Abstract
Excessive alcohol consumption leads to neurodegeneration, which contributes to cognitive decline that is associated with alcohol use disorders (AUDs). The endocannabinoid system has been implicated in the development of AUDs, but little is known about how the neurotoxic effects of alcohol impact the endocannabinoid system. Therefore, the current study investigated the effects of neurotoxic, binge-like alcohol exposure on components of the endocannabinoid system and related N-acylethanolamines (NAEs), and then evaluated the efficacy of fatty acid amide hydrolase (FAAH) inhibition on attenuating alcohol-induced neurodegeneration. Male rats were administered alcohol according to a binge model, which resulted in a transient decrease in [3H]-CP-55,940 binding in the entorhinal cortex and hippocampus following two days, but not four days, of treatment. Furthermore, binge alcohol treatment did not change the tissue content of the three NAEs quantified, including the endocannabinoid and anandamide. In a separate study, the FAAH inhibitor, URB597 was administered to rats during alcohol treatment and neuroprotection was assessed by FluoroJade B (FJB) staining. The administration of URB597 during binge treatment did not significantly reduce FJB+ cells in the entorhinal cortex or hippocampus, however, a follow up “target engagement” study found that NAE augmentation by URB597 was impaired in alcohol intoxicated rats. Thus, potential alcohol induced alterations in URB597 pharmacodynamics may have contributed to the lack of neuroprotection by FAAH inhibition.
Highlights
Excessive alcohol consumption represents a significant social, economic, and public health problem in the United States, with recent estimates showing 13.9% of Americans meeting the diagnostic criteria for an alcohol use disorder (AUD) [1]
The aim of the current study was to characterize the effect of neurotoxic binge alcohol treatment on components of the eCB system and to determine if enhancement of eCB/NAE tissue content is on components of the eCB system and to determine if enhancement of eCB/NAE tissue content is an an efficacious strategy for attenuating binge alcohol-induced neurodegeneration
Binge alcohol exposure did not change the tissue content of augmented anandamide (AEA), OEA, or PEA in the hippocampus or entorhinal exposure did not change the tissue content of AEA, OEA, or PEA in the hippocampus or entorhinal cortex. These data suggest that cannabinoid receptor 1 (CB1) receptor expression and/or function, and NAE metabolism cortex. These data suggest that CB1 receptor expression and/or function, and NAE metabolism is is resilient to neurotoxic patterns of alcohol exposure and may be permissive to pharmacological resilient to neurotoxic patterns of alcohol exposure and may be permissive to pharmacological modulation for attenuating alcohol-induced neuronal cell death
Summary
Excessive alcohol consumption represents a significant social, economic, and public health problem in the United States, with recent estimates showing 13.9% of Americans meeting the diagnostic criteria for an alcohol use disorder (AUD) [1]. The negative impact of excessive alcohol consumption on health and society warrants identification of new drug targets and development of pharmacotherapies for the treatment of AUDs. Current Food and Drug Administration (FDA) approved pharmacotherapies have had limited clinical utility due to their modest efficacy and/or compliance [7,8]. Brain Sci. 2017, 7, 158 is highlighted by the fact that less than 15% of patients with an AUD are prescribed medication [9,10]. AUDs are heterogeneous in nature and it is unlikely that a single drug or single drug target will be effective for all patients [8]. Current medication development for AUDs needs to focus on increasing the repertoire of available pharmacotherapies to increase effective treatment options across the spectrum of the disorder. The identification of new drug targets that underlie
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