Research Goals:
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develop and employ sophisticated behavioral paradigms that better recapitulate multiple aspects of substance use disorders
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utilize cell type-specific techniques to identify molecular mechanisms involved in the transcriptional and behavioral responses to psychostimulants and opioids
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develop and test novel pharmacotherapies and delivery systems for the treatment of substance use disorders.
Current Research Directions:
Epigenetic pharmacotherapy for substance use disorder
Repeated drug use alters the expression of hundreds of genes in reward-related brain regions, leading to maladaptive neuroadaptations and compulsive drug-seeking behaviors. Treatment strategies that have the ability to reverse or normalize the extensive transcriptional dysregulation caused by chronic drug use may have therapeutic utility. Recently, epigenetic pharmacotherapies have been shown to ameliorate psychostimulant- and opioid-induced transcriptional changes in animal models of substance use disorder (SUD). In particular, our research has revealed that the epigenetic reader protein, BRD4, is elevated in the nucleus accumbens and recruited to promoter regions of addiction-related genes. Additionally, we have found that pharmacological inhibition of BET proteins (BRD4, BRD3, and BRD2) attenuates transcriptional and behavioral responses to cocaine. In newer studies, we are investigating selective and safer approaches to target BET proteins. For example, we revealed that RVX-208, a clinically tested, BD2-selective BET inhibitor, attenuated cocaine-induced behavioral and transcriptional responses without causing side effects associated with non-selective BET inhibitors. In ongoing studies, our goal is to uncover the role of individual BET proteins and non-bromodomain BRD4 interactions involved in drug-seeking behaviors. Ultimately, these experiments may yield exciting new therapeutic avenues for SUD.
For additional information, please see our recent publications: PMID: 35314160, PMID: 32946883, PMID: 34757001, PMID: 31306644, PMID: 30504275, PMID: 26558777.
RNA-targeted therapeutics for substance use disorder
For several years, noncoding RNAs (ncRNAs) have been implicated in drug use and relapse, yet ncRNA-targeted therapeutics have not advanced to clinical studies in SUD patients. The lack of translational progress is largely due to the poor brain penetration properties of established RNA interference approaches (e.g., ASOs and siRNAs). A goal of our ongoing research is to discover, test, and improve RNA-targeted therapeutics for SUD. For this project, we are developing and testing two promising strategies: 1) brain-penetrant, polymeric nanoformulations for CNS delivery of RNA-targeted treatments (collaboration with Bahal lab at UConn) and 2) small molecules that selectively target SUD-relevant ncRNAs. These novel approaches will have broad implications for the future of SUD medicine and may also be expanded to other neuropsychiatric disorders.
For additional information, please see our recent publications: PMID: 36601439, PMID: 35351961.
Therapeutics for Opioid Use Disorder
Opioid use disorder (OUD) is a major health crisis in the United States. We have initiated multiple projects focused on developing new models and therapeutics for OUD. In a recent publication, we found that a metabolite of ketamine, (2R,6R)-Hydroxynorketamine (HNK), reduced somatic symptoms of withdrawal- and relapse-like behaviors in male and female mice. In ongoing experiments, we are investigating the behavioral, neuronal and molecular mechanisms involved in the therapeutic responses to HNK and low-dose ketamine in OUD models. In other recent experiments, we have compared how the route of delivery (oral vs. subcutaneous) of oxycodone affects subsequent withdrawal- and anxiety-like behaviors. Our results indicate that both routes of oxycodone administration are sufficient to elevate global withdrawal scores, but, when compared with oral consumption, subcutaneous oxycodone injections yielded more pronounced effects on some withdrawal-like behaviors. In ongoing collaborative studies we are developing new formulations to treat OUD and devices to monitor and reverse opioid-induced overdoses.
For additional information, please see our recent publications: PMID: 37864957; PMID: 38847447.
We thank the following organizations for generously funding our research.
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