Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors

Abstract

Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h-28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1-11d), and returned to pre-abstinence levels during protracted abstinence (17-27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naïve (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE-ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse.

Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood

“…Irritability has also been reported to be greater in adolescents at higher risk for substance use 50 . Irritability-like behavior has also been shown to increase during withdrawal from alcohol and nicotine in rodents 18 – 20 . However, to our knowledge, whether early exposure to cannabinoids affects irritability-like behavior has not been studied in animal models.…”

“…To test irritability-like behavior after WIN exposure, we used the bottle-brush test, based on the experimental method that was designed previously for mice 31 , 32 and slightly modified to better monitor rat behavior 19 . Currently, this model is increasingly used by both our laboratory and others as a measure of negative emotional states in animal models of addiction 18 – 20 . This method has advantages over other behavioral paradigms that measure aggressive/defensive behaviors, such as the social dominance/subordination paradigms and resident/intruder confrontation paradigm, because the experimenter has greater control over the mechanical stimulus and thus better precision in ensuring uniform provocation.…”

“…To address this issue, we tested the effect of adolescent exposure to the cannabinoid receptor agonist WIN on key addiction-related behaviors using a more complex animal model of drug addiction. The model included measures of irritability-like behavior, which has recently been used as a measure of the negative emotional state in animal models of addiction 18 – 20 . We also assessed cocaine-induced locomotion (i.e., cross-sensitization) in adolescence and adulthood and the acquisition of cocaine self-administration under conditions of short access (1 h) and long access (6 h; i.e., escalation of cocaine self-administration) in adulthood.…”

Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell

“…A compromised hypothalamic-pituitary-adrenal (HPA) axis function has become a valid feature underlying moderate to severe AUD [36,[47][48][49][50]. For example, baseline and peak corticosterone were higher in rats that did not demonstrate escalation of ethanol self-administration compared with rats that showed escalation in ethanol self-administration after ethanol challenge [47].…”

“…Rats were separated into high responders (HR) and low responders (LR) based on their drinking data. Operant behavior data, blood ethanol levels (BELs; [35]) and peak corticosterone levels [36] of twenty-one HR rats have been reported elsewhere. Behavior data, BELs and corticosterone data for twenty-three LR rats have never been published previously, and are compared with the previously published findings and reported here.…”