Self-Administration Results in Dynamic Changes in DNA Methylation of the Dorsal Medial Prefrontal Cortex throughout Forced Abstinence, and after Re-exposure to Cues.

摘要

Similar to the pattern observed in people with substance abuse disorders, laboratory animals will exhibit escalation of cocaine intake when the drug is readily available and will exhibit increased drug-seeking behaviors after long periods of abstinence. Additionally, there are long term changes in neuron structure, receptor function, and neurotransmission associated with abstinence from cocaine in humans and animals. DNA methylation is an epigenetic modification to the DNA structure that mediates mRNA expression to confer different cell types, but has recently been implicated in learning and memory mechanisms. The long-term control that DNA methylation has over gene expression in animals makes it a prime candidate for controlling gene expression over the course of abstinence in animals with previous drug experience. Therefore, here, I investigated the contribution of behavioral contingency of cocaine administration on escalation of cocaine intake and re-exposure to cocaine cues as well as DNA methylation and gene expression within the dorsal medial prefrontal cortex (dmPFC) in adult male Sprague-Dawley rats. I exposed rats to daily training for saline (1 h/ day) or cocaine (0.25 mg/kg/inf) in limited- (1 h access per day), prolonged- (6 h access per day), or limited + yoked-access (1 h contingent + 5 h non-contingent access per day) for 15 days. Rats were then put through forced abstinence for 1, 14, or 60 days, and then the dmPFC was dissected out. Saline- and prolonged-access rats were additionally separated into cue- and no cue- conditions after 60 days of abstinence, where cue rats were re-exposed to the operant chamber without cocaine delivery for 2 h. These studies led to 4 main findings. 1) cocaine contingency affects mRNA expression for glutamatergic genes, 2) DNA methylation changes dynamically throughout abstinence, 3) re-exposure to cocaine cues rapidly alters DNA methylation and mRNA expression, and 4) DNA methylation, hydroxymethylation, and transcription factor binding all contribute to altered mRNA expression.