Influences of social stress in the rewarding effects of mdma and alcohol

La adicción a las drogas es un importante problema en nuestra sociedad con graves consecuencias jurídicas, médicas y sociales para los consumidores. Se trata de un trastorno caracterizado por la pérdida de control sobre el uso de la droga, su búsqueda compulsiva y la aparición de un estado emocional negativo en ausencia de la misma. El alcohol es la droga legal más consumida tanto por adultos como por adolescentes. Por otra parte, entre las sustancias ilegales, los datos epidemiológicos apuntan que el éxtasis o MDMA es una sustancia ampliamente consumida entre los adolescentes y adultos jóvenes sobre todo en fiestas “rave” donde los consumidores pasan horas, incluso días, haciendo uso de esta sustancia. La adolescencia constituye un periodo de alta vulnerabilidad debido a la inmadurez cerebral, siendo muy perjudicial en esta fase de la vida el consumo de drogas y la exposición a situaciones ambientales negativas. En concreto, se ha demostrado que el estrés social puede provocar el inicio, escalada y la reinstauración en el consumo de drogas en modelos animales. Por ello, el objetivo del presente trabajo ha sido estudiar los factores implicados en las propiedades reforzantes de MDMA (1.25 y 10 mg/kg) y alcohol (1.25 y 2.5 g/kg), principalmente el efecto del estrés social agudo y repetido en ratones macho adolescentes y adultos jóvenes. Una de las técnicas metodológicas más utilizadas ha sido la inducción de estrés por derrota social mediante encuentros agonísticos (agudos o repetidos). Para evaluar si el estrés social modifica el valor reforzante de la MDMA o el alcohol se ha utilizado principalmente el paradigma de condicionamiento de lugar pero también se ha evaluado el consumo voluntario de alcohol (“two-bottle choice”). Este procedimiento y el de autoadministración (“second order”) se han utilizado para estudiar los efectos de los antagonistas opiáceos mu (naltrexona y GSK 1521498) en el consumo de alcohol en ratas. Asimismo otras técnicas conductuales han sido utilizadas para medir procesos como ansiedad, memoria, aprendizaje, interacción social o actividad motora entre otros tras la administración de derrota, MDMA o su combinación. Los datos obtenidos indican que la exposición al estrés social (tanto agudo como a largo plazo) incrementa los efectos reforzantes de MDMA y alcohol y produce diferentes alteraciones conductuales, por ejemplo una reducción de la conducta social, que pueden estar relacionadas con el incremento en los efectos reforzantes. Asimismo, la combinación de estrés y MDMA induce un importante deterioro de la memoria y el estado emocional. Los antagonistas glutamatérgicos (memantine y CNQX) y la inhibición de la síntesis de óxido nítrico (7-nitroindazole) bloquean los efectos reforzantes de la MDMA y también parecen estar implicados en los efectos del estrés. El antagonismo de los receptores opiáceos mu disminuye la búsqueda y consumo de alcohol. El avance en el conocimiento de los sistemas de neurotransmisión implicados en los efectos reforzantes de la MDMA y el alcohol y en la influencia del estrés sobre estos efectos puede contribuir al desarrollo de estrategias farmacológicas para el tratamiento de la adicción a la estas drogas.Drug addiction is a serious problem in our society and has serious legal, medical and social consequences for consumers. This disorder is characterised by an impaired control over substance use, compulsive drug seeking, and the emergence of a negative emotional state in the absence of the drug. With regard to legality, there are two broad types of substances of abuse: legal and illegal. Alcohol is the most consumed legal substance by adults and adolescents. Among illegal substances, epidemiologic data suggest that ecstasy, or MDMA, is a widely used substance among adolescents and young adults, especially in "raves", where consumers spend hours, even days, using this substance. Adolescence is a period of enhanced vulnerability due to the lack of brain maturation, and consumption of drugs of abuse and exposure to different negative environmental conditions is especially harmful at this stage of life. It has been demonstrated that social stress can trigger onset, escalation and reinstatement of drug use in animal models. Therefore, the objective of this work was to study the effects of acute and repeated social stress on the rewarding properties of alcohol and MDMA using the place preference paradigm (CPP) and the two-bottle choice procedure. In addition, we set out to evaluate the effects of social stress on several behaviours or processes (anxiety, depression, social interaction, learning and memory). We have also studied the neurobiological aspects underlying the rewarding effects of MDMA and their modulation by stress, assessing along the way the role of the glutamatergic system and nitric oxide (NO) pathway. Moreover, since alcohol is the main addictive substance consumed in the world, we have studied the role of the opioid system in the rewarding effects and intake of ethanol. Overall, our results indicate that exposure to social stress (both acute and long-term) increases the rewarding effects of MDMA and ethanol and induces different behavioural alterations, such as a reduction of social interaction, which is related with an increase in drug consumption. Glutamate antagonists and inhibition of NO synthesis block the rewarding effects of MDMA and antagonism of mu opioid receptors decreases alcohol seeking and intake. Advances in knowledge of the neurotransmitter systems implicated in the rewarding effects of MDMA and alcohol are likely to contribute to the development of pharmacological strategies for the treatment of drug addiction

