Alcoholism is a tremendous health and financial burden on our society. A growing literature indicates that the extended amygdala plays a key role in stress-reward interactions that may mediate key behavioral responses to chronic alcohol exposure. We demonstrated that chronic intermittent alcohol exposure up regulates CRF receptor dependent augmentation of glutamate release, as well as postsynaptic NMDA receptor function at extended amygdala glutamate synapses. We propose here to test a two-hit model, whereby affective disruptions produced by chronic alcohol exposure and withdrawal depend upon the coordinated pre- and postsynaptic regulation of extended amygdala glutamate synapses. We propose a series of experiments to map out mechanisms by which CRF receptor signaling regulates glutamate synapses, and to explore the alterations in NMDA receptor function that occur with alcohol exposure and withdrawal. We further propose to explore the impact of disruption of these processes on alcohol-abstinence induced depressive behaviors.
Alcoholism poses an enormous health and financial burden on our society. Currently, our understanding of the brain circuitries involved in alcoholism is far from complete. The successful completion of these proposed studies would result in important new information about neurons that may be involved in alcoholism, potentially creating new targets for therapeutics development.
|Harris, Nicholas A; Winder, Danny G (2018) Synaptic Plasticity in the Bed Nucleus of the Stria Terminalis: Underlying Mechanisms and Potential Ramifications for Reinstatement of Drug- and Alcohol-Seeking Behaviors. ACS Chem Neurosci 9:2173-2187|
|Bergstrom, Hadley C; Lipkin, Anna M; Lieberman, Abby G et al. (2018) Dorsolateral Striatum Engagement Interferes with Early Discrimination Learning. Cell Rep 23:2264-2272|
|Vranjkovic, Oliver; Pina, Melanie; Kash, Thomas L et al. (2017) The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective. Neuropharmacology 122:100-106|
|Pomrenze, Matthew B; Fetterly, Tracy L; Winder, Danny G et al. (2017) The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target? Alcohol Clin Exp Res 41:1986-1999|
|Silberman, Yuval; Fetterly, Tracy L; Awad, Elias K et al. (2015) Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala. Alcohol Clin Exp Res 39:2154-62|
|Flavin, Stephanie A; Winder, Danny G (2013) Noradrenergic control of the bed nucleus of the stria terminalis in stress and reward. Neuropharmacology 70:324-30|
|Conrad, Kelly L; Louderback, Katherine M; Milano, Elana J et al. (2013) Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement. Psychopharmacology (Berl) 227:109-16|
|Conrad, Kelly L; Davis, Adeola R; Silberman, Yuval et al. (2012) Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes. Neuropsychopharmacology 37:2253-66|
|Gosnell, Heather B; Silberman, Yuval; Grueter, Brad A et al. (2011) mGluR8 modulates excitatory transmission in the bed nucleus of the stria terminalis in a stress-dependent manner. Neuropsychopharmacology 36:1599-607|