The development of alcohol addiction is characterized by repeated binge/ intoxication episodes. Prominent theories of addiction suggest that drugs gain control over the individual, in part, by usurping glutamate-linked mechanisms of neuroplasticity within brain reward circuits. The preclinical studies in this application are focused on identifying alcohol-induced pathologies in brain reward circuits that underlie addiction. Preliminary results show that binge-like alcohol self-administration activates primary glutamatergic mechanisms of neuroplasticity (i.e., AMPA GluRI;CaMKIIa) in amygdala and accumbens nuclei that, in turn, are required for alcohol reinforcement. These novel findings suggest the main hypothesis of this application that the binge/intoxication stage of alcohol addiction is associated with adaptations in glutamatergic cell signaling in amygdala-accumbens circuits that regulate alcohol reinforcement.
Aim 1 will investigate the effects of binge-like alcohol self-administration on adaptive changes in AMPA GluRI and CaMKIIa protein expression in the amygdala and nucleus accumbens and will evaluate functional effects of alcohol self-administration on CaMKIIo-positive glutamatergic projections that are intrinsic (BLA to CeA) and extrinsic (BLA to AcbSh) to the amygdala using optogenetic and electrophysiological strategies.
Aim 2 will determine the functional role of AMPAR/CaMKII in the CeA and AcbSh, using pharmacological techniques and identify the functional involvement of CaMKIla-positive glutamatergic projections that are intrinsic/extrinsic to the amygdala in relation to binge-like alcohol self-administration, using optogenetic techniques. These studies will identify novel plasticity-linked molecular mechanisms and functional neural circuits that regulate binge-like alcohol self-administration. Finally, Aim 3 will characterize the role of AMPAR positive modulation in the CeA and AcbSh on escalated alcohol self-administration using pharmacological and optogenetic techniques. These studies will identify specific nuclei and circuits in which increased glutamate signaling contributes to escalated binge drinking. This Component will identify and validate novel mechanisms of a critical behavioral pathology that pervades the development and progression of alcohol addiction.
Alcohol addiction is a complex neuropsychiatric disorder that contributes to serious physical, psychiatric, and social problems. Emerging evidence indicates that alcohol causes maladaptive changes in brain regions that regulate the fundamental process of reward. The goal of this research is to increase understanding of how alcohol alters brain reward circuits and to identify pharmacological strategies for blocking this pathology.
|Guizzetti, Marina; Davies, Daryl L; Egli, Mark et al. (2016) Sex and the Lab: An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies. Alcohol Clin Exp Res 40:1182-91|
|Cannady, Reginald; Fisher, Kristen R; Graham, Caitlin et al. (2016) Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner. Addict Biol :|
|Marshall, S Alex; McKnight, Kyle H; Blose, Allyson K et al. (2016) Modulation of Binge-like Ethanol Consumption by IL-10 Signaling in the Basolateral Amygdala. J Neuroimmune Pharmacol :|
|Shnitko, Tatiana A; Spear, Linda P; Robinson, Donita L (2016) Adolescent binge-like alcohol alters sensitivity to acute alcohol effects on dopamine release in the nucleus accumbens of adult rats. Psychopharmacology (Berl) 233:361-71|
|Faccidomo, Sara; Reid, Grant T; Agoglia, Abigail E et al. (2016) CaMKII inhibition in the prefrontal cortex specifically increases the positive reinforcing effects of sweetened alcohol in C57BL/6J mice. Behav Brain Res 298:286-90|
|Suryanarayanan, A; Carter, J M; Landin, J D et al. (2016) Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol. Neuropharmacology 107:181-8|
|Eberhart, Johann K; Parnell, Scott E (2016) The Genetics of Fetal Alcohol Spectrum Disorders. Alcohol Clin Exp Res 40:1154-65|
|Crews, Fulton T; Vetreno, Ryan P; Broadwater, Margaret A et al. (2016) Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior. Pharmacol Rev 68:1074-1109|
|Knapp, Darin J; Harper, Kathryn M; Whitman, Buddy A et al. (2016) Stress and Withdrawal from Chronic Ethanol Induce Selective Changes in Neuroimmune mRNAs in Differing Brain Sites. Brain Sci 6:|
|Marcinkiewcz, Catherine A; Mazzone, Christopher M; D'Agostino, Giuseppe et al. (2016) Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature 537:97-101|
Showing the most recent 10 out of 165 publications