BERRIOS CARCAMO, PABLO ANDRES
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BERRIOS CARCAMO, PABLO ANDRES
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pablo.berrios@udd.cl
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55014632000

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Chronic Voluntary Morphine Intake Is Associated with Changes in Brain Structures Involved in Drug Dependence in a Rat Model of Polydrug Use

2023 , María Elena Quintanilla , Paola Morales , Daniela Santapau , Alba Ávila , Carolina Ponce , BERRIOS CARCAMO, PABLO ANDRES , OLIVARES, MARIA BELEN , Mario Herrera-Marschitz , EZQUER, EDUARDO MARCELO , Javiera Gallardo , Yedy Israel , EZQUER, EDUARDO FERNANDO

Chronic 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.

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Two-Month Voluntary Ethanol Consumption Promotes Mild Neuroinflammation in the Cerebellum but Not in the Prefrontal Cortex, Hippocampus, or Striatum of Mice

2024 , BERRIOS CARCAMO, PABLO ANDRES , Sarah Núñez , Justine Castañeda , GALLARDO ROJAS, JAVERA CAROLINA , María Rosa Bono , EZQUER, EDUARDO FERNANDO

Chronic ethanol exposure often triggers neuroinflammation in the brain’s reward system, potentially promoting the drive for ethanol consumption. A main marker of neuroinflammation is the microglia-derived monocyte chemoattractant protein 1 (MCP1) in animal models of alcohol use disorder in which ethanol is forcefully given. However, there are conflicting findings on whether MCP1 is elevated when ethanol is taken voluntarily, which challenges its key role in promoting motivation for ethanol consumption. Here, we studied MCP1 mRNA levels in areas implicated in consumption motivation—specifically, the prefrontal cortex, hippocampus, and striatum—as well as in the cerebellum, a brain area highly sensitive to ethanol, of C57BL/6 mice subjected to intermittent and voluntary ethanol consumption for two months. We found a significant increase in MCP1 mRNA levels in the cerebellum of mice that consumed ethanol compared to controls, whereas no significant changes were observed in the prefrontal cortex, hippocampus, or striatum or in microglia isolated from the hippocampus and striatum. To further characterize cerebellar neuroinflammation, we measured the expression changes in other proinflammatory markers and chemokines, revealing a significant increase in the proinflammatory microRNA miR-155. Notably, other classical proinflammatory markers, such as TNFα, IL6, and IL-1β, remained unaltered, suggesting mild neuroinflammation. These results suggest that the onset of neuroinflammation in motivation-related areas is not required for high voluntary consumption in C57BL/6 mice. In addition, cerebellar susceptibility to neuroinflammation may be a trigger to the cerebellar degeneration that occurs after chronic ethanol consumption in humans.

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Effect of human mesenchymal stem cell secretome administration on morphine self-administration and relapse in two animal models of opioid dependence

2022 , María Elena Quintanilla , Mauricio Quezada , Paola Morales , BERRIOS CARCAMO, PABLO ANDRES , Mario Herrera-Marschitz , EZQUER, EDUARDO MARCELO , Daniela Santapau , Israel Yacard, Yedy , EZQUER, EDUARDO FERNANDO

AbstractThe present study investigates the possible therapeutic effects of human mesenchymal stem cell-derived secretome on morphine dependence and relapse. This was studied in a new model of chronic voluntary morphine intake in Wistar rats which shows classic signs of morphine intoxication and a severe naloxone-induced withdrawal syndrome. A single intranasal-systemic administration of MSCs secretome fully inhibited (>95%; p < 0.001) voluntary morphine intake and reduced the post-deprivation relapse intake by 50% (p < 0.02). Since several studies suggest a significant genetic contribution to the chronic use of many addictive drugs, the effect of MSCs secretome on morphine self-administration was further studied in rats bred as high alcohol consumers (UChB rats). Sub-chronic intraperitoneal administration of morphine before access to increasing concentrations of morphine solutions and water were available to the animals, led UChB rats to prefer ingesting morphine solutions over water, attaining levels of oral morphine intake in the range of those in the Wistar model. Intranasally administered MSCs secretome to UChB rats dose-dependently inhibited morphine self-administration by 72% (p < 0.001); while a single intranasal dose of MSC-secretome administered during a morphine deprivation period imposed on chronic morphine consumer UChB rats inhibited re-access morphine relapse intake by 80 to 85% (p < 0.0001). Both in the Wistar and the UChB rat models, MSCs-secretome administration reversed the morphine-induced increases in brain oxidative stress and neuroinflammation, considered as key engines perpetuating drug relapse. Overall, present preclinical studies suggest that products secreted by human mesenchymal stem cells may be of value in the treatment of opioid addiction.

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Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

2020 , BERRIOS CARCAMO, PABLO ANDRES , Mauricio Quezada , María Elena Quintanilla , Paola Morales , EZQUER, EDUARDO MARCELO , Mario Herrera-Marschitz , Yedy Israel , EZQUER, EDUARDO FERNANDO

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system Xc− activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

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Intranasal mesenchymal stem cell secretome administration markedly inhibits alcohol and nicotine self-administration and blocks relapse-intake: mechanism and translational options

2019 , María Elena Quintanilla , EZQUER, EDUARDO FERNANDO , Paola Morales , Daniela Santapau , BERRIOS CARCAMO, PABLO ANDRES , Mario Herrera-Marschitz , EZQUER, EDUARDO MARCELO , Yedy Israel

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Product

Dataset - Metabolomics Workbench

2022 , BERRIOS CARCAMO, PABLO ANDRES

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Methadone directly impairs central nervous system cells in vitro

2024 , Cristian De Gregorio , Javiera Gallardo , BERRIOS CARCAMO, PABLO ANDRES , Álex Handy , Daniela Santapau , ANTONIA GONZALEZ MADRID , EZQUER, EDUARDO MARCELO , Paola Morales , Alejandro Luarte , Daniela Corvalán , Úrsula Wyneken , EZQUER, EDUARDO FERNANDO

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Microfabrication-based engineering of biomimetic dentin-like constructs to simulate dental aging

2024 , Simon Álvarez , Jose Morales , Paola Tiozzo-Lyon , Pablo Berrios , Valentina Barraza , Kevin Simpson , Andrea Ravasio , Xavier Monforte Vila , Andreas Teuschl-Woller , SCHUH, CHRISTINA , Sebastian Aguayo

Our study aimed to develop a novel in vitro microfabricated biomimetic dentin surface that simulates the complex surface microarchitecture of exposed dentin, as well as age-derived glycation of teeth, for the growth of polymicrobial oral biofilms.

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Aspirin and N‐acetylcysteine co‐administration markedly inhibit chronic ethanol intake and block relapse binge drinking: Role of neuroinflammation‐oxidative stress self‐perpetuation

2019 , Yedy Israel , María Elena Quintanilla , EZQUER, EDUARDO FERNANDO , Paola Morales , Daniela Santapau , BERRIOS CARCAMO, PABLO ANDRES , EZQUER, EDUARDO MARCELO , OLIVARES, MARIA BELEN , Mario Herrera‐Marschitz

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A Novel Morphine Drinking Model of Opioid Dependence in Rats

2022 , BERRIOS CARCAMO, PABLO ANDRES , Mauricio Quezada , Daniela Santapau , Paola Morales , OLIVARES, MARIA BELEN , Carolina Ponce , Alba Ávila , María Elena Quintanilla , EZQUER, EDUARDO MARCELO , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , Mario Herrera-Marschitz , Yedy Israel , EZQUER, EDUARDO FERNANDO

An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants’ presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.

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