Effects of Intermittent Alcohol Exposure on Emotion and Cognition: A Potential Role for the Endogenous Cannabinoid System and Neuroinflammation

Abstract

Intermittent alcohol exposure is a common pattern of adolescent alcohol use that can lead to binge drinking episodes. Alcohol use is known to modulate the endocannabinoid system (ECS), which is involved in neuronal communication, neuroplasticity, neuroinflammation and behavior. Adolescent male Wistar rats were exposed to 4-week intermittent alcohol intoxication (3 g/kg injections for 4 days/week) or saline (N = 12 per group). After alcohol deprivation, adult rats were assessed for emotionality and cognition and the gene expression of the ECS and other factors related to behavior and neuroinflammation was examined in the brain. Alcohol-exposed rats exhibited anxiogenic-like responses and impaired recognition memory but no motor alterations. There were brain region-dependent changes in the mRNA levels of the ECS and molecular signals compared with control rats. Thus, overall, alcohol-exposed rats expressed higher mRNA levels of endocannabinoid synthetic enzymes (N-acyl-phosphatidylethanolamine phospholipase D and diacylglycerol lipases) in the medial-prefrontal cortex (mPFC) but lower mRNA levels in the amygdala. Furthermore, we observed lower mRNA levels of receptors CB1 CB2 and peroxisome proliferator-activated receptor-α in the striatum. Regarding neuropeptide signaling, alcohol-exposed rats displayed lower mRNA levels of the neuropeptide Y signaling, particularly NPY receptor-2, in the amygdala and hippocampus and higher mRNA levels of corticotropin-releasing factor in the hippocampus. Additionally, we observed changes of several neuroinflammation-related factors. Whereas, the mRNA levels of toll-like receptor-4, tumor necrosis factor-α, cyclooxygenase-2 and glial fibrillary acidic protein were significantly increased in the mPFC, the mRNA levels of cyclooxygenase-2 and glial fibrillary acidic protein were decreased in the striatum and hippocampus. However, nuclear factor-κβ mRNA levels were lower in the mPFC and striatum and allograft inflammatory factor-1 levels were differentially expressed in the amygdala and hippocampus. In conclusion, rats exposed to adolescent intermittent alcohol displayed anxiety-like behavior and cognitive deficits in adulthood and these alterations were accompanied by brain region-dependent changes in the gene expression of the ECS and other signals associated with neuroinflammation and behavior. An intermittent adolescent alcohol exposure has behavioral and molecular consequences in the adult brain, which might be linked to higher vulnerability to addictive behaviors and psychopathologies.

Cognitive and neurobehavioral benefits of an enriched environment on young adult mice after chronic ethanol consumption during adolescence

“…The recognition, spatial and associative memory impairment detected in early adulthood by chronic EtOH intake during adolescence is consistent with recent findings showing cognitive and behavioral deficits (Sanchez‐Marin et al . ) and previous observations demonstrating that adolescent BD causes a decrease in hippocampal neurogenesis that persists into adulthood, altering brain plasticity and perturbing cognitive function (Pascual et al . ; Rodríguez‐Arias et al .…”

“…Actually, the behavioral and cognitive alterations observed in adult rats exposed to adolescent intermittent alcohol were associated with changes in gene expression of endocannabinoids and neuroinflammatory molecules in a brain region‐specific manner (Sanchez‐Marin et al . ). This is also surprising, specifically for the lack of improvement in the motor tasks given that exercise has been shown to improve motor performance and improve Purkinje cell function.…”

Alcohol‐induced cognitive deficits are associated with decreased circulating levels of the neurotrophin BDNF in humans and rats

“…All rats were firstly accustomed to the experimental conditions, including handling, for a period of 1 week (Sánchez‐Marín et al . ). Then, throughout the course of the experiment, half of the rats (ethanol group) had on their cages four bottles (Momeni & Roman ): One of them contained water, and the rest contained ethanol at different concentrations (5, 10 and 20 percent).…”

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism

“…WIN55 212.2, a CB receptor agonist, increased OPC proliferation in vitro, as well as MBP messenger RNA and protein expression in mice, whereas blocking the metabolism of endogenous CBs decreased OL excitotoxicity and demyelination in vitro, and preserved myelin integrity in a demyelinating mouse model . EtOH exposure alters CB ligands in several brain areas related to memory and addiction (e.g., PFC and amygdala). CB receptors on GABAergic neurons were implicated in modulating the effects of acute EtOH exposure in the amygdala, and systemic blockade or deletion of CB receptors was shown to lead to reduced voluntary EtOH consumption and operant responding for EtOH in rodents .…”