Sex Differences in Cocaine Sensitization Vary by Mouse Strain

Introduction: Preclinical literature, frequently utilizing rats, suggest females display a more rapid advancement of substance abuse and a greater risk of relapse following drug abstinence. In clinical populations, it is less clear as to what extent biological sex is a defining variable in the acquisition and maintenance of substance use. Even without considering environmental experiences, genetic factors are presumed to critically influence the vulnerability to addiction. Genetically diverse mouse models provide a robust tool to examine the interactions between genetic background and sex differences in substance abuse. Methods: We explored mouse strain variability in male vs. female behavioral sensitization to cocaine. Locomotor sensitization was observed following five consecutive days of subcutaneous cocaine across three genetically different mice strains: C57BL/6J, B6129SF2/J, and Diversity Outbred (DO/J). Results: Sex differences in cocaine locomotor sensitization was dependent on mouse strain. Specifically, we observed opposing sex differences in locomotor sensitization, with male C57BL/6J and female B6129SF2/J mice displaying heightened activity compared to their opposite sex counterparts. Conversely, no sex differences were observed in the DO/J mice. Acute cocaine administration resulted in locomotor differences across strains in male, but not female, mice. The magnitude of sensitization (or lack thereof) also varied by genetic background. Conclusions: While sex differences in drug addiction may be observed, these effects can be mitigated, or even reversed, dependent on genetic background. The clinical implications being that absent of understanding the genetic variables underlying vulnerability to addiction, sex provides little information regarding the predisposition of an individual to drug abuse.