Alcohol use disorder is a major public health issue associated with altered activation of brain stress systems, cognitive deficits, and escalated alcohol drinking. The prefrontal cortex (PFC) is a key structure involved in executive cognitive function and imposing inhibitory control over reward-motivated behaviors. Altered stress responsivity is implicated in the development and maintenance of excessive alcohol drinking, and both chronic ethanol and stress negatively impact PFC function. Cognitive deficits in individuals with alcohol use disorder are thought to hinder successful treatment and contribute to increased risk for relapse. Preclinical studies show that chronic ethanol exposure produces an exaggerated stress response in the PFC that mediates cognitive impairments and escalated ethanol drinking. In the current funding period, we identified chronic ethanol- sensitive proteins and K+ channel genes in the PFC and nucleus accumbens (NAc) of mice and monkeys. We also identified predictive relationships between candidate K+ channel genes and drinking in ethanol-dependent BXD recombinant inbred strains of mice, and pharmacological validation showed that positive modulation of a KCa2 channels significantly reduces escalated drinking in stressed, dependent mice. Moreover, we demonstrated that chronic stress elevates drinking only in ethanol dependent mice and enhances the magnitude of the early component of long-term potentiation (LTP) in the mouse PFC. In addition to the enhanced LTP we observed in the stressed mice, our preliminary data shows that glutamatergic signaling in the PFC is enhanced in macaques following chronic ethanol self-administration. While it is known that chronic ethanol and stress exposure elicit maladaptive plasticity in the PFC, the underlying neural mechanisms and the adaptations in the PFC circuitry induced by ethanol-stress interactions remain poorly understood. To address this gap in our knowledge, we propose three specific aims that will test the overarching hypothesis that disruption of PFC circuitry and plasticity underlies the excessive drinking and cognitive impairments produced by chronic stress and ethanol dependence. Studies in Aim 1 will test the hypothesis that chronic ethanol self- administration and interactions between ethanol dependence and stress produce functional adaptations in the PFC of monkeys and mice.
Aim 2 will test the efficacy of drugable proteogenetic targets to reduce escalated drinking in stressed dependent male and female mice. Finally, studies in Aim 3 will test the hypothesis that ethanol dependence and chronic stress produce aberrant signaling in PFC circuitry that contributes to escalated drinking and cognitive impairments. In addition to identifying drugable targets, the findings from these studies will provide data on the temporal aspects of circuit-specific, functional, and morphological adaptations produced by chronic stress and ethanol in the mouse and monkey PFC.
We expect that data collected from these proposed studies will advance our understanding of changes in the adult brain caused by alcohol and stress exposure. These studies will also provide evidence for the ability of novel drugs to reduce heavy drinking.
|Cannady, Reginald; Rinker, Jennifer A; Nimitvilai, Sudarat et al. (2018) Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior. Handb Exp Pharmacol 248:311|
|McGuier, Natalie S; Rinker, Jennifer A; Cannady, Reginald et al. (2018) Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents. Neuropharmacology 138:10-19|
|Nimitvilai, Sudarat; Uys, Joachim D; Woodward, John J et al. (2017) Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques. J Neurosci 37:3646-3660|
|Rinker, Jennifer A; Fulmer, Diana B; Trantham-Davidson, Heather et al. (2017) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol 58:33-45|
|Qi, Qianqian; Wang, Qian; Chen, Weizao et al. (2017) HIV-1 gp41-targeting fusion inhibitory peptides enhance the gp120-targeting protein-mediated inactivation of HIV-1 virions. Emerg Microbes Infect 6:e59|
|Rinker, Jennifer A; Mulholland, Patrick J (2017) Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models. Pharmacogenomics 18:555-570|
|Cannady, Reginald; McGonigal, Justin T; Newsom, Ryan J et al. (2017) Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior. J Neurosci 37:4359-4369|
|Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J et al. (2017) Ethanol Dependence Abolishes Monoamine and GIRK (Kir3) Channel Inhibition of Orbitofrontal Cortex Excitability. Neuropsychopharmacology 42:1800-1812|
|Su, Shan; Zhu, Yun; Ye, Sheng et al. (2017) Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors. J Virol 91:|
|Xu, Wei; Li, Haoyang; Wang, Qian et al. (2017) Advancements in Developing Strategies for Sterilizing and Functional HIV Cures. Biomed Res Int 2017:6096134|
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