0000000000095453
AUTHOR
Marina D. Reguilón
Neuroinflamación: pasarela entre el estrés y la adicción
Nuestros resultados respaldan el papel de la respuesta inflamatoria en los efectos que produce el estrés social sobre la respuesta a drogas.
Resilience to social defeat stress in adolescent male mice.
Adverse social experiences during adolescence are associated with the appearance of mental illness in adulthood. Social defeat (SD) is an ethologically valid murine model to study the consequences of social stress. In adolescent mice, SD induces depressive-like behaviors, increased anxiety and potentiates the reinforcing effects of cocaine and alcohol. However, not all mice exposed to SD will be susceptible to these effects. Adult mice resilient to the effects of SD show a consistent phenotype being resilient to depressive-like behaviors and to the increase in cocaine and alcohol consumption. The aim of the present study was to characterize the resilient phenotype to depressive-like behavio…
Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice
The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body’s metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-a…
Inoculación de estrés en la adolescencia: atenuación de los efectos reforzantes y motivacionales del etanol inducido por estrés social en ratones macho
Numerosos estudios han demostrado que la exposición a estrés social está relacionada con un mayor riesgo a desarrollar un trastorno por abuso de sustancias. Las experiencias estresantes durante la adolescencia pueden afectar al desarrollo del cerebro, ejerciendo así una influencia profunda y duradera en el desarrollo mental y la salud psicológica. Existe una hipótesis relacionada con la exposición al estrés en etapas tempranas de la vida que presupone que los individuos que han experimentado un estrés de moderada o baja intensidad, pueden adquirir cierta resistencia a exposiciones más profundas en la adultez. En este estudio nos propusimos estudiar esta hipótesis como una forma de potenciar…
Social Housing Conditions Modulate the Long-Lasting Increase in Cocaine Reward Induced by Intermittent Social Defeat
Social defeat is considered the most representative animal model for studying the consequences of social stress. Intermittent social defeat (ISD) has proved to enhance the response to cocaine hedonic properties. In the present research, we evaluated if different social housing conditions, as housing with a familiar conspecific or with a female, exert a protective effect modulating the negative consequences of ISD as the increased sensitivity to cocaine and the induction of anxiety-like behavior. To achieve this objective, non-stressed or ISD OF1 male mice were divided into five different experimental groups according to their social environment: standard housing (four adult males per cage);…
El consumo de dieta grasa en forma de atracón durante la adolescencia incrementa los efectos reforzantes del alcohol en ratones macho
Poster presentado al congreso de patología dual en madrid en abril de 2018.
Role of dopamine neurotransmission in the long-term effects of repeated social defeat on the conditioned rewarding effects of cocaine
Numerous studies report that social defeat stress alters dopamine (DA) neurotransmission in several areas of the brain. Alterations of the mesolimbic dopaminergic pathway are believed to be responsible for the increased vulnerability to drug use observed as a result of social stress. In the present study, we evaluated the influence of DA receptors on the long-term effect of repeated social defeat (RSD) on the conditioned rewarding and reinstating effects of cocaine. For this purpose, the D1R antagonist SCH 23390 and the D1R antagonist raclopride were administered 30 min before each social defeat and a cocaine-induced CPP procedure was initiated three weeks later. The expression of the D1R a…
Lavandula angustifolia Essential Oil and Linalool Counteract Social Aversion Induced by Social Defeat
Many vegetable extracts, essential oils, and their main constituents are active on the Central Nervous System (CNS). In fact, they have been used as sedatives, hypnotics, or tranquilizers for their activity in treating CNS disorders. In this research, we studied the possible activities of Lavandula angustifolia (LA) essential oil and of its main constituent, linalool, as anti-stress compounds on anxiety and social interaction and their in vitro effects on proteins (pERK and PKA) involved in the transmission of the signal. An acute intraperitoneal injection of linalool (100 mg/kg) and of LA essential oil (200 mg/kg) reduced motor activity without any anxiolytic effect, but significantly incr…
