Methamphetamine acutely inhibits voltage-gated calcium channels but chronically up-regulates L-type channels.

In neurons, calcium (Ca2+) channels regulate a wide variety of functions ranging from synaptic transmission to gene expression. They also induce neuroplastic changes that alter gene expression following psychostimulant administration. Ca2+ channel blockers have been considered as potential therapeutic agents for the treatment of methamphetamine (METH) dependence because of their ability to reduce drug craving among METH users. Here, we studied the effects of METH exposure on voltage-gated Ca2+ channels using SH-SY5Y cells as a model of dopaminergic neurons. We found that METH has different short- and long-term effects. A short-term effect involves immediate (<5min) direct inhibition of Ca2+ ion movements through Ca2+ channels. Longer exposure to METH (20min or 48h) selectively up-regulates the expression of only the CACNA1C gene, thus increasing the number of L-type Ca2+ channels. This up-regulation of CACNA1C is associated with the expression of the cAMP-responsive element-binding protein (CREB), a known regulator of CACNA1C gene expression, and the MYC gene, which encodes a transcription factor that putatively binds to a site proximal to the CACNA1C gene transcription initiation site. The short-term inhibition of Ca2+ ion movement and later, the up-regulation of Ca2+ channel gene expression together suggest the operation of cAMP-responsive element-binding protein- and C-MYC-mediated mechanisms to compensate for Ca2+ channel inhibition by METH. Increased Ca2+ current density and subsequent increased intracellular Ca2+ may contribute to the neurodegeneration accompanying chronic METH abuse. Methamphetamine (METH) exposure has both short- and long-term effects. Acutely, methamphetamine directly inhibits voltage-gated calcium channels. Chronically, neurons compensate by up-regulating the L-type Ca2+ channel gene, CACNA1C. This compensatory mechanism is mediated by transcription factors C-MYC and CREB, in which CREB is linked to the dopamine D1 receptor signaling pathway. These findings suggest Ca2+-mediated neurotoxicity owing to over-expression of calcium channels.