We analyzed time dependent behavioral responses to morphine and naloxone obtained from a large family of young adult BXD mice (n = 70 strains, including C57BL/6J and DBA/2J parents, 4 to 9 cases per strain) using the latest whole genome sequencing (WGS)-based genetic markers. These data include quantitative locomotor and behavior responses measured three hours after an acute morphine injection (50 mg/kg i.p.), followed by naloxone-induced withdrawal, obtained by Philip et al (2010). Locomotor data were analyzed in 15 min bins and mapped jointly for both sexes or independently for males and females. We confirmed a highly significant association between locomotor response and a genomic region that overlaps with Oprm1 on Chr 10 at 6.8 Mb (LOD maximum of 11.4) between 15-105 min, with a peak at 75 min. Effects were modestly dependent of sex. Strains that were B homozygotes run 76 meters farther than those that are D homozygotes after a morphine injection. We discovered a novel association between a locus on Chr 16 and a late phase locomotor response (after 150 min) in both sexes. This locus had a significant but transient epistatic interaction with the Oprm1 locus between 45-90 min, well before the main effect was detectable. The Chr 16 locus includes one compelling candidate fibroblast growth factor 12 (Fgf12). Null mutation of Fgf12 has been shown to cause locomotor deficits (e.g., ataxia) in mice. Analysis of genes correlated with both OPRM1 and FGF12 in six human brain regions (GTEx, v8) demonstrated an enrichment of genetic signals associated with SUD phenotypes, and a modest corroboration of variants in the FGF12 loci on Chr 3q28. To the best of our knowledge this is the first demonstration of a transient time dependent epistatic interaction modulating drug response in mammals; a finding with interesting mechanistic implications. Finally, this work demonstrates how high-quality FAIR+ data can be used with newly acquired data sets to yield striking results, and how joint mouse and human neurogenomic and mapping data can be merged at gene and network levels for bidirectional validation of potential SUD variants and molecular networks.

The social environment has long been recognized to play an important role in substance abuse disorders (SUD). Operant conditioning is the most widely used rodent model of SUD. However, most operant chambers do not accommodate more than one rat at a time. Here, we introduce PeerPub; a novel social operant chamber. PeerPub uses a touch sensor to record the number of licks on drinking spouts. It then delivers a drop of solution with a fixed volume as the reward to the tip of the spout when the number of licks meets the requirement of a reinforcement schedule. A radio-frequency identification (RFID) chip implanted on top of each rat's skull tracks the identity of the rat. The system is controlled by a Raspberry Pi computer. We tested PeerPub using male Wistar Kyoto rats in daily one-hour sessions where supersac, a solution containing glucose and saccharin, was delivered under a fixed ratio 5 schedule. We found that male rats consumed more supersac in group housing rather than in isolated conditions. These data demonstrated the utility of PeerPub in modeling the interaction between motivated behavior and social context. We anticipate devices like PeerPub will help demonstrate the role of the social environment in SUD phenotypes. The design of PeerPub is available at http://github.com/nijie321/PeerPub .