Dysregulation of c-Jun N-terminal kinase phosphorylation in alcohol dependence

Abstract

Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disease characterized by the emergence of negative emotional states and the development of motivational deficits that manifest during alcohol withdrawal. Accordingly, alcohol may be sought after and taken in excessive amounts to alleviate withdrawal-related symptoms. To develop more effective treatments for AUD, it is necessary to identify potential molecular targets that underlie the transition from initial alcohol use to alcohol dependence, and our previous work has implicated a role for potentiated glucocorticoid receptor (GR) signaling in this regard. As a key negative regulator of GR-mediated signaling, the current study first measured c-Jun N-terminal kinase (JNK) phosphorylation in animals following an acute alcohol challenge. We found that JNK phosphorylation (pJNK) was significantly increased in the hippocampus, frontal cortical regions, and striatum of adult male Wistar rats following alcohol challenge, indicating that initial alcohol exposure increases JNK activity across several brain regions. A separate group of adult male Wistar rats were made dependent via chronic, intermittent ethanol vapor exposure and were trained to self-administer alcohol. We found that alcohol-dependent animals consumed significantly more alcohol and escalated their drinking over time compared to non-dependent animals. We then measured alterations in JNK phosphorylation in this alcohol-dependent group during acute withdrawal and found that pJNK was selectively decreased in the dorsal hippocampus, dorsomedial prefrontal cortex, and cingulate cortex. These findings demonstrate that withdrawal from chronic alcohol exposure leads to region-specific deficits in JNK phosphorylation. JNK signaling dysregulation *

Generation and validation of a CRF1:Cre transgenic rat: The role of central amygdala CRF1 in nociception and anxiety-like behavior

“…Nociception. Mechanical and thermal nociception were measured using the Von Frey (Pahng et al, 2017) and Hargreaves (Avegno et al, 2018) assays, respectively, as previously described.…”

Pathophysiological mechanisms of alcoholic myopathy - Lessons from rodent models

“…For example, animals are trained to press a lever for alcohol to be delivered through the oral route, or in some cases directly into the brain. These models allow for the assessment of motivation to consume alcohol, such as after traumatic brain injury (Stielper et al, 2019) and to elucidate possible factors underlying motivation for alcohol, such as altered glucocorticoid receptor signaling (Pahng et al, 2019).…”