The current focus of Dr. Breese's laboratory is to understand the mechanism by which chronic ethanol adaption enhances the increase in stress-induced anxiety and depressive-like behavior during ethanol abstinence. Thus, a major goal of Dr. Breese's research is to define the role of stress in alcoholism—a view that led to proposing the kindling-stress hypothesis to account for the negative characteristics of stress involvement in alcoholism. To accomplish this goal, one essential component is to define the basis of neural change after chronic alcohol exposure that facilitates stress-induced negative affect. A recent effort found that stress increases cytokine mRNAs in brain—a change which is enhanced when stress is applied after chronic ethanol exposure.  Involvement is now attempting to explore the means by which stress in a sterile environment increases cytokines in brain.    Based upon the hypothesis that CRF and cytokines both mediate stress by interacting, studies will be performed to test this hypothesis that this interaction is critical for stress increasing cytokine mRNAs in brain.  Since work defined the specific sites in brain that support the action of CRF to facilitate the stress sensitization of anxiety, efforts will now defining whether stress increases cytokines in those brain sites related to CRF induction of negative affect.  Another major focus will involve electrophysiology to assess if cytokines act as transmitters on neural function in the central amygdala—a site known to be critical for negative affect.   A longer term focus will be on defining the neural pathways from critical brain sites that support stress-induced negative affect associated with stress after chronic ethanol with the use of optogenetics.  Consequently, multidisciplinary approaches integrating neuropharmacological, neuro-anatomical, molecular, biochemical, electrophysiological and optogenetic approaches will be used to identify the neurobiological basis of the persisting chronic alcohol cumulative adaptation within relevant brain sites which support facilitation of stress-induced negative affect. Collectively, these avenues of research may allow defining therapies by which stress can be prevented in the alcoholic as a means to minimize the high relapse rate associated with alcoholism.

Representative Publications:

1. Knapp, DJ, Overstreet DA, Huang M, Wills TA, Whitman, BA, Angel, RA, Sinnett SE,, Breese GR. Effects of a stressor and corticotropin releasing factor on ethanol deprivation-induced ethanol intake and anxiety-like behavior in alcohol-preferring P Rats.  Psychopharmacology 218:179-189, 2011
2. Knapp, DJ, Whitman, BA, Wills TA, Angel, RA, Overstreet DA, Criswell HE, Ming Z, Breese GR Cytokine involvement in stress may depend on corticotrophin releasing factor to sensitize ethanol withdrawal anxiety.  Brain Behavior Immunity.  25: S146-S154, 2011
3. Kelm MK, Criswell HE, Breese GR. Ethanol-enhanced GABA release: a focus of G protein-coupled receptors. Brain Res Rev. 65:113-123, 2011
4. Breese, G.R., Sinha, R. and Heilig M.  Chronic ethanol neuroadaptation and stress contribute to susceptibility for alcohol relapse.  Pharmacology and Therapeutics.  129:149-171, 2011
5. 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.