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.
|Smith, Christopher T; Sierra, Yecenia; Oppler, Scott H et al. (2014) Ovarian cycle effects on immediate reward selection bias in humans: a role for estradiol. J Neurosci 34:5468-76|
|Sparta, Dennis R; Hovelsø, Nanna; Mason, Alex O et al. (2014) Activation of prefrontal cortical parvalbumin interneurons facilitates extinction of reward-seeking behavior. J Neurosci 34:3699-705|
|Coleman Jr, Leon Garland; Liu, Wen; Oguz, Ipek et al. (2014) Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility. Pharmacol Biochem Behav 116:142-51|
|Kietzman, Henry W; Everson, Joshua L; Sulik, Kathleen K et al. (2014) The teratogenic effects of prenatal ethanol exposure are exacerbated by Sonic Hedgehog or GLI2 haploinsufficiency in the mouse. PLoS One 9:e89448|
|Smith, Christopher T; Swift-Scanlan, Theresa; Boettiger, Charlotte A (2014) Genetic polymorphisms regulating dopamine signaling in the frontal cortex interact to affect target detection under high working memory load. J Cogn Neurosci 26:395-407|
|Qin, Liya; Crews, Fulton T (2014) Focal thalamic degeneration from ethanol and thiamine deficiency is associated with neuroimmune gene induction, microglial activation, and lack of monocarboxylic acid transporters. Alcohol Clin Exp Res 38:657-71|
|Jennings, Joshua H; Stuber, Garret D (2014) Tools for resolving functional activity and connectivity within intact neural circuits. Curr Biol 24:R41-50|
|Swift-Scanlan, Theresa; Smith, Christopher T; Bardowell, Sabrina A et al. (2014) Comprehensive interrogation of CpG island methylation in the gene encoding COMT, a key estrogen and catecholamine regulator. BMC Med Genomics 7:5|
|Cook, Jason B; Werner, David F; Maldonado-Devincci, Antoniette M et al. (2014) Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3?,5?-THP and reduces long-term operant ethanol self-administration. J Neurosci 34:5824-34|
|Zou, Jian Y; Crews, Fulton T (2014) Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling. PLoS One 9:e87915|
Showing the most recent 10 out of 72 publications