L-type Calcium Channel SNP rs1006737: characterizing the genetic risks in MUD (Methamphetamine Use Disorder)

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ABSTRACT Methamphetamine (METH) causes structural damage to the brain. This leads to serious cognitive dysfunction and other comorbid conditions (e.g., depression, cardiac dysfunction, etc.) that can persist even during abstinence, thus negatively impacting recovery. METH also induces immune dysfunction and injures neurons leading to neuronal death. However, it remains unclear whether brain inflammation plays a critical role during abstinence and whether continued inflammation contributes to persisting cognitive deficits. We also do not know whether genetic factors can regulate brain inflammation and response to METH exposure and withdrawal. Filling this gap in our knowledge is critical to developing effective treatment to improve outcomes for METH addicts. We found that long-term exposure to METH in a cell culture system resulted in increased expression of the L-type calcium (Ca2+) channel gene, leading to more Ca2+ entry into the cells. Too much Ca2+ in the cytosol is toxic to the cell. Genetic variants of the L-type Ca2+ channel gene, associated with a gain-of- function mutation and increased Ca2+ influx, have been implicated in various neuropsychiatric disorders like depression, which has been associated with cytokine/chemokine dysfunction. The release of specific pro- inflammatory markers is Ca2+-dependent. An increase of Ca2+ influx through L-type Ca2+ channels may drive more release of these cytokine/chemokine markers. Our long-term goal is to understand the mechanisms by which genetics underlie the changes in systemic and central nervous system (CNS) inflammation and how chronic inflammation may alter brain function and cognition during current METH use and abstinence. Our central hypothesis is that individuals with gain-of-function SNP s1006737 risk A/A genotype that promotes higher intracellular Ca2+ load will exhibit higher levels of pro-inflammatory markers in response to METH compared to METH-users without these risk alleles. Our Specific Aims are to 1) Compare brain gamma- aminobutyric acid (GABA), glutamate (Glu), myo-inositol (mI), and N-acetyl-aspartate (NAA) levels of Methamphetamine Use Disorder (MUD) subjects with the A/A and those with A/G (or G/G) genotypes and with non-MUD (A/A) subjects; and 2) Compare the plasma levels of pro-inflammatory markers of MUD subjects with different genotypes (A/A vs. A/G and G/G) and with non-MUD (A/A) subjects and determine epigenetic changes (i.e., DNA methylation levels). This Imaging-Science Track Award for Research Transition (I/START) application will allow the PI to adopt neuroimaging methodologies to test a hypothesis-driven by preliminary basic science findings.