The overall strategy of the INIA-Stress consortium is to take a cross-species approach to define adaptations of the cortical-limbic-HPA axis produced by excessive alcohol exposure as a platform for studying the reciprocal relationship between stress and excessive drinking. This project proposes to define the status of monoamine neurotransmission and GABAergic neuroactive steroid responsivity in key brain structures involved in stress, motivation, reinforcement and ultimately the regulation of excessive ethanol drinking. It will serve as one node for comparison of monkey and mouse tissues, with microarray, genetic, electrophysiology and HPA axis measures serving as other nodes. The overarching hypothesis of this project is that chronic ethanol exposure produces monoamine system adaptations which reduce activity during abstinence, leading to a state of low monoamine function which would produce dysphoria and potentially a drive to consume alcohol. Further, we predict that these adaptations are exacerbated by subsequent exposure to stress. Of particular interest is the novel finding that KORs become supersensitive during chronic ethanol exposure, especially given the efficacy of naltrexone, a non-selective opioid receptor antagonist, in treating alcoholism.
Four aims are proposed, including 1) DA changes after chronic intermittent ethanol (CIE) exposure in mice and monkeys 2) CIE followed by forced swim stress in mice 3) Monoamine tissue levels in mice and monkeys and 4) GABAergic neuroactive steroids response to CIE and stress.
These aims will provide a comprehensive assessment of monoamine changes induced by chronic ethanol exposure and the differential impact of a stress challenge on a background of chronic ethanol adaptations.

Public Health Relevance

Defining the critical adaptations in monoamine systems induced by chronic EtOH exposure and their relationship to subsequent stress/anxiety will be a major step forward in creating clinical interventions that could prevent the most common deterrent to recovery from alcoholism - stress-induced relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA014091-11
Application #
8423706
Study Section
Special Emphasis Panel (ZAA1-DD (51))
Program Officer
Grandison, Lindsey
Project Start
2003-02-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
11
Fiscal Year
2013
Total Cost
$240,288
Indirect Cost
$83,225
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Siciliano, Cody A; Karkhanis, Anushree N; Holleran, Katherine M et al. (2018) Cross-Species Alterations in Synaptic Dopamine Regulation After Chronic Alcohol Exposure. Handb Exp Pharmacol :
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Melchior, James R; Jones, Sara R (2017) Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo. Mol Cell Neurosci 85:93-104
Karkhanis, Anushree; Holleran, Katherine M; Jones, Sara R (2017) Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction. Int Rev Neurobiol 136:53-88
Siciliano, Cody A; Locke, Jason L; Mathews, Tiffany A et al. (2017) Dopamine synthesis in alcohol drinking-prone and -resistant mouse strains. Alcohol 58:25-32
Fordahl, Steve C; Jones, Sara R (2017) High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling. ACS Chem Neurosci 8:290-299
Salvatore, Michael F; Calipari, Erin S; Jones, Sara R (2016) Regulation of Tyrosine Hydroxylase Expression and Phosphorylation in Dopamine Transporter-Deficient Mice. ACS Chem Neurosci 7:941-51
Siciliano, Cody A; Calipari, Erin S; Yorgason, Jordan T et al. (2016) Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core. Drug Alcohol Depend 158:159-63
Brust, Tarsis F; Morgenweck, Jenny; Kim, Susy A et al. (2016) Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal 9:ra117
Siciliano, Cody A; Calipari, Erin S; Yorgason, Jordan T et al. (2016) Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques. Psychopharmacology (Berl) 233:1435-43

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