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

PMCID: PMC12173464

PMID: 40527326

DOI: 10.1111/gbb.70029

Journal: Genes, brain, and behavior

Publication Date: 2025-6-17

Authors: Khan AH, Bagley JR, LaPierre N, Gonzalez‐Figueroa C, Spencer TC, et al.

Key Points

• 145 unique genetic loci were identified for saline self-administration, indicating complex genetic regulation of behavioral endpoints
• Only one genetic locus overlapped between saline and cocaine self-administration, suggesting distinct genetic mechanisms
• The study underscores the importance of considering genetic variability and environmental influences in understanding behavioral and potentially addictive responses

Summary

This genome-wide association study (GWAS) investigated genetic factors underlying intravenous self-administration (IVSA) behaviors in mice, focusing on saline administration as a control model. Using a sophisticated linear mixed model analysis of 84 mouse strains over 10 days, researchers identified 145 significant genetic loci associated with various behavioral endpoints of saline self-administration, compared to only 17 loci for cocaine administration.

The study revealed complex genetic mechanisms underlying behavioral self-administration, with notable findings including four genes (Myh4, Npc1, Zfp60, and 5031434O11Rik) potentially implicated in locomotor activity and behavioral regulation. Notably, the research demonstrated substantial inter-individual differences in self-administration behaviors and highlighted the distinct genetic basis between saline and cocaine self-administration, suggesting that environmental factors play a significant role in drug-seeking behaviors.