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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    449—Cocaine: Neural Mechanisms of Addiction III

    Monday, November 11, 2013, 1:00 pm - 5:00 pm

    449.10: Transcriptomic study of environmental enrichment and cocaine-taking behavior in rat nucleus accumbens

    Location: Halls B-H

    *Y. ZHANG1, F. KONG2, H. M. SPRATT2, M. SINHA2, C. R. ANDERSEN2, D. LI1, X. FAN1, B. A. LUXON2, T. A. GREEN1;
    1Pharmacol. and Toxicology, 2Biochem. & Mol. Biol., Univ. of Texas Med. Br., Galveston, TX

    Abstract Body: Environmental enrichment is a paradigm where animals are exposed to exercise, novelty and social contact. It has been reported that environmental enrichment produces a protective phenotype against drug addiction during rat drug self-administration. However, the molecular mechanism behind this phenotype remains unclear. In this project, a next generation RNA sequencing strategy, gene ontology (GO), Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis were used to investigate differentially regulated mRNA expression in rat nucleus accumbens (NAcc) by cocaine and environmental enrichment. Our results show that environmental enrichment regulates more genes than cocaine, about 95% genes of which are down-regulated by enrichment. In addition, GO, IPA and gene set enrichment analyses were used to confirm the reliability of the RNA sequencing result and highlights many biological functions and canonical pathways affected by cocaine or enrichment. These include the protein kinase A pathway, the retinoic acid signaling pathway and the protein ubiquitination pathway, each of which give us directions for further studies. Based on these results, ongoing experiments are investigating target molecules by making shRNA viral vectors to knock down expression in vivo to further explore the molecular mechanisms of the protective enrichment phenotype. The results of this study thus suggest that mRNA expression, which is involved in many potentially important molecular pathways, is differentially regulated by environmental enrichment and cocaine.

    Lay Language Summary: In the current study, 3.5 billion segments of mRNA were sequenced to investigate the mechanisms underlying addiction. Our prior research has shown that rats reared in an enriched environment with toys and social contacts are less susceptible to cocaine self-administration than rats reared in isolation. The current experiment is a discovery-based approach to identify novel mechanisms for addiction. Among the many results, we discovered regulation in genes involved in the signaling pathway of Vitamin A. The specifics are detailed below:
    Environment and life experience in early stage of life significantly influence subsequent behavior. Rats reared in an environment where they live in big cage, explore and play with various kinds of toys and communicate with peers have different “personality” and responses to addictive drugs. During adolescence, exposure to novelty, exercise and social contact can decrease the vulnerability to addictive drugs, such as cocaine and amphetamine. Specifically, enriched rats acquire self-administration more slowly, extinguish more quickly and display less drug-seeking behavior. Nevertheless, it is still a mystery what exactly happened in the brains of rats that experienced enriched condition compared with those in isolated condition.
    To discover the underlying mechanisms of the protective effect of environmental enrichment, we investigated messenger RNA expression in the reward center of the brain, the nucleus accumbens, to see how they are changed by cocaine and what the fundamental differences between enriched and isolated rats are. With cutting-edge next generation sequencing technology, over 100 million segments of mRNA (50 base pairs in length) were sequenced twice in every rat. Then these segments were aligned to the rat genome to identify the corresponding gene. The abundance of the segments indicates the expression level of the transcript.
    Based on the sequencing result, about 14,000 genes were identified. Of these, about 1300 genes are changed between enriched and isolated rats. These genes are involved in many essential fundamental biological functions, such as neuronal excitability and regulation, etc.
    One of the interesting changes is that genes related to the metabolism of Vitamin A are significantly altered by environmental enrichment. Vitamin A is an essential nutrient for mammals, playing critical roles in embryonic development, vision health, immune response, etc. Usually, animals get Vitamin A from diet such as carrot. Based on our results we hypothesize that experiencing the enriched environment results in increased Vitamin A signaling in brain through the Vitamin A product, retinoic acid, suggesting the potential relationship between Vitamin A and drug seeking behavior. To confirm this hypothesis, in future study, we will reduce Vitamin A signaling by repressing related gene expression, and see whether it changes rats behavior during cocaine self-administration.
    Drug addiction has been a serious problem bringing medical and social burdens to this country. Drug dependence is a complicated issue due to the wide age range of abusers, individual differences in response to drugs, and treatment at different phase of addiction. Understanding the mechanisms of the protective effect of environmental enrichment addresses a fundamental gap of addiction research. In this project, we identified a series of novel mechanisms of the protective effect of environmental enrichment, which is associated with multiple functions and biological processes in brain, and provides several potential directions for future study.