Oxytocin signaling as a target to block social defeat-induced increases in drug abuse reward
There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature rega…
Correction: Indomethacin blocks the increased conditioned rewarding effects of cocaine induced by repeated social defeat
It is well established that repeated social defeat stress can induce negative long-term consequences such as increased anxiety-like behavior and enhances the reinforcing effect of psychostimulants in rodents. In the current study, we evaluated how the immune system may play a role in these long-term effects of stress. A total of 148 OF1 mice were divided into different experimental groups according to stress condition (exploration or social defeat) and pre-treatment (saline, 5 or 10 mg/kg of the anti-inflammatory indomethacin) before each social defeat or exploration episode. Three weeks after the last social defeat, anxiety was evaluated using an elevated plus maze paradigm. After this tes…
Antagonism of corticotropin-releasing factor CRF 1 receptors blocks the enhanced response to cocaine after social stress
Numerous studies have shown that social defeat stress induces an increase in the rewarding effects of cocaine. In this study we have investigated the role played by the main hypothalamic stress hormone, corticotropin-releasing factor (CRF), in the effects that repeated social defeat (RSD) induces in the conditioned rewarding effects and locomotor sensitization induced by cocaine. A total of 220 OF1 mice were divided into experimental groups according to the treatment received before each social defeat: saline, 5 or 10 mg/kg of the nonpeptidic corticotropin-releasing factor CRF1 receptor antagonist CP-154,526, or 15 or 30 µg/kg of the peptidic corticotropin-releasing factor CRF2 receptor ant…
Dopamine D2 receptors mediate the increase in reinstatement of the conditioned rewarding effects of cocaine induced by acute social defeat
Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D1- and D2-like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on …
Oxytocin reverses ethanol consumption and neuroinflammation induced by social defeat in male mice
Abstract Oxytocin (OXT) modulates social interactions, attenuates stressful responses and can decrease drug-seeking and taking behaviors. In previous studies, we observed that social defeat (SD) induced a long-lasting increase in ethanol intake and neuroinflammation in male mice. We also know that OXT blocks the increase in cocaine reward induced by SD. Therefore, in the present study we aimed to evaluate the effect of 1 mg/kg of OXT administered 30 min before each episode of SD on ethanol consumption and the neuroinflammatory response in adult male mice. Three weeks after the last SD, mice underwent oral ethanol self-administration (SA) procedure, and striatal levels of the two chemokines …
Voluntary wheel running protects against the increase in ethanol consumption induced by social stress in mice
Abstract Previous studies have shown that exposure to social defeat (SD), a model of social stress, produces a long-term increase in the consumption of ethanol, most likely through an increase in the neuroinflammation response. The aim of the present study was to evaluate whether exposure to physical activity in the form of voluntary wheel running (VWR) could block the increase in ethanol consumption and the neuroinflammatory response induced by social stress. Mice were exposed to either 4 sessions of repeated social defeat (RSD) or a non-stressful experience. During the whole procedure, half of the mice were exposed to controlled physical activity, being allowed 1 h access to a low-profile…
Endogenous oxytocin is essential for the buffering effects of pair housing against the increase in cocaine reward induced by social stress.
Social factors have a dual influence on addictive disorders. While social defeat stress in rodents increases the response to drug reward, positive social conditions, such as pair housing, increase stress resilience. The objective of the present study was to confirm whether oxytocin (OT) mediates this social buffering. To this end, male mice were housed in pairs and administered the OT receptor antagonist atosiban prior to each stress episode or for ten days after the stress protocol. The response to cocaine was assessed using a conditioned place preference paradigm. Our results confirmed that OT activity mediates the protective effect of pair housing and highlights its therapeutic potential.
