Differing Genetics of Saline and Cocaine Self‐Administration in the Hybrid Mouse Diversity Panel

TL;DR

This study compares the genetic factors influencing saline and cocaine self-administration in mice, finding distinct genetic bases for the two behaviors.

Contribution

The study reveals a distinct genetic basis for saline and cocaine self-administration and identifies specific genes linked to saline self-administration.

Findings

145 loci were identified for saline self-administration compared to 17 for cocaine.

Genes 5031434O11Rik, Zfp60, Myh4, and Npc1 were linked to saline self-administration.

These genes are previously associated with locomotor activity despite no strong behavioral link observed.

Abstract

To identify genes that regulate the response to the potentially addictive drug cocaine, we performed a control experiment using genome‐wide association studies (GWASs) and RNA‐Seq of a panel of inbred and recombinant inbred mice undergoing intravenous self‐administration of saline. A linear mixed model increased statistical power for the analysis of the longitudinal behavioral data, which was acquired over 10 days. A total of 145 loci were identified for saline compared to 17 for the corresponding cocaine GWAS. Only one locus overlapped. Transcriptome‐wide association studies (TWASs) using RNA‐Seq data from the nucleus accumbens and medial frontal cortex identified 5031434O11Rik and Zfp60 as significant for saline self‐administration. Two other genes, Myh4 and Npc1, were nominated based on proximity to loci for multiple endpoints or a cis locus regulating expression. All four genes have previously been implicated in locomotor activity, despite the absence of a strong relationship between saline taking and distance traveled in the open field. Our results indicate a distinct genetic basis for saline and cocaine self‐administration, and suggest some common genes for saline self‐administration and locomotor activity.

Longitudinal genome scans for saline intravenous self‐administration over 10 days in the hybrid mouse diversity panel.

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