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

Abstract

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 CpGbinding 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.

Negative consequences of early-life adversity on substance use as mediated by corticotropin-releasing factor modulation of serotonin activity

“…Maternal separation from PND 1–14 increases the rewarding effects of acute amphetamine exposure during adulthood, as measured by a decrease in intracranial self-stimulation current threshold ( Der-Avakian and Markou, 2010 ). Similar to findings following social isolation/social disruption, maternal separation results in greater methamphetamine self-administered and earlier acquisition while not altering extinction or cue-induced reinstatement ( Moffett et al, 2006 ; Lewis et al, 2013 , 2106 ). Exposure to maternal separation also has effects on alcohol and opiate intake and preferences during adulthood.…”

Selective Activation of Striatal NGF-TrkA/p75NTR/MAPK Intracellular Signaling in Rats That Show Suppression of Methamphetamine Intake 30 Days following Drug Abstinence

“…Although MeCP2 is known as gene silencer, recent evidence suggests it also binds to methylated non-CG sites ( Chen et al, 2015 ) and can function as a transcriptional activator by association with pCREB ( Chahrour et al, 2008 ). However, it is important to note a recent study that reported decreased METH SA after virally mediated knockdown of MeCP2 in the nucleus accumbens ( Lewis et al, 2016 ). These findings implicate potentially distinct roles of this protein in various brain regions following METH SA.…”

Impact of Early Life Stress on Reward Circuit Function and Regulation

“…A consistent finding is that ELS increases self-administration of various psychostimulants. For example, maternal separation increases active lever responses as well as the number of infusions of methamphetamine in male Long-Evans rats ( 111 , 112 ). Studies focused on cocaine largely find that ELS increases cocaine-seeking behaviors.…”