Background: Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide, being nonalcoholic steatohepatitis (NASH) its most clinically relevant form. Given the risks associated with taking a liver biopsy, the design of accurate non-invasive methods to identify NASH patients is of upmost importance. BMP2 plays a key role in metabolic homeostasis; however, little is known about

Abstract

Drug use is a growing problem in actual society. Usually, the first experience with drugs takes place during adolescence, being cannabis the most used illicit drug. Although cannabis could be considered a harmless drug, we are beginning to appreciate its consequences. Chronic exposure to addictive drugs has shown to imbalance glutamate homeostasis in Nucleus Accumbens (NAc), altering plasticity mechanisms such as long-term depression. Therefore, it is crucial to elucidate the mechanisms underlying these alterations and how to reverse them. It is known the activation of cannabinoid receptors in astrocytes modulate synaptic plasticity and could be involved in glutamate homeostasis. However, the functional role of astrocytes in alterations derived from chronic drug exposure is not fully understood. In this study, we analyzed how astrocytes contribute to alterations produced by tetrahydrocannabinol (THC). Using fiber photometry in vivo we analyzed astrocytic activity (Ca2+ and glutamate dynamics) in NAc after 1mg/kg THC chronic administration in wildtype and p38αMAPK-/- (Astrop38α) mice4 and we performed electrophysiology experiments to analyze synaptic plasticity. Moreover, we performed behavioral tests to assess whether THC had reinforcing properties or affected learning and memory. Furthermore, using a chemogenetic approaches (DREADDs) we activated NAc astrocytes to analyze their behavioral implications. We observed: 1)THC increases astrocytic calcium activity; 2)THC induces glutamate release in NAc in wildtype, but not Astrop38α; 3)NAc astrocytes are involved in learning; 4)Removal of p38αMAPK in NAc astrocytes restores THC-related impairments. Altogether, our results reveal astrocytes as critical elements for the maintenance of glutamate signaling, with a significant role in drug-use-related alterations.