Cannabidiol treatment might promote resilience to cocaine and methamphetamine use disorders: A review of possible mechanisms

Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia (Fischer et al., 2015). The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations (neurotransmitter and intracellular signalling pathways changes), the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders

Hypericum perforatum L. prevents the acquisition of and promotes resilience against stress-induced reinstatement of the conditioned place preference induced by cocaine.

Abstract Cocaine use disorder is a serious problem worldwide, and there are no approved medications for its treatment. A novel approach to the treatment of drug addiction is the use of natural products, and, in this context, preclinical evidence suggests that Hypericum perforatum L. (Hypericum) is effective against alcohol and other substance use disorders. We hypothesised that Hypericum could also be useful as a treatment for cocaine use disorder, and so we set out to test its effectiveness in a mice model of cocaine addiction. In the first experiment we evaluated its effects on the acquisition of cocaine-induced conditioned place preference (CPP). Adult male mice were conditioned with cocaine (25 mg/kg), cocaine with Hypericum (75, 150 or 300 mg/kg) or the plant extract alone (300 mg/kg). In the second experiment, we tested the effects of Hypericum on stress-induced reinstatement of cocaine CPP. All the mice were conditioned with cocaine (25 mg/kg) and, after extinction of CPP, the reinstating effects of social defeat (alone or with 75, 150 or 300 mg/kg of Hypericum) were evaluated. All the doses of Hypericum prevented the acquisition of cocaine-induced CPP. Furthermore, the plant extract dose-dependently reduced the reinstating effects of social defeat. Therefore, Hypericum is effective in reducing the rewarding effects of cocaine and prevents the stress-induced reinstatement of cocaine CPP in mice. The mechanisms underlying these positive effects of Hypericum perforatum L. need to be determined by future research. Our results endorse Hypericum as a natural treatment for cocaine dependence

Programa de Intervención Cognitivo-Conductual y Familiar para el Tratamiento de Adolescentes con Adicción a la Cocaína

La adicción a la cocaína es un problema de salud pública con prevalencia ascendente. La edad de inicio de consumo se está reduciendo, poniendo en riesgo la salud de los adolescentes, quienes todavía en desarrollo, se ven más gravemente afectados por su consumo, tanto a nivel físico como psicológico. Por ello, el objetivo del trabajo es el diseño de un programa de intervención eficaz para adolescentes con adicción a la cocaína que persiga la abstinencia, la prevención de recaídas y la mejora de su calidad de vida. Se fundamenta en Terapia Cognitivo Conductual (TCC) y Terapia Familiar (TF), las cuales han demostrado eficacia en adultos. Participarán 8 jóvenes de entre 15 y 18 años y un máximo de 16 familiares. Se compone de 37 sesiones con formato grupal e individual, además de 4 sesiones de evaluación de eficacia del programa. La frecuencia de las sesiones es semanal con evaluación a los 3 y 9 meses. Se espera que, al finalizar el programa, presenten habilidades para mantenerse abstemios, un menor craving y una mejora en su calidad de vida a corto y largo plazo. Resulta una propuesta innovadora por la combinación de TCC y TF y la especificidad de su población diana.<br /

La inoculación de estrés revierte las consecuencias a largo plazo de la derrota social sobre los efectos reforzantes de la cocaína en ratones macho

