A hallmark of cocaine addiction is continued drug craving and relapse propensity despite long-term drug abstinence. Development of effective cocaine addiction treatments therefore requires therapies that decrease the likelihood of relapse to cocaine abuse in the recovering addict. 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).
Cocaine addiction generally starts with recreational use and deteriorates over time into a compulsive and chronically relapsing drug-taking disorder [1
]. Stress, environmental cues, and conditioned stimuli have been demonstrated clinically to play a role in cocaine relapse [2
]. While initiating drug abstinence can be accomplished through in-patient treatment, maintaining cocaine abstinence has proven difficult [5
]. In controlled clinical trials, prolonged cocaine abstinence is often achieved by only a minority of patients [6
]. 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
There is a growing understanding of the acute gene/protein expression changes with cocaine administration (either non-contingently or self-administered) that may be important to the development and expression of cocaine-responsive behavior [11
], but only a small number of studies have examined whether these changes revert to normal levels or remain altered with cocaine abstinence. Observations of molecular changes persisting into or occurring during this abstinence period provide the opportunity to identify genes and their protein counterparts that could be used as therapeutic targets to decrease relapse liability.
The development of animal models of cocaine abuse and abstinence has led to the identification of rodent behaviors similar to those of human cocaine abusers. Most notably, time-dependent increases in cocaine seeking and taking behaviors have been observed in the rat model of cocaine abuse and enforced abstinence employed in this study [12
]. Similar observations have been made using other animal models of prolonged abstinence from cocaine [15
]. Molecular analyses of these models have not only identified changes in gene or protein expression [12
], but have also correlated gene expression with cocaine-responsive behaviors [20
]. Many of the existing reports used targeted approaches to quantify specific gene and protein expression changes during abstinence from cocaine. Large-scale discovery studies with long-term enforced abstinence following cocaine self-administration are limited and transcriptomic studies, in particular, have not been conducted.
The self-administration paradigm used in this study exhibits increased reinforcing efficacy, drug seeking, and drug taking with at least 7 days, and as long as 100 days, of abstinence after a period of cocaine self-administration [12
]. Examination of mesolimbic structures in these animals is warranted by the roles that these structures, including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), play in reward and behavioral responses to stimuli. Both of these brain regions have been implicated in cocaine abuse and withdrawal through imaging [23
], behavioral [20
], and molecular [12
] studies. We have conducted targeted mRNA and epigenetic analysis from this model previously [12
]. The aim of the present study was to extend this initial analysis of mesolimbic dopaminergic terminal regions by providing a genome-wide characterization in both the mPFC and the NAc of rats following 10 days of cocaine self-administration and after increasing periods of enforced abstinence from cocaine (1, 10, and 100 days). Identification of genes persistently altered in expression by cocaine or altered during a period of cocaine abstinence provides insight into the mechanisms involved in the long-term behavioral changes that occur with cocaine abuse and illuminates novel potential new targets for pharmacological intervention.