Person: Ezquer, Fernando
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Ezquer
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Publication Morphine self-administration is inhibited by the antioxidant N‐acetylcysteine and the anti-inflammatory ibudilast; an effect enhanced by their co-administration(2024) Quintanilla, María Elena; Morales, Paola; Santapau, Daniela; Gallardo, Javiera; Rebolledo, Rocío; Riveras, Gabriel; Acuña, Tirso; Herrera-Marschitz, Mario; Israel, Yedy; Ezquer, FernandoBackground The treatment of opioid addiction mainly involves the medical administration of methadone or other opioids, aimed at gradually reducing dependence and, consequently, the need for illicit opioid procurement. Thus, initiating opioid maintenance therapy with a lower level of dependence would be advantageous. There is compelling evidence indicating that opioids induce brain oxidative stress and associated glial activation, resulting in the dysregulation of glutamatergic homeostasis, which perpetuates drug intake. The present study aimed to determine whether inhibiting oxidative stress and/or neuroinflammation reduces morphine self-administration in an animal model of opioid dependence. Methods Morphine dependence, assessed as voluntary morphine self-administration, was evaluated in Wistar-derived UChB rats. Following an extended period of morphine self-administration, animals were administered either the antioxidant N-acetylcysteine (NAC; 40 mg/kg/day), the anti-inflammatory ibudilast (7.5 mg/kg/day) or the combination of both agents. Oxidative stress and neuroinflammation were evaluated in the hippocampus, a region involved in drug recall that feeds into the nucleus accumbens, where the levels of the glutamate transporters GLT-1 and xCT were further assessed. Results Daily administration of either NAC or ibudilast led to a mild reduction in voluntary morphine intake, while the co-administration of both therapeutic agents resulted in a marked inhibition (-57%) of morphine self-administration. The administration of NAC or ibudilast markedly reduced both the oxidative stress induced by chronic morphine intake and the activation of microglia and astrocytes in the hippocampus. However, only the combined administration of NAC + ibudilast was able to restore the normal levels of the glutamate transporter GLT-1 in the nucleus accumbens. Conclusion Separate or joint administration of an antioxidant and anti-inflammatory agent reduced voluntary opioid intake, which could have translational value for the treatment of opioid use disorders, particularly in settings where the continued maintenance of oral opioids is a therapeutic option.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.Publication No evidence for exosome treatment in reducing alcohol relapse – a failed confirmatory multi-center study(2025) Meinhardt, Marcus; Habelt, Bettina; Skorodumov, Ivan; Schwarz, Cindy; Bernhardt, Nadine; Winter, Christine; Hardar, Ravit; Müller, Christian; Israel, Yedy; Ezquer, Fernando; Spanagel, RainerPreclinical studies have suggested that intranasal administration of mesenchymal stem cell-derived exosomes can reduce alcohol intake and relapse-like behavior in rodents. To assess the translational potential of these findings, we conducted a preregistered, multi-center preclinical randomized controlled trial (preRCT) across several German research sites. Using the alcohol deprivation effect (ADE) model in both male and female Wistar rats, we evaluated whether exosome treatment attenuates relapse-like drinking behavior following repeated deprivation phases. Given the hurdles in standardizing exosome isolation, dosage, and intranasal delivery into the brain, we performed first a functional validation experiment of intranasally delivered exosomes. For providing such a functional proof, we conducted electrocorticography (ECoG) recording and showed that exosomes are capable of mitigating impaired electrophysiological activity in the prefrontal cortex in rats that underwent the ADE procedure. However, contrary to previously published positive findings, our confirmatory multi-site preRCT results did not demonstrate a significant reduction in ethanol consumption during an ADE in Wistar rats following exosome treatment. No sex or site-specific effects were observed. Given the absence of efficacy, the study was terminated early in alignment with the 3R principles of animal research ethics. These findings suggest that the previously reported benefits of exosome treatment may be model-specific and do not generalize to a broader genetic background or experimental model. Our results emphasize the necessity of replication across diverse preclinical models and rat lines prior to clinical translation and highlight the importance of publishing null results to improve transparency and reproducibility in addiction research.