Early life stress and chronic variable stress in adulthood interact to influence methamphetamine self-administration in male rats.

Early life stress interacts with adult stress to differentially modulate neural systems and vulnerability to various psychiatric illnesses. However, the effects of early life stress and adult stress on addictive behaviors have not been sufficiently investigated. We examined the effects of early life stress in the form of prolonged maternal separation, followed in early adulthood by either 10 days of chronic variable stress or no stress, on methamphetamine self-administration, extinction, and cue-induced reinstatement. We observed that chronic variable stress in adulthood reduced methamphetamine self-administration in rats with a history of early life stress. These findings add to an emerging body of literature suggesting interactions between early life and early adulthood stressors on adult behavioral phenotypes.

Interactions between Early Life Stress, Nucleus Accumbens MeCP2 Expression, and Methamphetamine Self-Administration in Male Rats.

Early life stress (ELS) is highly related to the development of psychiatric illnesses in adulthood, including substance use disorders. A recent body of literature suggests that long-lasting changes in the epigenome may be a mechanism by which experiences early in life can alter neurobiological and behavioral phenotypes in adulthood. In this study, we replicate our previous findings that ELS, in the form of prolonged maternal separation, increases adult methamphetamine self-administration (SA) in male rats as compared with handled controls. In addition, we show new evidence that both ELS and methamphetamine SA alter the expression of the epigenetic regulator methyl CpG-binding protein 2 (MeCP2) in key brain reward regions, particularly in the nucleus accumbens (NAc) core. In turn, viral-mediated knockdown of MeCP2 expression in the NAc core reduces methamphetamine SA, as well as saccharin intake. Furthermore, NAc core MeCP2 knockdown reduces methamphetamine, but not saccharin, SA on a progressive ratio schedule of reinforcement. These data suggest that NAc core MeCP2 may be recruited by both ELS and methamphetamine SA and promote the development of certain aspects of drug abuse-related behavior. Taken together, functional interactions between ELS, methamphetamine SA, and the expression of MeCP2 in the NAc may represent novel mechanisms that can ultimately be targeted for intervention in individuals with adverse early life experiences who are at risk for developing substance use disorders.