Symptoms of withdrawal are believed to contribute significantly to sustaining alcoholism. Pharmacological evidence has been obtained that endogenous compounds, including a benzodiazepine (BZD)-inverse agonist, CRF, and glutamate, play a major role in withdrawal-induced anxiety, a symptom observed during withdrawal from chronic ethanol treatment (withdrawal). Further withdrawal produces changes in metabolic activity in specific regions of brain with are proposed to be due to release of endogenous transmitters which contribute to anxiety. In addition, comparison of male and female rats have revealed gender differences when rats were performing conflict tasks during withdrawal. From such data, we suggest the anxiety and increased metabolic activity observed during withdrawal are cause by an orchestrated release of these endogenous compounds that act on central BZD receptors (CBRs), peripheral BZD receptors (PBRs), CRF, and glutamate receptors and that this increased release during withdrawal is influence by gender. To gain support of this view, Specific Aim I will identify changes in metabolic activity using 2- deoxyglucose (2-DG) accumulation and Fos expression to identify brain areas involved in the anxiety response to a challenge with air puff or elevated-plus maze in male and female rats in the presence and absence of withdrawal. Subsequently, we will use antagonists of CRF, CBRs, PBRs and glutamate receptors and antisense deoxynucleotides for the peptides to see how specific metabolic events and the anxiety induced by ethanol withdrawal are affected.
In specific Aim II, we will confirm and extend observations that the endogenous inverse agonist, diazepam binding inhibitor (DBI), which acts on CBRs and PBRs, as well as the CRF peptide is altered after chronic ethanol, during withdrawal, and when male and female rats are challenged with tasks reflecting anxiety during and in the absence of withdrawal. This determination will be made by measuring content of the peptides with radioimmunoassay or quantitative immunohistochemistry. The determination of the peptides will be coupled to measurement of their levels of mRNA within specific regions of brain using in situ hybridization.
Specific Aim III will test the hypothesis that treatment with antagonists of the endogenous compounds, which blocked anxiety and central metabolic activity caused by a single withdrawal, will prevent sensitization of symptoms resulting from multiple withdrawals from chronic ethanol treatment. Once completed, these aims are expected to support the hypothesis that endogenous compounds acting on CBRs, PBRs, glutamate, or CRF receptors in specific regions of brain contribute to metabolic changes and to the anxiety to differing degrees in males and females during withdrawal from chronic ethanol exposure and that repeated withdrawals accentuate these withdrawal-induced changes.
|Jaramillo, Anel A; Randall, Patrick A; Stewart, Spencer et al. (2018) Functional role for cortical-striatal circuitry in modulating alcohol self-administration. Neuropharmacology 130:42-53|
|Bohnsack, John Peyton; Hughes, Benjamin A; O'Buckley, Todd K et al. (2018) Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence. Neuropsychopharmacology 43:1518-1529|
|Coleman Jr, Leon G; Zou, Jian; Qin, Liya et al. (2018) HMGB1/IL-1? complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun 72:61-77|
|Coleman Jr, Leon G; Crews, Fulton T (2018) Innate Immune Signaling and Alcohol Use Disorders. Handb Exp Pharmacol 248:369-396|
|Harper, Kathryn M; Knapp, Darin J; Park, Meredith A et al. (2017) Age-related differences in anxiety-like behavior and amygdalar CCL2 responsiveness to stress following alcohol withdrawal in male Wistar rats. Psychopharmacology (Berl) 234:79-88|
|Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan et al. (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56-73|
|Vetreno, Ryan P; Patel, Yesha; Patel, Urvi et al. (2017) Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise. Brain Behav Immun 60:333-345|
|Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz et al. (2017) Adult rat cortical thickness changes across age and following adolescent intermittent ethanol treatment. Addict Biol 22:712-723|
|Crews, Fulton T; Walter, T Jordan; Coleman Jr, Leon G et al. (2017) Toll-like receptor signaling and stages of addiction. Psychopharmacology (Berl) 234:1483-1498|
|Coleman Jr, Leon G; Zou, Jian; Crews, Fulton T (2017) Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation 14:22|
Showing the most recent 10 out of 126 publications