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. KYN levels in plasma, cerebellum, hippocampus, striatum and limbic forebrain were studied at the end of the CPP procedure. Changes in the KYN pathway after exposure to pharmacological (oxytocin and indomethacin) and environmental interventions (environmental enrichment) were also evaluated. Our results showed that defeated susceptible (SD-S) mice had higher conditioning scores than resilient mice (SD-R). In addition, although KYN concentration was elevated in all defeated mice, SD-R mice showed smaller increases in KYN concentration in the cerebellum than SD-S mice. Oxytocin or Indomethacin treatment before SD normalized cocaine-induced CPP, although the increase in the KYN pathway was maintained. However, environmental enrichment before SD normalized cocaine-induced CPP and prevented the increase in the KYN pathway. The present study highlights the role of the KYN pathway and anti-inflammatory drugs acting on TRP metabolism as pharmacological targets to potentiate resilience to social stress effects

Influx of kynurenine into the brain is involved in the reduction of ethanol consumption induced by Ro 61‐8048 after chronic intermittent ethanol in mice

Background and Purpose: The kynurenine pathway has been proposed as a target for modulating drug abuse. We previously demonstrated that inhibition of kynurenine 3-monooxygenase (KMO), using Ro 61-8048, reduces ethanol consumption in a binge drinking model. Here, we investigate the effect of the kynurenine pathway modulation in ethanol-dependent mice. Experimental Approach: Adult male and female mice were subjected to a Chronic Intermittent Ethanol (CIE) paradigm. On the last day of CIE, mice were treated with Ro 61-8048, Ro 61-8048 + PNU-120596, a positive allosteric modulator of α7nAChR, and Ro 61-8048 + L-leucine or probenecid, which blocks the influx or efflux of kynurenine from the brain, respectively. Ethanol, water consumption and preference were measured and kynurenine levels in plasma and limbic forebrain were determined. Key Results: Ro 61-8048 decreases consumption and preference for ethanol in both sexes exposed to the CIE model, an effect that was prevented by PNU-120596. The Ro 61-8048-induced decrease in ethanol consumption depends on the influx of kynurenine into the brain. Conclusion and Implications: Inhibition of KMO reduces ethanol consumption and preference in both male and female mice subjected to CIE model by a mechanism involving α7nAChR. Moreover, this centrally-mediated effect depends on the influx of peripheral kynurenine to the brain and can be prolonged by blocking the efflux of kynurenine from the brain. Here, for the first time, we demonstrate that the modulation of the kynurenine pathway is an effective strategy for the treatment of ethanol dependence in both sexe

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Modulation of the kynurenine pathway in the treatment of alcoholic dependence : neurochemical factors and cognitive-behavioral responses associated with ethanol abuse

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 19-01-2023El etanol es la droga más consumida en todo el mundo y constituye el principal ingrediente de las bebidas alcohólicas. Se ha establecido que al año se producen 3 millones de muertes en todo el mundo relacionadas con el consumo de etanol y, además, se ha asociado con hasta 200 enfermedades o patologías (OMS, 2018).El consumo abusivo y continuado de etanol produce dependencia, un trastorno crónico caracterizado por la compulsión en la búsqueda de la droga, la pérdida de control para limitar su uso y la aparición de un estado emocional negativo cuando no se consigue acceder a ella, lo que conduce a la recaída (Koob & Volkow, 2016). Durante este proceso, se producen una serie de cambios neuroadaptativos en los circuitos cerebrales y sistemas de neurotransmisores, que persisten en el tiempo y determinan la vulnerabilidad a la recaída (Koob & Volkow, 2016). Entre estos circuitos, destaca la vía dopaminérgica mesocorticolímbica, que desempeña un papel clave en el refuerzo positivo y la recompensa y, por tanto, en el desarrollo de la dependencia (Melichar et al., 2001; Wise, 2009). En los últimos años, se ha demostrado que las diferencias sexuales pueden desempeñar un papel diferencial en la respuesta y la sensibilidad al etanol (Flores-Bonilla & Richardson, 2019). Estos cambios en los circuitos cerebrales están asociados con diferentes alteraciones entre las que destacan la ansiedad, los trastornos del estado de ánimo como la depresión y los déficits cognitivos (McHugh & Weiss, 2019; Oslin & Cary, 2003)...Ethanol is the most widely consumed drug in the world and is the main ingredient in alcoholic beverages. It has been established that every year there are 3 million deaths worldwide related to the consumption of ethanol and, in addition, it has been associated with up to 200 diseases or pathologies (OMS, 2018).The abusive and continuous consumption of ethanol causes dependence, a chronic disorder characterized by the compulsion to seek the drug, the loss of control to limit its use, and the appearance of a negative emotional state when it is not possible to access it (Koob & Volkow, 2016). During this process, a series of neuroadaptive changes occur in brain circuits and neurotransmitter systems, which persist over time and determine vulnerability to relapse (Koob & Volkow, 2016). Among these circuits, the mesocorticolimbic dopaminergic pathway plays a key role in positive reinforcement and reward and, therefore, in the development of dependence (Melichar et al., 2001; Wise, 2009). In recent years, it has been shown that sex differences may play a differential role in ethanol response and sensitivity (Flores-Bonilla & Richardson, 2019). These changes in brain circuits are associated with different alterations, among which anxiety, depression, and cognitive deficits are common (McHugh & Weiss, 2019; Oslin & Cary, 2003)...Fac. de MedicinaTRUEunpu

Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice

Background and purposeAlcohol abuse has been associated with erectile dysfunction (ED), but the implicated molecular mechanisms are unresolved. This study analyses the role of alterations in soluble guanylyl cyclase (sGC) in ED.Experimental approachED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm. Erectile function was assessed in anaesthetised mice in vivo by evaluating intracavernosal pressure (ICP) and in vitro in isolated mice corpora cavernosa (CC) mounted in a myograph. Protein expression and reactive oxygen species were analysed by western blot and dihydroethidium staining, respectively.Key resultsIn CIE mice, we observed a significant decrease in the relaxant response of the CC to stimulation of NO release from nitrergic nerves by electrical field stimulation, to NO release from endothelial cells by acetylcholine, to the PDE5 inhibitor sildenafil, and to the sGC stimulator riociguat. Conversely, the response to the sGC activator cinaciguat, whose action is independent of the oxidation state of sGC, was significantly enhanced in these CC. The responses to adenylyl cyclase stimulation with forskolin were unchanged. We found an increase in reactive oxygen species in the CC from CIE mice as well as an increase in CYP2E1 and NOX2 protein expression. In vivo pre‐treatment with tempol prevented alcohol‐induced erectile dysfunction.Conclusions and implicationsOur results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration in the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism.Ministerio de Economía y Competitividad (España)Ministerio de Ciencia e Innovación (España)Ministerio deSanidad, Servicios Sociales e Igualdad (España)European CommissionUniversidad Complutense de MadridBanco SantanderDepto. de Farmacología, Farmacognosia y BotánicaFac. de MedicinaTRUEpubAPC financiada por la UC

Decreased kynurenine pathway potentiate resilience to social defeat effect on cocaine reward

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. KYN levels in plasma, cerebellum, hippocampus, striatum and limbic forebrain were studied at the end of the CPP procedure. Changes in the KYN pathway after exposure to pharmacological (oxytocin and indomethacin) and environmental interventions (environmental enrichment) were also evaluated. Our results showed that defeated susceptible (SD-S) mice had higher conditioning scores than resilient mice (SD-R). In addition, although KYN concentration was elevated in all defeated mice, SD-R mice showed smaller increases in KYN concentration in the cerebellum than SD-S mice. Oxytocin or Indomethacin treatment before SD normalized cocaine-induced CPP, although the increase in the KYN pathway was maintained. However, environmental enrichment before SD normalized cocaine-induced CPP and prevented the increase in the KYN pathway. The present study highlights the role of the KYN pathway and anti-inflammatory drugs acting on TRP metabolism as pharmacological targets to potentiate resilience to social stress effects.Ministerio de Economía y Competitividad, Dirección General de InvestigaciónMinisterio de Ciencia e InnovaciónMinisterio de Sanidad, Consumo y Bienestar SocialUniversidad Complutense de MadridInstituto de Salud Carlos III, Red de Trastornos AdictivosUnión EuropeaDepto. de Farmacología y ToxicologíaFac. de MedicinaTRUEpu