Alcoholism is characterized by a loss of control over drinking and increased risk of adverse events including traumatic injury, organ damage and loss of normal social interactions. The neural substrates that underlie the transition from controlled social drinking to uncontrolled alcohol abuse are not fully understood, but they likely involve disruption of brain areas responsible for assessing risk versus reward and in inhibiting maladaptive behaviors. During the current funding cycle, we have focused on defining the actions of acute and chronic ethanol on neurons within the orbitofrontal cortex (OFC), a part of the prefrontal cortex that is critical for choice and decision-making. Results from these studies show that acute ethanol inhibits OFC neuron activity via effects on processes that regulate intrinsic excitability and synaptic glutamatergic transmission. Further, chronic ethanol exposure disrupts OFC-dependent behaviors and results in marked enhancement of OFC excitability and glutamate synaptic plasticity, which may contribute to escalation in drinking associated with ethanol dependence. In this continued Center Project, we propose three major aims designed to expand on our findings by addressing the selectivity of these changes with respect to connections between OFC neurons and brain areas involved in goal-directed and habit-based behaviors. These studies will use our well-characterized mouse model of chronic intermittent ethanol (CIE) exposure and will: (1) use retrograde labeling, slice electrophysiology and optogenetic stimulation to interrogate the input and output function of OFC neurons projecting to areas involved in reward, action and habit (e.g., ventral tegmental area and dorsal and ventral striatum). Alterations in dendritic complexity and spine morphology of OFC neurons that project to these areas will be examined using a novel AAV/Rabies transynaptic labeling technique and Cre-dependent lines (e.g., TH- Cre; D1-Cre; D2-Cre) that provide synapse specific control of connectivity; (2) test how CIE treatment alters the intrinsic excitability of OFC neurons and alters the ability of local (glycine) and long-distance (monoamines) modulators to regulate OFC neuron excitability and synaptic function. These studies will also use retrograde labeling and slice electrophysiology to identify projection-specific changes in the modulation of neuronal function of OFC neurons in control and CIE exposed animals; and (3) test how controlling OFC output via excitotoxic lesions and inhibitory and excitatory DREADDs impacts drinking before and following repeated cycles of CIE exposure. Results from these studies will yield important new insights into the role that OFC neurons play in the escalation of drinking observed during the development of ethanol dependence.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Specialized Center (P50)
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Special Emphasis Panel (ZAA1)
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Medical University of South Carolina
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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; Lopez, Marcelo F; Woodward, John J (2018) Effects of monoamines on the intrinsic excitability of lateral orbitofrontal cortex neurons in alcohol-dependent and non-dependent female mice. Neuropharmacology 137:1-12
Dowdle, Logan T; Brown, Truman R; George, Mark S et al. (2018) Single pulse TMS to the DLPFC, compared to a matched sham control, induces a direct, causal increase in caudate, cingulate, and thalamic BOLD signal. Brain Stimul 11:789-796
Zamudio-Bulcock, Paula A; Homanics, Gregg E; Woodward, John J (2018) Loss of Ethanol Inhibition of N-Methyl-D-Aspartate Receptor-Mediated Currents and Plasticity of Cerebellar Synapses in Mice Expressing the GluN1(F639A) Subunit. Alcohol Clin Exp Res 42:698-705
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
Harlan, Benjamin A; Becker, Howard C; Woodward, John J et al. (2018) Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol. Neuropsychopharmacology 43:2064-2074
Hanlon, Colleen A; Dowdle, Logan T; Henderson, J Scott (2018) Modulating Neural Circuits with Transcranial Magnetic Stimulation: Implications for Addiction Treatment Development. Pharmacol Rev 70:661-683
Hanlon, Colleen A; Dowdle, Logan T; Gibson, Nicole B et al. (2018) Cortical substrates of cue-reactivity in multiple substance dependent populations: transdiagnostic relevance of the medial prefrontal cortex. Transl Psychiatry 8:186
Gioia, Dominic A; Xu, Minfu; Wayman, Wesley N et al. (2018) Effects of drugs of abuse on channelrhodopsin-2 function. Neuropharmacology 135:316-327
Anton, Raymond F; Latham, Patricia K; Voronin, Konstantin E et al. (2018) Nicotine-Use/Smoking Is Associated with the Efficacy of Naltrexone in the Treatment of Alcohol Dependence. Alcohol Clin Exp Res 42:751-760

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