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Dissertation/Thesis Abstract

Roles for Histone H3 Dopaminylation in Drug-Induced Transcriptional and Behavioral Plasticity
by Lepack, Ashley E., Ph.D., Icahn School of Medicine at Mount Sinai, 2021, 206; 28148532
Abstract (Summary)

Cocaine use disorder is characterized by the loss of control over drug intake and enduring vulnerability to relapse during periods of attempted abstinence and/or treatment. Despite the prevalence and severity of SUD as well as the negative health and economic burden on our society, our understanding of the precise molecular underpinnings and neuronal pathology of the long-lasting effects of addiction remain relatively unclear. In addition, currently there are no FDA-approved pharmacological therapeutics for the treatment of cocaine dependence. Chronic use of drugs, such as cocaine, can perturb the reward pathways in the brain, resulting in long-lasting changes in neuronal plasticity and function. Indeed, vulnerability to relapse is hypothesized to result from “rewiring” of the brain reward circuitries, particularly in the ventral tegmental area (VTA) dopamine neurons, caused by long-lived changes in gene expression. Precisely how cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. Here, we find that a previously uncharacterized histone modification, H3 glutamine 5 dopaminylation (H3Q5dop), plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine after a period of extended access to the drug showed an accumulation of intracellular dopamine concentrations and increased levels of H3Q5dop in the VTA. A similar effect was observed in rats undergoing withdrawal from chronic heroin. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-induced gene expression changes in the VTA, attenuated cue-induced dopamine release in the nucleus accumbens (NAc) and reduced relapse-like cocaine-seeking behavior. VTA dopaminergic neurons project to multiple brain regions, including the NAc and medial prefrontal cortex (mPFC), where dopamine neurotransmission dictates aspects of drug-related behavior. We further investigated the role of H3Q5dop in these projection regions following prolonged abstinence from volitional cocaine. Similar to what we observed in the VTA, levels of H3Q5dop were increased in the NAc, however these effects were not seen in the mPFC. Reducing H3Q5dop in the NAc core, but not the mPFC, also attenuated relapse-like cocaine-seeking behaviors. Lastly, we investigated potential protein reader domains for H3Q5dop. Here, we find that H3Q5dop has more binding interactions with effector proteins compared to other monoaminylated states. Together these findings establish a neurotransmission-independent role for nuclear dopamine in regulating addiction-relevant transcriptional plasticity in the brain.

Indexing (document details)
Advisor: Maze, Ian, Kenny, Paul
Commitee: Akbarian, Schahram, Nestler, Eric, Schaefer, Anne, Casaccia, Patrizia, Pierce, Christopher
School: Icahn School of Medicine at Mount Sinai
Department: Neurosciences
School Location: United States -- New York
Source: DAI-B 82/9(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Neurosciences, Public health
Keywords: Addiction, Dopamine, Epigenetics, Histone, Ventral Tegmental Area, Behavioral plasticity, Chronic drug use, Substance Use Disorder
Publication Number: 28148532
ISBN: 9798582572619
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