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They also induce neuroplastic changes that alter gene expression following psychostimulant administration. Ca<jats:sup>2+<\/jats:sup>channel blockers have been considered as potential therapeutic agents for the treatment of methamphetamine (<jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>) dependence because of their ability to reduce drug craving among<jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>users. Here, we studied the effects of<jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>exposure on voltage\u2010gated Ca<jats:sup>2+<\/jats:sup>channels using<jats:styled-content style=\"fixed-case\">SH<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">SY<\/jats:styled-content>5Y cells as a model of dopaminergic neurons. We found that<jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>has different short\u2010 and long\u2010term effects. A short\u2010term effect involves immediate (&lt;\u00a05\u00a0min) direct inhibition of Ca<jats:sup>2+<\/jats:sup>ion movements through Ca<jats:sup>2+<\/jats:sup>channels. Longer exposure to<jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>(20\u00a0min or 48\u00a0h) selectively up\u2010regulates the expression of only the<jats:italic><jats:styled-content style=\"fixed-case\">CACNA<\/jats:styled-content>1C<\/jats:italic>gene, thus increasing the number of L\u2010type Ca<jats:sup>2+<\/jats:sup>channels. This up\u2010regulation of<jats:italic><jats:styled-content style=\"fixed-case\">CACNA<\/jats:styled-content>1C<\/jats:italic>is associated with the expression of the<jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content>\u2010responsive element\u2010binding protein (CREB), a known regulator of<jats:italic><jats:styled-content style=\"fixed-case\">CACNA<\/jats:styled-content>1C<\/jats:italic>gene expression, and the<jats:italic><jats:styled-content style=\"fixed-case\">MYC<\/jats:styled-content><\/jats:italic>gene, which encodes a transcription factor that putatively binds to a site proximal to the<jats:italic><jats:styled-content style=\"fixed-case\">CACNA<\/jats:styled-content>1C<\/jats:italic>gene transcription initiation site. The short\u2010term inhibition of Ca<jats:sup>2+<\/jats:sup>ion movement and later, the up\u2010regulation of Ca<jats:sup>2+<\/jats:sup>channel gene expression together suggest the operation of cAMP\u2010responsive element\u2010binding protein\u2010 and C\u2010<jats:styled-content style=\"fixed-case\">MYC<\/jats:styled-content>\u2010mediated mechanisms to compensate for Ca<jats:sup>2+<\/jats:sup>channel inhibition by<jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>. Increased Ca<jats:sup>2+<\/jats:sup>current density and subsequent increased intracellular Ca<jats:sup>2+<\/jats:sup>may contribute to the neurodegeneration accompanying chronic<jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>abuse.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13104-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>Methamphetamine (METH) exposure has both short\u2010 and long\u2010term effects. Acutely, methamphetamine directly inhibits voltage\u2010gated calcium channels. Chronically, neurons compensate by up\u2010regulating the L\u2010type Ca<jats:sup>2+<\/jats:sup>channel gene,<jats:italic>CACNA1C<\/jats:italic>. This compensatory mechanism is mediated by transcription factors C\u2010MYC and CREB, in which CREB is linked to the dopamine D1 receptor signaling pathway. These findings suggest Ca<jats:sup>2+<\/jats:sup>\u2010mediated neurotoxicity owing to over\u2010expression of calcium channels.<\/jats:p>","DOI":"10.1111\/jnc.13104","type":"journal-article","created":{"date-parts":[[2015,3,25]],"date-time":"2015-03-25T11:33:02Z","timestamp":1427283182000},"page":"56-65","source":"Crossref","is-referenced-by-count":25,"title":["Methamphetamine acutely inhibits voltage\u2010gated calcium channels but chronically up\u2010regulates L\u2010type channels"],"prefix":"10.1111","volume":"134","author":[{"given":"Marilou A.","family":"Andres","sequence":"first","affiliation":[{"name":"Bekesy Laboratory of Neurobiology Pacific Biosciences Research Center University of Hawaii Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M.","family":"Cooke","sequence":"additional","affiliation":[{"name":"Bekesy Laboratory of Neurobiology Pacific Biosciences Research Center University of Hawaii Honolulu Hawaii USA"},{"name":"Department of Biology University of Hawaii Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick P.","family":"Bellinger","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology John A. 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