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  • Addiction
  • History of cocaine self-administration alters transcriptome-wide responses to cocaine re-exposure throughout the brain’s reward circuitry

    • D. M. WALKER ;
    • E. S. CALIPARI ;
    • H. M. CATES ;
    • E. LOH ;
    • A. GODINO ;
    • P. MEWS ;
    • E. J. NESTLER ;

    Information from abstracts and lay language summaries is embargoed until the conclusion of the scientific presentation.

    334—Brain Circuits Affected by Cocaine

    Monday, November 13, 2017, 8:00 am - 12:00 noon

    334.29 History of cocaine self-administration alters transcriptome-wide responses to cocaine re-exposure throughout the brain’s reward circuitry

    Location: Halls A-C

    1Neurosci., Icahn Sch. of Med. At Mount Sinai, New York, NY; 2Neurosci., 3Icahn Sch. of Med. at Mount Sinai, New York, NY; 4Pharmacol., Weill Cornell Med. Col., New York, NY; 5Icahn Sch. Med. At Mount Sinai, New York, NY

    Abstract Body: Cocaine addiction is a chronic, relapsing disorder involving maladaptive plasticity in brain reward circuits associated with changes in gene expression. The behavioral responses to self-administration withdrawal and re-exposure have been well-defined in rodent models. However, the gene expression changes underlying the observed circuit wide and behavioral dysregulation remains elusive. We hypothesized that chronic cocaine “re-programs” the transcriptome, resulting in sensitization and desensitization of molecular targets upon re-exposure to cocaine. To test this hypothesis, we assigned male mice to one of six groups: saline or cocaine self-administration (SA) + 24hr withdrawal (WD) (S24/C24); saline/cocaine SA + 30d WD + acute saline/cocaine + 1hr (SS/SC/CS/CC). Then we conducted RNA-sequencing on 6 interconnected reward associated brain regions (PFC, NAc, DS, BLA, vHIP, VTA) to determine how a history of cocaine SA influences transcriptome-wide responses at baseline and after cocaine re-exposure. We focused on patterns of gene expression that were altered in response to specific stimuli when compared to the same baseline (S24). Genes that were uniquely altered by acute cocaine after cocaine SA+WD (CC) displayed region-specific regulation, with the greatest numbers seen in NAc, DS, and BLA. Further analysis revealed that the transcription factor, Hnf4a, is a predicted upstream regulator in all three regions and associated with genes that control RNA posttranscriptional processes and neurological diseases. In contrast, genes uniquely altered by cocaine SA + acute saline (CS), possibly a reflection of genes exhibiting “craving,” were most affected in vHIP and PFC and associated with neuronal branching. Regulation of subsets of these primed, desensitized, and incubating genes correlates with the SA behavior displayed by individual mice. These data provide further insight into the relationship between these correlated brain regions. Further, this is the most comprehensive picture to date of transcriptome-wide regulation by cocaine SA and WD throughout the brain’s reward circuitry, and it will guide future studies of the molecular basis of cocaine addiction.

    Lay Language Summary: Our research indicates that a history of cocaine self-administration in mice alters gene expression throughout the brain and changes how the brain responds to cocaine re-exposure after prolonged withdrawal.
    Cocaine addiction is a complex, chronic, relapsing disorder that affects over a million people in the USA. Illicit drug use and abuse exacts an enormous toll on society, including costs associated with social programs, law enforcement as well as rising health care costs, all totaling >$400 billion/year. Despite the crippling economic and social costs of addiction, treatment options remain few and the majority of people who enter a treatment program will relapse within a year. An understanding of the brain changes associated with addiction and how best to manage them is critical for the development of treatment options for those suffering from cocaine addiction.
    It is well known that there is a strong genetic component to addiction. However, mounting evidence suggests that external factors (e.g., stress, age of first exposure, trauma, etc.) work in concert to influence addiction. Indeed, exposure to drugs of abuse is a key risk factor for the progression of addiction. It is thought that long-term exposure to cocaine and other illicit drugs changes the brain and its sensitivity to drugs of abuse or cues associated with those drugs. A cardinal feature of addiction, relapse, is especially difficult to manage, as it can occur after prolonged periods of abstinence and can be triggered by cues associated with previous drug use, suggesting that drugs of abuse permanently alter neuronal function and physiology to be responsive to environmental stimuli, including drug re-exposure.
    In this study, mice were trained to press a lever that was paired with the delivery of an i.v. cocaine injection, or as a control, saline injection. After a 10-day period of self-administration, animals were split into testing groups: short-term withdrawal (24 hr) or long-term withdrawal (30 days) with re-exposure to the drug-associated context in the presence or absence of cocaine. Using a technique called RNA-sequencing, we analyzed all the genes expressed in six areas of the brain important for addiction to determine how gene expression is changed by exposure to cocaine and after prolonged withdrawal, as well as if those genes are re-activated by exposure to drug related cues or cocaine. We identified numerous genes that are expressed in response to re-exposure to cocaine after long-term withdrawal, which are not altered in response to an initial cocaine dose. Importantly, a subset of these genes are regulated commonly across the brain regions studied and share common upstream regulators.
    The findings from this study provide promising evidence that key regulators of gene expression throughout the brain are responsive to cocaine re-exposure after a period of abstinence. These key regulators and the genes that they influence might serve as targets for pharmaceutical treatments of cocaine addiction and relapse.