Files
Abstract
Methamphetamine (MA) is a powerful psychostimulant and its excessive use is linked to neurotoxicity and neuropsychiatric disorders. However, not all initial users develop drug use disorders and it is possible that genetic differences render some individuals more susceptible to the addictive properties of MA compared to others. Genetic differences in avidity for MA have been studied using two replicate sets of selectively bred MA drinking (MADR) mouse lines that voluntarily consume either high (MAHDR) or low (MALDR) amounts of MA. Selective breeding alters allele frequencies; thus, alleles that increase MA drinking (MADR) have aggregated in the MAHDR line mice, whereas alleles that reduce MA intake have aggregated in the MALDR line mice. A gene mapping study identified a major effect genetic locus on mouse chromosome (Chr) 10 that accounts for more than 50% of the genetic variance associated with this differential MA intake. Oprm1 lies within the mapped region and previous gene expression analysis added support for Oprm1 as a candidate gene on Chr 10 that influences MA drinking. Based on published basic and human clinical data and preliminary data obtained within our laboratory, I hypothesized that Oprm1 genetic variation and mu-opioid receptor (MOP-r)- regulated systems are important in influencing MA intake.