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

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.

Grant Number: 1R03DA055970-01A1
NIH Institute/Center: NIH
Principal Investigator: Marilou Andres