性安非他明治疗的大鼠中，安非他明介导的ERK 1/2磷酸化没有增加，除非LTCCs被阻断，在这种情况下，腹侧被盖区多巴胺神经元中存在强烈的磷酸化。磷酸酶表达的检查显示VTA中钙调磷酸酶[蛋白磷酸酶2B（PP 2B）]和MAP激酶磷酸酶-1（MKP-1）增加。使用原位杂交组织化学和免疫印迹分析，我们进一步研究的mRNA和蛋白质表达的LTCC亚型Ca（v）1.2和Ca（v）1.3在腹侧被盖区多巴胺神经元在药物幼稚的动物和大鼠慢性苯丙胺治疗后。我们发现Ca（v）1.2 mRNA和蛋白水平增加，Ca（v）1.3无变化。总之，我们的研究结果表明，LTCC诱导的第二信使途径的变化慢性安非他明暴露后的一个方面涉及激活MAP激酶磷酸酶途径的上调Ca（v）1.2腹侧被盖区多巴胺能神经元。
L-type Ca2+ channels (LTCCs) play an important role in chronic psychostimulant-induced behaviors. However, the Ca2+ second messenger pathways activated by LTCCs after acute and recurrent psychostimulant administration that contribute to drug-induced molecular adaptations are poorly understood. Using a chronic amphetamine treatment paradigm in rats, we have examined the role of LTCCs in activating the mitogen-activated protein ( MAP) kinase pathway in the ventral tegmental area (VTA), a primary target for the reinforcing properties of psychostimulants. Using immunoblot and immunohistochemical analyses, we find that in chronic saline-treated rats a challenge injection of amphetamine increases phosphorylation of MAP[ extracellular signal-regulated kinase 1/2 (ERK1/2)] kinase in the VTA that is independent of LTCCs. However, in chronic amphetamine-treated rats there is no increase in amphetamine-mediated ERK1/2 phosphorylation unless LTCCs are blocked, in which case there is robust phosphorylation in VTA dopamine neurons. Examination of the expression of phosphatases reveals an increase in calcineurin [ protein phosphatase 2B (PP2B)] and MAP kinase phosphatase-1 (MKP-1) in the VTA. Using in situ hybridization histochemistry and immunoblot analyses, we further examined the mRNA and protein expression of the LTCC subtypes Ca(v)1.2 and Ca(v)1.3 in VTA dopamine neurons in drug-naive animals and in rats after chronic amphetamine treatment. We found an increase in Ca(v)1.2 mRNA and protein levels, with no change in Ca(v)1.3. Together, our results suggest that one aspect of LTCC-induced changes in second messenger pathways after chronic amphetamine exposure involves activation of the MAP kinase phosphatase pathway by upregulation of Ca(v)1.2 in VTA dopaminergic neurons.