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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA010761-23
Application #
9404939
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
23
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Laguesse, Sophie; Morisot, Nadege; Shin, Jung Hoon et al. (2017) Prosapip1-Dependent Synaptic Adaptations in the Nucleus Accumbens Drive Alcohol Intake, Seeking, and Reward. Neuron 96:145-159.e8
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
Anderson, Rachel I; Becker, Howard C (2017) Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol. Alcohol Clin Exp Res 41:1402-1418
Witkiewitz, Katie; Wilson, Adam D; Pearson, Matthew R et al. (2017) Temporal Stability of Heavy Drinking Days and Drinking Reductions Among Heavy Drinkers in the COMBINE Study. Alcohol Clin Exp Res 41:1054-1062
Litten, Raye Z; Falk, Daniel E; O'Malley, Stephanie S et al. (2017) Letter to Editor in Response to Johnson's Commentary (2017) on the Witkiewitz and Colleagues (2017) Article. Alcohol Clin Exp Res 41:1381-1382
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
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
Trantham-Davidson, Heather; Centanni, Samuel W; Garr, S Corrin et al. (2017) Binge-Like Alcohol Exposure During Adolescence Disrupts Dopaminergic Neurotransmission in the Adult Prelimbic Cortex. Neuropsychopharmacology 42:1024-1036
Rinker, Jennifer A; Mulholland, Patrick J (2017) Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models. Pharmacogenomics 18:555-570
Stewart, Scott H; Reuben, Adrian; Anton, Raymond F (2017) Relationship of Abnormal Chromatographic Pattern for Carbohydrate-Deficient Transferrin with Severe Liver Disease. Alcohol Alcohol 52:24-28

Showing the most recent 10 out of 179 publications