Oleoylethanolamide Modulates BDNF-ERK Signaling and Neurogenesis in the Hippocampi of Rats Exposed to Δ9-THC and Ethanol Binge Drinking During Adolescence.

Daniel Silva-Peña,Fernando Rodríguez De Fonseca,Antonio Vargas,Leticia Rubio,Francisco Javier Pavón,Francisco Alén,Patricia Rivera,Nuria García-Marchena,Juan Suárez,Antonia Serrano

doi:10.3389/fnmol.2019.00096

Abstract

Oleoylethanolamide is an endogenous NAE that modulates ethanol-seeking behavior and ethanol-induced neuroinflammation. In the present study we further analyze the role of OEA in hippocampal neurogenesis, BDNF-ERK signaling, and spatial memory that are affected by alcohol. Additionally, we addressed the effects of OEA on the association of alcohol and cannabis, a frequent combination in human alcohol addicts, and whose long-term effects are far from being understood. To this end, OEA (10 mg/kg/day, i.p.) was pharmacologically administered for 5 days/week in a preclinical model of adolescent rats with binge-like consumption (1 day/week) of ethanol (3 g/kg, i.g.) combined or not with acute administrations of Δ9-THC (5 mg/kg, i.p.) for 5 weeks. OEA restored ethanol/THC-related decreases in both short-term spatial memory (spontaneous alternation by Y-maze) and circulating levels of BDNF, reduced cell proliferation (Mki67 and IdU+ cells) and maturation (Dcx, Calb1), and improved cell survival (Casp3 and BrdU+ cells) in the dorsal hippocampus. Interestingly, OEA alone or combined with THC also decreased the mRNA levels of neurotrophic factors (Bdnf, Ntf3) and the NT3 receptor TrkC, but increased the BDNF receptor TrkB in the hippocampus of ethanol-exposed rats. These effects were likely associated with a OEA-specific phosphorylation of AKT and ERK1, key signaling regulators of cell proliferation and survival. These results suggest a regulatory role of OEA in short-term spatial memory and hippocampal neurogenesis through BDNF/AKT/ERK1 signaling in response to acute THC in an alcoholic context during adolescence.

Highlights

The excessive consumption of alcohol is associated with alterations in brain physiology, structure and function
(1 day/week) of ethanol (3 g/kg, i.g.) together with acute administrations of delta-9-tetrahydrocannabinol or dronabinol (9-THC) (5 mg/kg, i.p.) for 5 weeks during adolescence, we explored the effects of OEA treatment on (1) spatial memory-like behavior, (2) mRNA expression of components of the neurotrophic –BDNF/NT3– system, (3) phosphorylation of intracellular protein kinases (AKT, ERK), and (4) cell proliferation, maturation, and survival in the dorsal hippocampus
In the present study we evaluated the effects of OEA treatment (10 mg/kg, i.p.), 48 h after acute administration of THC (5 mg/kg, i.p.) and/or ethanol binge (3 g/kg, i.g.), on the mRNA levels of main components of the neurotrophic (BDNF and NT3) system, the phosphorylation of intracellular protein kinases (AKT, ERK), and the cell proliferation, maturation and survival in the dorsal hippocampus

Summary

Introduction

The excessive consumption of alcohol is associated with alterations in brain physiology, structure and function. The effects of alcohol are concentration-dependent and the patterns of excessive alcohol intake, such as binge drinking, are becoming predominant, especially in young drinkers. Alcohol binge drinking is defined as the pattern of consumption that increases the blood alcohol. Exposure to alcohol binges increases subsequent alcohol intake during adolescence, but not adulthood (Fabio et al, 2014). Alcohol intake initiation in binge episodes may induce long-lasting consequences in the adult brain and increases lifetime risks of developing adult psychopathology, alcohol use disorders (AUD) (Crews et al, 2016). Alcohol-induced neurodegeneration is associated with changes in neuronal processes such as apoptosis and neuronal proliferation and maturation (Nixon and Crews, 2004)

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Conclusion