Introducción: Estudios científicos han demostrado que el estrés por derrota social modifica el efecto reforzante de diferentes drogas. Además, se ha observado que la inoculación de estrés en etapas tempranas de la vida podría fomentar la resiliencia a eventos estresantes futuros, promoviendo el aprendizaje y las habilidades de afrontamiento. Objetivo: comprobar si la inoculación de estrés revierte el efecto que la derrota social induce sobre el efecto reforzante de la cocaína. Material y método: 30 ratones macho sufrieron una derrota social puntual en la adolescencia (día postnatal 27) como método de inducción de estrés. En la vida adulta, la mitad de ellos (grupo IN+DSR) fueron expuestos a cuatro episodios de derrota social repetida (días postnatales 47-56) mientras que la otra mitad de animales se utilizaron como grupo control (grupo IN+EXPL). Tres semanas después todos los animales fueron condicionados con cocaína 1mg/kg utilizando el paradigma de condicionamiento de preferencia de lugar. Resultados: ningún animal mostró condicionamiento de preferencia de lugar. Conclusiones: la inoculación de estrés revierte las consecuencias a largo plazo de la derrota social sobre los efectos reforzantes de la cocaína. Posibles implicaciones prácticas podrían derivarse de estos resultados indagando en nuevas estrategias preventivas o tratamientos terapéuticos para trastornos desencadenados o exacerbados por eventos estresantes.<br /

Resilience to the short- and long-term behavioral effects of intermittent repeated social defeat in adolescent male mice

Background Exposure to intermittent repeated social defeat (IRSD) increases the sensitivity of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Some animals are resilient to this effect of IRSD, though research exploring this inconsistency in adolescent mice is scarce. Thus, our aim was to characterize the behavioral profile of mice exposed to IRSD during early adolescence and to explore a potential association with resilience to the short- and long-term effects of IRSD. Methods Thirty-six male C57BL/6 mice were exposed to IRSD during early adolescence (PND 27, 30, 33 and 36), while another 10 male mice did not undergo stress (controls). Defeated mice and controls then carried out the following battery of behavioral tests; the Elevated Plus Maze, Hole-Board and Social Interaction Test on PND 37, and the Tail Suspension and Splash tests on PND 38. Three weeks later, all the mice were submitted to the CPP paradigm with a low dose of cocaine (1.5 mg/kg). Results IRSD during early adolescence induced depressive-like behavior in the Social Interaction and Splash tests and increased the rewarding effects of cocaine. Mice with low levels of submissive behavior during episodes of defeat were resilient to the short- and long-term effects of IRSD. In addition, resilience to the short-term effects of IRSD on social interaction and grooming behavior predicted resilience to the long-term effects of IRSD on cocaine reward. Conclusion Our findings help to characterize the nature of resilience to the effects of social stress during adolescence

Aportación metodológica para determinar el índice de calidad del medio ambiente urbano y edificado del Área Metropolitana de Barcelona

El presente trabajo está orientado hacia la determinación de una metodología que evalúa características socio-residenciales, diagnostica el estado de bienestar del medio ambiente urbano del Área Metropolitana de Barcelona (AMB), responde al estado en que se encuentran las viviendas pre-existentes al 2001. La investigación incorpora una aportación al enfoque de valoración inmobiliaria sustentada en técnicas de valores sociales como parte de un contexto integral. La orientación al desarrollo sostenible constituye dar un enfoque de valoración inmobiliaria, es decir, retomando el valor de uso como una combinación de valores urbanos y de satisfacción residencial en la base del análisis. La hipótesis de la investigación nace a partir de desarrollar una metodología sustentada en indicadores parciales (simples) idóneos para la obtención del Índice de Calidad Edificada del AMB obtenido por el método del indicador sintético de distancia DP2. El objetivo de la investigación es demostrar la validación del método del indicador sintético de distancia.This work is oriented towards the determination of a methodology to assess socio-residential characteristics, diagnoses the welfare state of the urban environment in the metropolitan area of Barcelona (AMB), responds to the state that are pre-existing dwellings to 2001 . The research incorporates a contribution to real estate valuation approach supported by techniques of social values as part of a comprehensive context. The sustainable development orientation is an approach to property valuation, returning the value in use as a combination of urban values and residential satisfaction in the analysis. The hypothesis of the research stems from developing a methodology supported by partial indicators (simple) suitable for obtaining Built Quality Index of AMB obtained by the method of the synthetic indicator DP2 away. The objective of this research is to demonstrate the validation of the method of the synthetic indicator away.Peer Reviewe

