Recent studies have implicated histone-modifying enzymes as key regulators of chromatin state that contribute to cocaine-mediated changes in gene expression, neuroadaptations and seeking behaviors. However, only a limited number of histone-modifying proteins have been studied in the context of addiction, and particularly lacking are studies of epigenetic 'reader'proteins called bromodomains. Of the histone- modifying enzymes implicated in addiction, several are known to form complexes with multiple proteins in order to epigenetically alter transcription, but the underlying mechanisms involved in these interactions remain poorly understood. Growing evidence suggests that cell-type specific long noncoding RNAs (lncRNAs) modulate the function of these epigenetic proteins and/or complexes by acting as scaffolds that help recruit these processes to specific genomic loci. Therefore, investigating the role of lncRNAs in reward-related brain areas offers a fundamentally new approach to identify novel epigenetic mechanisms involved in addiction. In this application we aim to identify novel histone-modifying proteins involved in cocaine intake and determine the interactions between cocaine-related epigenetic targets and lncRNAs that are altered following self-administration of cocaine. We hypothesize that development of cocaine self-administration habit, in part, results from a coordinated change in expression of select histone-modifying proteins and specific lncRNAs that work in concert to epigenetically alter gene transcription. To test this hypothesis, the following aims are proposed:
Specific Aim 1 : Test the hypothesis that intra-accumbal knockdown of bromodomain genes affects cocaine self-administration. Preliminary data collected from our laboratory indicates that specific bromodomain proteins play an important role in cocaine reward and are increased in the nucleus accumbens following cocaine self-administration.
Aim 1 will test whether these bromodomains regulate cocaine self- administration under restricted and extended access conditions.
Specific Aim 2 : Test the hypothesis that unique long noncoding RNA - protein interactions occur in the nucleus accumbens following cocaine self- administration. Long noncoding RNAs are key regulators of chromatin state, but it is unclear how these transcripts interact with epigenetic proteins to contribute to drug dependence. These studies will identify novel interactions between lncRNAs and histone-modifying proteins in the nucleus accumbens and determine if these associations are altered following yoked, restricted and extended access to cocaine self-administration. By revealing novel epigenetic targets and unchartered epigenetic mechanisms implicated in cocaine intake, a better understanding of these systems may ultimately lead to new therapeutic avenues for cocaine addiction.
Drug addiction is associated with long-lasting changes in the brain that contribute to addiction-related behaviors. This research study will investigate epigenetic mechanisms that underlie cocaine-induced changes in the brain's reward pathways. Results from these experiments may lead to new advances in the treatment of drug addiction.
| Lohse, Ines; Al-Ali, Hassan; Volmar, Claude-Henry et al. (2018) Ex vivo drug sensitivity testing as a means for drug repurposing in esophageal adenocarcinoma. PLoS One 13:e0203173 |
| Barbier, E; Johnstone, A L; Khomtchouk, B B et al. (2017) Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. Mol Psychiatry 22:1746-1758 |
| Jones, Candace; Barrera, Ingrid; Brothers, Shaun et al. (2017) Oxytocin and social functioning. Dialogues Clin Neurosci 19:193-201 |
| Wahlestedt, Claes (2017) Emerging Epigenetic Therapies in Neuroscience: Focus on Bromodomain-Containing Drug Targets. Neuropsychopharmacology 42:374 |
| Heilig, M; Barbier, E; Johnstone, A L et al. (2017) Reprogramming of mPFC transcriptome and function in alcohol dependence. Genes Brain Behav 16:86-100 |
| Khorkova, Olga; Wahlestedt, Claes (2017) Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 35:249-263 |
| Sartor, Gregory C; Powell, Samuel K; Velmeshev, Dmitry et al. (2017) Cocaine alters Homer1 natural antisense transcript in the nucleus accumbens. Mol Cell Neurosci 85:183-189 |
| Sartor, Gregory C; Powell, Samuel K; Brothers, Shaun P et al. (2015) Epigenetic Readers of Lysine Acetylation Regulate Cocaine-Induced Plasticity. J Neurosci 35:15062-72 |
| Khorkova, O; Hsiao, J; Wahlestedt, C (2015) Basic biology and therapeutic implications of lncRNA. Adv Drug Deliv Rev 87:15-24 |
| Zeier, Zane; Esanov, Rustam; Belle, Kinsley C et al. (2015) Bromodomain inhibitors regulate the C9ORF72 locus in ALS. Exp Neurol 271:241-50 |
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