Glyoxalase 1 involvement in alcohol drinking and alcohol-motivated behaviors

Opioid addiction is a heritable substance use disorder with an unknown genetic etiology. Mammalian model organisms permit a comprehensive approach to bridging genetic variation with neurobiological mechanisms of addiction-relevant behaviors. The closely related C57BL/6J and C57BL/6NJ substrains show extremely limited genetic diversity, yet show differences in alcohol consumption, binge eating, psychostimulant-induced locomotor activity, and naloxone aversion. Here, we replicated strain differences in psychostimulant-induced locomotor activity with methamphetamine and used quantitative trait locus (QTL) mapping to identify a QTL on chromosome 5 (52-99 Mb) that co-mapped with a striatal cis-expression QTL (eQTL) for Gabra2 (71 Mb). We also co-mapped QTLs for opioid-induced locomotor activity and withdrawal induced by the mu opioid receptor agonist oxycodone to distal chromosome 1 (LOD=4.7-9.8; 152-181 Mb). We backcrossed F2 mice based on this QTL genotype to C57BL/6J to fine map a region containing a well-known neurobehavioral QTL “hotspot” (chr1: 172-178 Mb). Shared haplotype analysis of C57BL/6NJ and classical inbred strains combined with cis-eQTL analysis of F2 mice identified two strong positional candidate genes for oxycodone behaviors Aim2, and Rgs7. Pathway analysis in opioid withdrawn F2 mice identified two major hub genes underlying opioid dependence Mapt and App. Finally, we identified a major QTL for naloxone-induced aversive behavior on chromosome 18 (LOD=6.2; 35-62 Mb) near a striatal cis-eQTL for Onecut2 (64 Mb), a gene involved in neurodevelopment of the locus coeruleus. To summarize, systems genetics and fine mapping in a reduced complexity cross revealed compelling candidate genes underlying addiction traits. FUNDING: NIDA R03DA038287, NIDA R21DA038738, NIDA R00DA029635, BurroughsWellcome Transformative Training Program in Addiction Science (TTPAS),