Alcoholism is a chronic, relapsing disorder, characterized by withdrawal syndromes of negative emotional symptoms that putatively promote relapse via negative reinforcement mechanisms. The present application tests the overarching hypothesis that excitatory glutamatergic signaling in the amygdala is altered during ethanol withdrawal, partly due to actions of corticotropin-releasing factor systems and neuronal pentraxin 2, and thereby promote negative emotional symptoms and relapse risk during abstinence. To test this hypothesis, SPECIFIC AIM 1 will use site-specific administration of recently available, highly available classand subunit selective antagonists of ionotropic glutamate receptors to test their functional involvement in the increased anxiety-like behavior and ethanol self-administration of alcohol withdrawal.
SPECIFIC AIM 2 will use glutamate system-restricted knockdown of CRF1 signaling to test the hypothesis that CRF1-driven increases in glutamatergic signaling originating from the BLA promotes anxiety-like behavior and ethanol self-administration during withdrawal from chronic intermittent ethanol exposure. Finally, SPECIFIC AIM 3 will use dominant negative Narp-mediated knockdown of Narp function and glutamate system-restricted overexpression of the Nptx2 gene to test the hypothesis that chronic intermittent ethanol-induced Narp, via increased trafficking of AMPAR to the post-synaptic density leads to increased anxiety-like behavior and ethanol self-administration behavior. The studies will involve close collaboration with the Roberto/Siggins, Parsons and Mandyam research components, benefit from the consultation of Dr. Catherine Rivier, and rely closely upon the Animal Models (Koob/George) and Viral Vector (Contet) Cores of the proposed TSRI-ARC
The proposed studies will reveal neuroadaptive changes in excitatory stress neurocircuitry of the brain that result from chronic intermittent exposure or access to ethanol. Understanding the mechanisms associated with ethanol-induced plasticity of amygdala glutamatergic circuitry may yield new prophylactic and therapeutic approaches to alcoholism.
|Kim, Airee; Zamora-Martinez, Eva R; Edwards, Scott et al. (2015) Structural reorganization of pyramidal neurons in the medial prefrontal cortex of alcohol dependent rats is associated with altered glial plasticity. Brain Struct Funct 220:1705-20|
|Cohen, Ami; Soleiman, Matthew T; Talia, Reneta et al. (2015) Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus. Psychopharmacology (Berl) 232:453-63|
|Montane Jaime, Lazara Karelia; Shafe, Samuel; Liang, Tiebing et al. (2014) Subjective response to alcohol and ADH polymorphisms in a select sample of young adult male East Indians and Africans in Trinidad and Tobago. J Stud Alcohol Drugs 75:827-38|
|Buck, Cara L; Malavar, Jordan C; George, Olivier et al. (2014) Anticipatory 50 kHz ultrasonic vocalizations are associated with escalated alcohol intake in dependent rats. Behav Brain Res 271:171-6|
|Herman, Melissa Ann; Roberto, Marisa (2014) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol :|
|Kallupi, Marsida; Oleata, Christopher S; Luu, George et al. (2014) MT-7716, a novel selective nonpeptidergic NOP receptor agonist, effectively blocks ethanol-induced increase in GABAergic transmission in the rat central amygdala. Front Integr Neurosci 8:18|
|Rivier, Catherine (2014) Role of hypothalamic corticotropin-releasing factor in mediating alcohol-induced activation of the rat hypothalamic-pituitary-adrenal axis. Front Neuroendocrinol 35:221-33|
|Buck, Cara L; Vendruscolo, Leandro F; Koob, George F et al. (2014) Dopamine D1 and *-opioid receptor antagonism blocks anticipatory 50ýýkHz ultrasonic vocalizations induced by palatable food cues in Wistar rats. Psychopharmacology (Berl) 231:929-37|
|Gilpin, Nicholas W; Roberto, Marisa; Koob, George F et al. (2014) Kappa opioid receptor activation decreases inhibitory transmission and antagonizes alcohol effects in rat central amygdala. Neuropharmacology 77:294-302|
|Zorrilla, Eric P; Logrip, Marian L; Koob, George F (2014) Corticotropin releasing factor: a key role in the neurobiology of addiction. Front Neuroendocrinol 35:234-44|
Showing the most recent 10 out of 98 publications