develop and employ complex behavioral paradigms that better recapitulate multiple aspects of compulsive drug-seeking behaviors
utilize cell type- and connection-specific techniques to identify molecular mechanisms involved in the transcriptional and behavioral responses to psychostimulants and opioids
develop and test novel pharmacotherapies and nanoparticle delivery systems for the treatment of substance use disorder.
Current Research Directions:
Cell type-specific mechanisms of substance use disorder
It has become evident that brain regions associated with reward and addiction are composed of diverse cell types that have differential molecular compositions, connections, and involvement in drug-seeking behaviors. Using a combination of molecular tools and animal models of substance use disorder, we aim to identify and manipulate molecular factors in a cell type- and connection-specific manner. Ongoing experiments are examining the role of epigenetic factors in D1R- and D2R-expressing neurons in the striatum. These precise mechanistic insights may facilitate the development of novel therapeutics for substance use disorder.
Epigenetic pharmacotherapy for substance use disorder
Drugs of abuse alter the expression of hundreds of genes in reward-related brain regions, which following repeated use leads 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 behavioral, transcriptional, and physiological changes in animal models of substance use disorder. 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 BRD4 attenuates transcriptional and behavioral responses to cocaine. Ongoing experiments are exploring a role for BRD4 and other epigenetic readers in behavioral responses to opioids and other drugs of abuse. In collaborations with members of the medicinal chemistry and pharmaceutics disciplines, we also aim to develop novel epigenetic inhibitors and nanoparticle delivery methods for the treatment of substance abuse.
Allosteric modulators for the treatment of opioid and psychostimulant use disorders
Side effects associated with neuropharmacotherapies are a major impediment of clinical utility and patient adherence. In an attempt to reduce the side effects that are often associated with traditional receptor agonist and antagonist, some pharmaceutical companies have shifted their attention to allosteric modulators. An allosteric modulator binds to a receptor site distinct from the orthosteric site of the endogenous agonist and increases (positive allosteric modulator, PAM) or decreases (negative allosteric modulator, NAM) the effects of the endogenous agonist. Simply explained, agonists and antagonists work like a light switch in that they turn “on” receptor activity (agonists) or turn “off” receptor activity (antagonist or inverse agonist). Positive and negative allosteric modulators, on the other hand, work more like a dial-controlled light in that their binding “brightens” or “dims” the effects of the endogenous ligand. Thus, PAMs and NAMs may potentially have fewer side effects than an agonist, inverse agonist, or antagonist. Ongoing studies in our lab are examining a role for allosteric modulators of cannabinoid receptors and epigenetic factors for the treatment of substance use disorder.
In recent collaborative studies, we identified novel epigenetic mechanisms in animal models for Alzheimer’s disease and cocaine-induced cardiovascular disease. Ongoing collaborative studies are exploring nanoparticle-mediated delivery of micro-RNAs to the brain, epigenetic mechanisms in liver damage, and epigenetic factors involved in motivation for natural rewards.