Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model.
This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with "temperament," including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor.
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109; sflagel@umich.edu akil@umich.edu.
Shelly B
SB
Flagel
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Sraboni
S
Chaudhury
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109;
Maria
M
Waselus
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109;
Rebeca
R
Kelly
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109;
Salima
S
Sewani
Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35233.
Sarah M
SM
Clinton
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109;
Robert C
RC
Thompson
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109;
Stanley J
SJ
Watson
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109; sflagel@umich.edu akil@umich.edu.
Huda
H
Akil
D000818:Animals; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012651:Self Medication
D017448:Receptors, Dopamine D2; D016222:Fibroblast Growth Factor 2
addiction; dopamine; fibroblast growth factor; nucleus accumbens; reinstatement