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.
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Candace R
CR
Lewis
Interdepartmental Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA.
Ryan M
RM
Bastle
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Tawny B
TB
Manning
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Sarah M
SM
Himes
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Paulette
P
Fennig
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Phoebe R
PR
Conrad
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Jenna
J
Colwell
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Broc A
BA
Pagni
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Lyndsay A
LA
Hess
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Caitlin G
CG
Matekel
Interdepartmental Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA.|School of Life Sciences, Arizona State University, Tempe, AZ, USA.
Jason M
JM
Newbern
Department of Psychology, Arizona State University, Tempe, AZ, USA.|Interdepartmental Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA.
M Foster
MF
Olive
D000818:Animals; D000831:Animals, Newborn; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D005518:Food Preferences / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012646:Self Administration; D013315:Stress, Psychological / Q000503:physiopathology*
D000697:Central Nervous System Stimulants; D051783:Methyl-CpG-Binding Protein 2; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D008694:Methamphetamine