El estrés social produce ansiedad e incrementa los efectos reforzantes de la cocaína: utilidad de los antiinflamatorios
poster presentado al congreso de patología dual en madrid en abril de 2018
Critical role of TLR4 in uncovering the increased rewarding effects of cocaine and ethanol induced by social defeat in male mice
Abstract Background Substance use disorders and social stress are currently associated with changes in the immune system response by which they induce a proinflammatory state in neurons and glial cells that eventually modulates the reward system. Aims The aim of the present work was to assess the role of the immune TLR4 (Toll-like receptors 4) and its signaling response in the increased contextual reinforcing effects of cocaine and reinforcing effects of ethanol (EtOH) induced by social defeat (SD) stress. Methods Adult male C57BL/6 J wild-type (WT) mice and mice deficient in TLR4 (TLR4-KO) were assigned to experimental groups according to stress condition (exploration or SD). Three weeks a…
Decreased kynurenine pathway potentiate resilience to social defeat effect on cocaine rewa
The kynurenine (KYN) pathway of tryptophan (TRP) degradation is activated by stress and inflammatory factors. It is now well established that social stress induces the activation of the immune system, with central inflammation and KYN metabolism being two of the main factors linking stress with depression. The aim of the present study was to evaluate the long-lasting changes in the KYN pathway induced by social defeat (SD) associated with the resilience or susceptibility to an increase in the conditioned rewarding effects of cocaine. Mice were exposed to repeated SD and 3 weeks later, a conditioned place preference (CPP) induced by a subthreshold dose of cocaine (1.5 mg/kg) was developed. K…
Indomethacin blocks the increased conditioned rewarding effects of cocaine induced by repeated social defeat
It is well established that repeated social defeat stress can induce negative long-term consequences such as increased anxiety-like behavior and enhances the reinforcing effect of psychostimulants in rodents. In the current study, we evaluated how the immune system may play a role in these long-term effects of stress. A total of 148 OF1 mice were divided into different experimental groups according to stress condition (exploration or social defeat) and pre-treatment (saline, 5 or 10 mg/kg of the anti-inflammatory indomethacin) before each social defeat or exploration episode. Three weeks after the last social defeat, anxiety was evaluated using an elevated plus maze paradigm. After this tes…
Ethanol intake in male mice exposed to social defeat: Environmental enrichment potentiates resilience
Large preclinical evidence shows that exposure to social defeat (SD) increases vulnerability to drug abuse, increasing the consumption of ethanol. However, not all subjects are equally affected by the changes induced by stress. Previous reports have evidenced that the resilient phenotype to depressive-like behaviors after SD is associated with the resistant phenotype to cocaine-increased rewarding effects and the smaller neuroinflammatory response. The aim of the present study was to further clarify whether the resilient profile to depressive-like behavior also predicts a protection against the increase in ethanol intake induced by SD. The neuroinflammatory profile was studied after the end…
Oxytocin Signaling as a Target to Block Social Defeat-Induced Increases in Drug Abuse Reward
There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature rega…
Behavioural and neurochemical effects after repeated administration of N-ethylpentylone (ephylone) in mice
N-ethyl-pentylone (NEP), also known as "ephylone" and N-ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1 mice were acutely (1, 3, 10 mg/kg, i.p.) or repeatedly (1, 3, 10 mg/kg, i.p., 5 days, twice/day) exposed to NEP, and anxiety-like behaviour, aggr…
Social defeat stress: mechanisms underlying the increase in rewarding effects of drugs of abuse
Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces longlasting consequence…
Dos mundos conectados: Cómo la exposición al estrés social nos hace más vulnerables al consumo de drogas
L'estres es un dels principals factors de risc que poden induir l'esser huma a desenvolupar trastorns com la depressio, l'ansietat o el consum de drogues. Una de les principals fonts d'estres es la interaccio social, que pot portar a situacions com l'assetjament escolar o laboral. En aquest article revisarem la relacio tan estreta que hi ha entre l'exposicio a situacions estressants i l'increment en el consum de la cocaina o l'alcohol. Exposarem els principals resultats obtinguts amb models animals, ja que ens permeten estudiar els mecanismes cerebrals involucrats en l'impacte de l'estres sobre el consum de drogues. Per a concloure, detallarem els principals mecanismes que explicarien el po…