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Gail Harmata

Mentor: John Wemmie, MD, PhD & Brian J. Dlouhy, MD

Year Entered Into Program: 2015

Terminal Degree(s) Received: PhD 2021

Research Description

Acid-sensing ion channels in drug-related behaviors and neuroplasticity

Alcohol and Addiction. Alcohol abuse and dependence are a significant public health burden in the United States, affecting millions of Americans [1]. Alcohol abuse often follows a "cycle of addiction" [2], which can be difficult to escape. This cycle begins when drug exposure leads to compulsive drug use and drug seeking, often leading to physiological dependence.  Upon abstinence, acute physical withdrawal may or may not occur, followed by the compulsion to resume drug-seeking (craving) and subsequent relapse, thus perpetuating the cycle. Rehabilitation approaches for alcohol abuse and addiction are inadequate, as relapse occurs in more than 60% of cases within a year [2].  Additionally, pharmacological therapies have limited efficacy [3,4]. Thus, finding improved treatments that attenuate craving and relapse, and break the cycle of addiction is a high priority. A better understanding of the molecular mechanisms of alcohol addiction and craving may be crucial for achieving this goal.

Alcohol and Plasticity. Like other drugs of abuse, alcohol consumption precipitates synaptic changes and plasticity, particularly within mesolimbic reward circuit. In the nucleus accumbens (NAc), a structure associated with addiction, increased dopamine release has been reported after acute alcohol intake [5] [6]. Additionally, alcohol exposure is linked to altered glutamatergic signaling in the NAc; for example, alcohol exposure in drug-na"ve mice increased synaptic GluA1 AMPAR subunits in the NAc [7]. Furthermore, alcohol- associated changes in glutamatergic NMDA and AMPA receptors [8-12] and synaptic plasticity [13] have been found at other sites in the reward circuit.

ASIC1A modifies drug-seeking for cocaine and morphine, and modulates synaptic plasticity in response to cocaine. Recent work from our lab indicates that acid-sensing ion channel 1A (ASIC1A) protects against addiction-related behaviors to cocaine and morphine [14]. ASIC1A is a cation channel sensitive to extracellular protons that is enriched in dendritic spines [15]. ASIC1A is abundant in multiple reward circuit sites, including medium spiny neurons in the NAc [16,17] and contributes to synaptic transmission and plasticity as well as learning and memory [15]. The role of ASIC1A in drug-seeking behavior and plasticity was highlighted by the increased preference by ASIC1A global-knockout (KO) for the drug-paired side of the chamber in conditioned place preference (CPP) for both cocaine and morphine; this increased CPP to cocaine was also observed in NAc-specific-ASIC1A knockout mice [14].  Additionally, our lab found altered AMPA/NMDA ratios in KO mice in the NAc, which were normalized by acute cocaine administration [14]. Given its involvement in both cocaine- and morphine-induced behavior and plasticity, I hypothesize that ASIC1A may also be involved in mediating the behavioral and plasticity effects of other drugs of abuse, such as alcohol.

Awards

  • Fellowship appointment on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2017-present
  • Institutional support on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2016-2017

Publications

  1. Rhone, A.E., Kovach, C.K., Harmata, G.I.S., Sullivan, A.W., Tranel, D., Ciliberto, M.A., Howard, M.A., Richerson, G.B., Steinschneider, M., Wemmie, J.A., Dlouhy, B.J.:  A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy. JCI Insight, 5(6):e134852, 2020.  PMCID: PMC7213805