Alcoholism is a pervasive, chronic societal problem, with a high incidence of recidivism despite prolonged sobriety. Thus determination of mechanisms which predispose individuals to development of alcoholism is of great importance for finding new mechanisms of combating this disease. Stress is considered a major risk factor for relapse;stressful experiences can elevate alcohol craving in dependent individuals, even after the cessation of the stress exposure. However, the mechanisms by which stress modulates alcohol (ethanol) drinking remain largely unknown. One means by which stress may elevate ethanol drinking is by triggering the same neuroadaptations caused by chronic alcohol use. The studies in this proposal will investigate one putative common modulator of stress- and ethanol-induced neuroadaptations, amygdalar neuronal pentraxin 2 (NP2), and its ability to regulate operant ethanol self-administration using a novel model of stress exposure prior to the commencement of operant training, which yields marked increases in """"""""relapse"""""""" drinking 2 months later. The observed elevation in self-administration after a protracted post-stress period are akin to elevations in alcohol abuse in observed in patients with post-traumatic stress disorder (PTSD). To address the role of NP2 in regulating stress pre-exposure-induced elevation in """"""""relapse"""""""" drinking in rats, I will first determine whether NP2 expression in the amygdala is differentially elevated not only immediately after stress experience, but also during periods of withdrawal and during relapse. In addition I will determine whether this is caused by glucocorticoid signaling, which occurs under stressful conditions. Next I will determine whether the proposed elevation in NP2 in the amygdala is responsible for the elevation in """"""""relapse"""""""" drinking due to stress pre-exposure 2 months eariier by blocking its expression via RNA interference. Finally, as NP2 has been proposed to increase synaptic complexity via synaptic recruitment of AMPA receptors, I will investigate whether stress pre-exposure alters the synaptic distribution of AMPA receptors and dendritic complexity in the amygdala, and the requirement of NP2 for observed changes. Together these studies will address a novel putative modulator of stress-induced elevations in alcohol intake. Thus the targets identified herein will not only increase our understanding of one mechanism by which stress may increase alcohol intake, but this research may also identify useful new targets for the development of therapies to treat PTSD, alcoholism and other stress-related disorders.
