Abstract

Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice from 62 BXD strains and the C57BL/6J and DBA/2J founder strains. We used relative preference for the active and inactive levers to dissociate preference for sensory stimuli from locomotion and exploration phenotypes. We identified genomic regions on chromosome 4 (155.236‐155.742 Mb) and chromosome 13 (72.969‐89.423 Mb) associated with distinct behavioral components of OSS. Using publicly available behavioral data and mRNA expression data from brain regions involved in reward processing, we identified (a) genes within these behavioral QTL exhibiting genome‐wide significant cis‐eQTL and (b) genetic correlations among OSS phenotypes, ethanol phenotypes and mRNA expression. From these analyses, we nominated positional candidates for behavioral QTL associated with distinct OSS phenotypes including Gnb1 and Mef2c. Genetic covariation of Gnb1 expression, preference for sensory stimuli and multiple ethanol phenotypes suggest that heritable variation in Gnb1 expression in reward circuitry partially underlies the widely reported relationship between sensation seeking and substance use.

Highlights

  • Substance abuse is a heritable disease with devastating effects on individuals and society.[1,2] Variance in the initial choice to experiment with addictive substances and the progression to addiction that is observed in some users can be partially explained by the multifaceted sensation seeking personality trait.[3]

  • Positional candidates were those genes that (a) were located within the 2-LOD confidence interval (CI) of a behavioral QTL, (b) exhibited significant ciseQTL in brain regions involved in reward processing[26] including the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC) or hippocampus (HIPP) (GeneNetwork accession IDs: GN228, GN156, GN135 and GN112) and (c) exhibited mRNA expression that covaried with the phenotype used to map the behavioral QTL

  • We examined the genetic correlations among Gnb[1] expression in reward-related brain regions, operant sensation seeking (OSS) active lever preference and behaviors related to substance use

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Summary

| INTRODUCTION

Substance abuse is a heritable disease with devastating effects on individuals and society.[1,2] Variance in the initial choice to experiment with addictive substances and the progression to addiction that is observed in some users can be partially explained by the multifaceted sensation seeking personality trait.[3] Similar phenomena have been observed in preclinical studies using rodents: mice and rats which exhibit high exploration in a novel environment or preference for a novel environment over a familiar one exhibit potentiation of substance use or addiction-like behavior.[4,5,6,7,8] Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms,[9] but the genes and networks underlying these relationships remain elusive. We used systems genetics techniques including eQTL mapping and genetic covariation of gene candidate mRNA expression, OSS phenotypes and substance use phenotypes to identify candidate genes driving OSS and to assess the possibility of pleiotropic effects of these gene candidates on both OSS and substance use phenotypes

| MATERIALS AND METHODS
| RESULTS
Findings
| DISCUSSION
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