Olor a Nenuco. Estímulos químicos de cría y su impacto en la madre

Una correcta conducta maternal es fundamental para la supervivencia de la descendencia y la maduración de su sistema nervioso. Esta investigación analiza el sustrato neuroendocrino de la conducta maternal en ratones, para ayudar a comprender la etiología de sus posibles alteraciones. El objetivo es entender por qué las madres muestran mayor motivación hacia las crías que las hembras vírgenes. Nuestra hipótesis plantea que, durante la gestación, factores endocrinos podrían estimular determinados centros del cerebro de las madres haciéndolos más sensibles a las feromonas de crías. Para poner a prueba esta hipótesis hemos expuesto a madres y a hembras vírgenes a dos tipos de estímulo, crías y botones. Mediante la detección inmunohistoquímica de c-Fos medimos la actividad neuronal de sus centros quimiosensoriales (bulbos olfativos principal y accesorio, córtex piriforme, amígdala medial y cortical). El análisis estadístico (anova de dos factores, hembra y estímulo) no mostró diferencias significativas entre madres y comadres en la activación de los centros quimiosensoriales al exponerlas a crías o botones, aunque sí una tendencia a una mayor actividad en la amígdala medial posterodorsal en madres, independiente del estímulo. Finalmente, observamos una correlación significativa entre conducta maternal y actividad neuronal en centros quimiosensoriales en el grupo de hembras expuestas a crías, que sugieren el uso de circuitos neuronales diferentes entre madres y vírgenes durante su interacción con las crías.Appropriate maternal behaviour is essential for offspring survival and for its neurodevelopment. This research analyses the neuroendocrine substrate of maternal behaviour in mice, to help understanding the aetiology of their possible disorders. Our goal is to understand why mothers show higher motivation towards offspring than virgin females. Our hypothesis postulates that changes induced by gestational hormones could sensitize specific mothers’ brain centres to pup pheromones. For this purpose, we exposed dams and virgin females to two different stimuli, pups and buttons. Through immunohistochemical detention of c-Fos, we assessed the neuronal activity in their chemosensory centres (main and accessory olfactory bulbs, piriform cortex, medial and cortical amygdala). A twoway ANOVA, with female and stimulus as factors, did not show differences between dams or virgins in the activation of chemosensory centres when exposed to pups or buttons, although it showed a nearly significant trend towards higher activation of the medial amygdala in dams, irrespective of the stimulus. Finally, we observed significant correlations between maternal behaviour and the activity of chemosensory centres in the group of females exposed to pups, which suggest the use of different neuronal circuits by dams and virgin females during their interaction with pups

Effects of Plantago ovata Husk on Levodopa (with Carbidopa) Bioavailability in Rabbits with Autonomic Gastrointestinal Disorders

P. 1434-1442Gastrointestinal dysfunction is common in Parkinson’s disease. Fiber therapy could be used to reduce the symptoms of gastrointestinal motility disorders. In a previous study, we showed that slowed gastrointestinal motility modified levodopa pharmacokinetics: area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) decreased and the elimination was delayed. In this study, we evaluated whether or not the hydrosoluble fiber Plantago ovata husk is useful in improving levodopa pharmacokinetics in rabbits with autonomic gastrointestinal disorders induced by the administration of the anticholinergic biperiden. Levodopa carbidopa (20:5 mg/kg), biperiden (100 g/ kg), and P. ovata husk (at two different doses: 100 and 400 mg/kg) were administered orally to rabbits for two periods of time (7 or 14 days). In all groups of animals, the AUC values were approximately 50% higher on the final day of treatment than on day 1. Cmax was also higher, with the greater increase at the 400 mg/kg dose of fiber, which resulted in a boost of approximately 35%. On day 1 of treatment and with both doses of fiber, AUC values were very similar to those obtained in previous work in rabbits with normal gastrointestinal motility, but the Cmax was lower. However, after 7 or 14 days, the AUC values were higher, but Cmax remained lower. The greatest differences were observed in plasma concentration before drug administration (Cmin), for which the highest increase was obtained with the dose of 400 mg/kg fiber on day 14 of treatment (349.8%). P. ovata husk could be beneficial in patients with Parkinson’s disease because it regulates stool transit in the intestine and because it improves levodopa pharmacokinetics when gastrointestinal peristalsis is slowed. These changes could lead to a possible delay in the onset of dyskinesias and to changes in prognosis.S