An animal model of differential genetic risk for methamphetamine intake

Abstract

The question of whether genetic factors contribute to risk for methamphetamine (MA) use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine-associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the development of a binge model of MA intake, examining the effect of withdrawal from chronic MA on MA intake, and studying potential Taar1 gene × gene and gene × environment interactions. These and other studies are intended to improve our genetic model with regard to its translational value to human addiction.

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly

“…Further, the MA-conditioned response expressed by B6 mice following subchronic drug exposure predicted both subsequent MA reinforcement and voluntary intake. Notwithstanding a full dose-response analysis of place-conditioned behavior, our study outcomes related to individual variance in MA reward/aversion in isogenic B6 mice are very much in line with average differences between the MAH/LDR lines (15) and argue that individual differences in the initial perception of MA’s interoceptive effects as positive or negative (i.e., MA-preference or avoidance) predict risk of subsequent MA-taking also in an isogenic model of MA abuse. Further, examination of published (15) and recent place-conditioning data from MALDR mice at a late stage in selection also indicate individual differences, such that about one-third (35%) exhibit CPP, while the rest exhibit a neutral response (23%) or CPA (42%; Suppl.…”

“…Consistent with this, the divergent MA-taking phenotypes of MAH/LDR mice (a well-validated genetic model of vulnerability/resiliency to MA addiction-related traits) reflect marked line differences in the motivational valence of MA’s effects, with the high MA-taking MAHDR line exhibiting high sensitivity to the rewarding properties of low-dose MA, but insensitivity to high-dose MA-aversion (15). The B6 progenitor of the MA drinking lines has been reported to consume less MA than the DBA/2J progenitor (14); however, herein, B6 mice voluntarily consumed unadulterated MA solutions and exhibited oral MA reinforcement.…”

“…Not shown, MA intake under these reinforcement schedules was also predicted by CPP Score (for both schedules: r=0.40, p=0.003, N=51). Thus, akin to MAH/LDR mice (15), MA-preference in our B6 model extends across place- and operant-conditioning paradigms.…”

“…To test the hypothesis that NAC glutamate anomalies accompany genetic predisposition to consume MA, we conducted in vivo microdialysis and immunoblotting procedures on mouse lines selectively bred to exhibit MA High Drinking (MAHDR) and MA Low Drinking (MALDR) (14,15). We next examined whether individual variance in MA-preference/taking might correlate with indices of NAC glutamate transmission in an isogenic model that involved screening a large (N=186) group of inbred C57BL/6J (B6) mice for MA-reward/aversion using place-conditioning procedures, employed to study the genetics and neuropharmacology of MA addiction vulnerability/resiliency and locomotor hyper-activity (7,9,16–18).…”

A Mouse Model for Binge-Level Methamphetamine Use

“…Bidirectional short-term selective breeding methods (Belknap et al, 1997) were used to produce multiple replicate sets of MA drinking (MADR) selected lines in which one member of each set was MA high drinking (MAHDR) and the other was MA low drinking (MALDR). These mice have been used to identify genetic risk factors and genetically-correlated traits that are associated with protection from excessive MA intake (Phillips and Shabani, 2015). …”