Abstract
BackgroundMany studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability.ResultsWhole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p < 0.05; ± 1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis.ConclusionsTogether, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.
Highlights
Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence
All cocaine selfadministering groups were maintained on a continuous access (24 hours/day) discrete trials (DT) schedule for 10 days
We have previously reported a directed analysis of immediate early genes (IEGs; activity-related cytoskeletal associated protein (Arc), early growth response 1 (Egr1), FBJ osteosarcoma oncogene (Fos), and nuclear receptor subfamily 4a1 (Nr4a1)) and neuropeptides (NPY and cocaine and amphetamine-related transcript (CART)) in this animal model [12]
Summary
Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. A central theme of cocaine abuse research is the role of neurobiological changes (e.g., electrophysiology, neurochemistry, neuroanatomy, epigenetic, transcriptomic, proteomic) in the development and maintenance of the addicted behavioral phenotype (i.e., increased drug-seeking and drug-taking). In controlled clinical trials, prolonged cocaine abstinence is often achieved by only a minority of patients [6,7,8]. This may be due to increases in cocaine craving during drug abstinence [9]. Understanding the persistent neurobiological changes that contribute to continued drug craving during abstinence and relapse potential represents an important step towards identifying treatments that reduce the likelihood of relapse [10]
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