George R. Breese, Ph.D.

Summary Statement:

The focus of Dr. Breese's laboratory is to understand the mechanism of the acute and chronic actions of ethanol on brain function and how these actions relate to prolonged alcohol exposure producing persistent adaptive changes in brain. The nature of cumulative adaptive change by repeated withdrawals is reminiscent of the “kindling” of seizures that follows repeated withdrawals from ethanol. The primary initial strategy to evaluate the neural basis of the persistent adaptation is to discover those brain sites that support specific behavioral changes associated with withdrawal from repeated chronic alcohol exposures. Then, the basis of the adaptive changes within the specific brain sites identified can be pursued. Neuropharmacological, neuroanatomical, molecular, biochemical and electrophysiological approaches are used to identify the neurobiological basis of the persisting cumulative adaptation within relevant brain sites induced by the repeated ethanol withdrawals. Collectively, these approaches may allow us to define therapies by which the relapse rate in alcoholism can be minimized.

Another major focus of Dr. Breese's research is defining the role of stress in alcoholism—a view that led to proposing the kindling-stress hypothesis to account for the characteristics of alcoholism. In support of this hypothesis, research found that stress after repeated alcohol exposures induces an anxiety response not seen in controls, a reflection of adaptive change induced by previous chronic ethanol. Importantly, stress during abstinence from repeated episodes of ethanol drinking also enhances an ethanol deprivation effect (increased voluntary ethanol drinking)—a model of loss of control. Subsequently, studies demonstrated that stress applied prior to a limited exposure to chronic alcohol results in a facilitation of anxiety during withdrawal. The examination of the potential neural mechanism involved in this stress-induced sensitization of withdrawal-induced anxiety revealed that CRF and endogenous cytokines appear to mediate the action of stress. Work is underway to define the specific sites in brain that support the action of CRF to facilitate the ethanol deprivation effect as well as the sites that support sensitization of ethanol withdrawal anxiety. Additionally, future work is earmarked to define the sites in brain that support the action of cytokines to facilitate withdrawal anxiety. Finally, based upon the hypothesis that CRF and cytokine interact to mediate stress, studies will be performed to test this hypothesis. Finally, a longer term focus will be to determine if an epigenetic mechanism is responsible for the persistent adaptive consequences in brain induced by chronic ethanol exposure.

Representative Publications:

1. Breese, G.R., Overstreet, D.H., Knapp, D.J., Stress sensitization of the ethanol withdrawal-induced reduction in social interaction: inhibition by CRF-1 and benzodiazepine receptor antagonists and a 5-HT1A agonist. Neuropsychopharmacology 29:470-482, 2004.
2. Breese, G.R., Overstreet, D.H., Knapp, D.J. Conceptual framework for the etiology of alcoholism—a “kindling”/stress hypothesis. Psychopharmacology 178:367-380, 2005.
3. Breese, G.R., Knapp, D.J., Criswell, H.E., Moy, S., Papadeas, S.T., Blake, B.L. The neonate-6-hydroxydopamine-lesioned rat: A model for clinical neuroscience and neurobiological principles. Brain Res. Reviews, 48:57-73, 2005.
4. Breese, G.R., Chu, K Dayas, C.V., Funk, D., Knapp,D.J., Koob,G.F., Le D.A., O’Dell, L.E., Overstreet, D.H., Roberts, A.J., Sinha, R., Valdez, G.R., Weiss, F. Stress enhancement of craving during sobriety: Risk of relapse. Alcoholism: Clin. Exp. Res 29:185-195, 2005.
5. Breese, G.R., Overstreet, D.H., Knapp, D.J. Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior during extended abstinence: Inhibition by CRF-1 and benzodiazepine receptor antagonists and by a 5-HT1A-receptor agonist. Neuropsychopharmacology, 30:1662-1669. 2005.
6. Breese, G.R., Overstreet, D.H., Knapp, D.J. Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior during extended abstinence: Inhibition by CRF-1 and benzodiazepine receptor antagonists and by a 5-HT1A-receptor agonist. Neuropsychopharmacology, 30:1662-1669. 2005.
7. Kelm MK, Criswell HE, Breese GR. Calcium release from presynaptic internal Stores is required for ethanol to increase spontaneous gamma-aminobutyric acid release onto cerebellum Purkinje neurons. J Pharmacol Exp Ther. 323: 356-364, 2007.
8. Kelm MK, Criswell HE, Breese GR. The role of protein kinase A in the ethanol-induced Increase in spontaneous GABA release onto cerebellum Purkinje neurons. J. Neurophysiology. 100:3417-3428, 2008.
9. Papadeas, S.T., Halloran, C., McCown, T.J., Breese, G.R., Blake, B.L. Changes in apical dendritic structure correlate with sustained ERK1/2 phosphorylation in medial prefrontal cortex of a rat model of dopamine D1 receptor agonist sensitization. J Comp Neurol. 5ll: 271-285, 2008.
10. Wills, T.A., Knapp, D.J., Overstreet D.H., Breese, G.R. Sensitization, duration, and pharmacological blockade of anxiety-like behavior following repeated ethanol withdrawal in adolescent and adult rats. 33:455-463, 2009.
11. Huang, M., Overstreet, D.H., Knapp, D.J., Angel, R., Wills, T.A., Navarro M., Rivier, J., Vale,W.W., Breese, G.R. Corticotropin releasing factor (CRF) sensitization of ethanol withdrawal-induced anxiety-like behavior is brain site specific and mediated by CRF-1 receptors: relation to stress-induced sensitization. J Pharmacol Exp Ther. 332:298-307, 2010.
12. Kelm MK, Weinberg R, Criswell HE, Breese GR. The PLC/IP3R/PKC Pathway is required for ethanol-enhanced GABA Release. Neuropharmacology. 58:1179-1186, 2010.
13. Breese, G.R., Sinha, R. and Heilig M. Chronic ethanol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharmacology and Therapeutics, 2010.