The main objective of the current proposal is to examine the effects of post-traumatic stress disorder (PTSD) on alcohol dependence. The proposed career transition award will provide new training for the applicant in animal models of PTSD and in biochemical techniques that will complement the applicant's experience with behavioral animal models of alcoholism. The training phase of the award will leave the applicant prepared to lead an independent research program in the R00 phase of the award. The R00 phase of the award and the independent research career of the applicant beyond this award will continue to focus on the negative reinforcement aspects of alcoholism and their neural overlap with other psychiatric disorders. Following exposure to a traumatic stressor, PTSD is a long-term pathological state marked by increases in anxiety and arousal, decreases in the ability to perceive pleasure, and generalization and avoidance of trauma- related stimuli. Alcohol dependence is compulsive alcohol use despite adverse consequences, loss of control when taking alcohol, and development of tolerance that results in withdrawal symptoms in the absence of the drug. Excessive alcohol consumption can be driven by the ability of the drug to alleviate aversive symptoms, including those produced by a pre-existing emotional disorder (e.g., PTSD). It is hypothesized that animals that exhibit maladaptive stress responses will exhibit higher susceptibility to alcohol dependence. Because PTSD patients and alcoholics exhibit similar patterns of neural dysregulation in the limbic system, it is hypothesized that the amygdala and BNST serve as a neural interface for overlapping/additive effects of PTSD and alcohol dependence. It is hypothesized that neuromodulators involved in the brain stress response (i.e. corticotropin- releasing factor [CRF], neuropeptide Y [NPY], and norepinephrine [NE]) and ubiquitous in these limbic circuits are similarly and additively dysregulated in PTSD and alcohol dependence.
Individuals with pre-existing emotional disorders (e.g., PTSD) are highly vulnerable to develop alcohol dependence. This project will examine the overlapping neural mechanisms of PTSD and alcoholism that contribute to the similar behavioral dysregulation seen in the two disorders. A major goal of this project will be to pharmacologically block PTSD-induced increases in the vulnerability to develop alcohol dependence.
|Teng, Sophie X; Katz, Paige S; Maxi, John K et al. (2015) Alcohol exposure after mild focal traumatic brain injury impairs neurological recovery and exacerbates localized neuroinflammation. Brain Behav Immun 45:145-56|
|Gilpin, Nicholas W; Herman, Melissa A; Roberto, Marisa (2015) The central amygdala as an integrative hub for anxiety and alcohol use disorders. Biol Psychiatry 77:859-69|
|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|
|Roltsch, Emily A; Baynes, Brittni B; Mayeux, Jacques P et al. (2014) Predator odor stress alters corticotropin-releasing factor-1 receptor (CRF1R)-dependent behaviors in rats. Neuropharmacology 79:83-9|
|Whitaker, Annie M; Gilpin, Nicholas W; Edwards, Scott (2014) Animal models of post-traumatic stress disorder and recent neurobiological insights. Behav Pharmacol 25:398-409|
|El Hajj, Elia C; El Hajj, Milad C; Voloshenyuk, Tetyana G et al. (2014) Alcohol modulation of cardiac matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs favors collagen accumulation. Alcohol Clin Exp Res 38:448-56|
|Kallupi, Marsida; Vendruscolo, Leandro F; Carmichael, Casey Y et al. (2014) Neuropeptide YY(2)R blockade in the central amygdala reduces anxiety-like behavior but not alcohol drinking in alcohol-dependent rats. Addict Biol 19:755-7|
|Edwards, S; Baynes, B B; Carmichael, C Y et al. (2013) Traumatic stress reactivity promotes excessive alcohol drinking and alters the balance of prefrontal cortex-amygdala activity. Transl Psychiatry 3:e296|
|Gilpin, Nicholas W; Roberto, Marisa (2012) Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence. Neurosci Biobehav Rev 36:873-88|