Person: Ezquer, Fernando
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Publication Chronic Voluntary Morphine Intake Is Associated with Changes in Brain Structures Involved in Drug Dependence in a Rat Model of Polydrug Use(2023) Ezquer, Fernando; Ezquer, Marcelo; Gallardo, Javiera; Quintanilla, María; Morales, Paola; Santapau, Daniela; Ávila, Alba; Ponce, Carolina; Berrios, Pablo; Olivares, Belén; Herrera, Mario; Israel, YedyChronic opioid intake leads to several brain changes involved in the development of dependence, whereby an early hedonistic effect (liking) extends to the need to self-administer the drug (wanting), the latter being mostly a prefrontal-striatal function. The development of animal models for voluntary oral opioid intake represents an important tool for identifying the cellular and molecular alterations induced by chronic opioid use. Studies mainly in humans have shown that polydrug use and drug dependence are shared across various substances. We hypothesize that an animal bred for its alcohol preference would develop opioid dependence and further that this would be associated with the overt cortical abnormalities clinically described for opioid addicts. We show that Wistar-derived outbred UChB rats selected for their high alcohol preference additionally develop: (i) a preference for oral ingestion of morphine over water, resulting in morphine intake of 15 mg/kg/day; (ii) marked opioid dependence, as evidenced by the generation of strong withdrawal signs upon naloxone administration; (iii) prefrontal cortex alterations known to be associated with the loss of control over drug intake, namely, demyelination, axonal degeneration, and a reduction in glutamate transporter GLT-1 levels; and (iv) glial striatal neuroinflammation and brain oxidative stress, as previously reported for chronic alcohol and chronic nicotine use. These findings underline the relevance of polydrug animal models and their potential in the study of the wide spectrum of brain alterations induced by chronic morphine intake. This study should be valuable for future evaluations of therapeutic approaches for this devastating condition.Publication Intragastric administration of short chain fatty acids greatly reduces voluntary ethanol intake in rats(2024) Quintanilla, María; Santapau, Daniela; Diaz, Eugenio; Valenzuela, Ignacio; Medina, Nicolas; Landskron, Glauben; Dominguez, Antonia; Morales, Paola; Ramírez, David; Hermoso, Marcela; Olivares, Belén; Berríos, Pablo; Ezquer, Marcelo; Herrera, Mario; Israel, Yedy; Ezquer, FernandoAlcohol use disorder (AUD) represents a public health crisis with few FDA-approved medications for its treatment. Growing evidence supports the key role of the bidirectional communication between the gut microbiota and the central nervous system (CNS) during the initiation and progression of alcohol use disorder. Among the different protective molecules that could mediate this communication, short chain fatty acids (SCFAs) have emerged as attractive candidates, since these gut microbiota-derived molecules have multi-target effects that could normalize several of the functional and structural parameters altered by chronic alcohol abuse. The present study, conducted in male alcohol-preferring UChB rats, shows that the initiation of voluntary ethanol intake was inhibited in 85% by the intragastric administration of a combination of SCFAs (acetate, propionate and butyrate) given before ethanol exposure, while SCFAs administration after two months of ethanol intake induced a 90% reduction in its consumption. These SCFAs therapeutic effects were associated with (1) a significant reduction of ethanol-induced intestinal inflammation and damage; (2) reduction of plasma lipopolysaccharide levels and hepatic inflammation; (3) reduction of ethanol-induced astrocyte and microglia activation; and (4) attenuation of the ethanol-induced gene expression changes within the nucleus accumbens. Finally, we determined that among the different SCFAs evaluated, butyrate was the most potent, reducing chronic ethanol intake in a dose-response manner. These findings support a key role of SCFAs, and especially butyrate, in regulating AUD, providing a simple, inexpensive, and safe approach as a preventive and intervention-based strategy to address this devastating disease.