Targeting the endocannabinoid system for therapeutic purposes

The endocannabinoid system is an endogenous neuromodulatory system that regulates a plethora of physiological functions, including the modulation of memory, anxiety, pain, synaptic plasticity and neuronal excitability, among others. The activation of this system through exogenous or endogenous cannabinoid agonists has been proposed as a therapeutic strategy in different pathological states, although an important caveat to their use is the possible central adverse effects, such as memory impairment, anxiety and tolerance. The activity of the endocannabinoid system has been recently found involved in the pathophysiological conditions leading to obesity and fragile X syndrome, and the blockade of this system has also been investigated as a possible therapeutic approach. This thesis mainly focuses on the behavioral, paying more attention on the cognitive effects, cellular and molecular effects of exogenous and endogenous cannabinoids in order to identify potential therapeutic effects minimizing the negative consequences associated to the cannabinoid activation. This experimental research has been centered on the modulation of the positive and negative effects of Δ9-tetrahydrocannabinol, the main psychoactive component of the Cannabis sativa plant, the possibility to enhance the endogenous tone of specific endocannabinoids to improve certain therapeutic applications of cannabinoids, and the effects of inhibiting the endocannabinoid system in the amelioration of different traits associated to fragile X syndrome. The combination of behavioral, cellular and molecular approaches allowed the elucidation of different important aspects of the endocannabinoid system as an interesting therapeutic target.El sistema endocannabinoid és un sistema neuromodulador endogen que regula diferents funcions fisiològiques com la memòria, l’ansietat, el dolor i l’excitabilitat neuronal entre altres. L’activació d’aquest sistema per agonistes exògens o endògens ha estat usada com a estratègica terapèutica en diferents estats patològics tot i que els efectes adversos, com la pèrdua de memòria, l’ansietat o la tolerància, són el principal problema pel seu ús. El sistema endocannabinoid també s’ha trobat alterat en malalties com la obesitat o la síndrome del cromosoma X fràgil i, per tant, el bloqueig d’aquest sistema també s’ha emprat com a aproximació terapèutica. Aquesta tesis es centra en els efectes comportamentals i moleculars de l’administració exògena del Δ9-Tetrahydrocannabinol, el component principal de la planta Cannabis sativa, i en la modulació endògena del sitema endocannabinoid per tal de potenciar els efectes terapèutics minimitzant els efectes adversos dels cannabinoids. A més, en aquesta tesis també hem estudiat els posibles efectes terapèutics del bloqueig dels receptors cannabinoides en la síndrome del cromosoma X fràgil. La combinació d’aproximacions moleculars, farmacològiques, electrofisiològiques i comportamentals han permès el descobriment de diferents aspectes importants que permeten demostrar que el sistema endocannabinoid és una diana terapèutica molt interessant

Bio Protoc

The novel object recognition (NOR) task is a behavioral test commonly used to evaluate episodic-like declarative memory and it relies on the innate tendency of rodents to explore novelty. Here we present a maze used to evaluate NOR memory in mice that reduces the time of the assay while improving reliability of the measurements by increasing the exploratory behavior. This memory test, being performed in a two-arms maze, is suitable for several strains of mice (including inbreed and outbreed) and does not require extended training sessions allowing an accurate temporal assessment of memory formation. This particular maze increases the mouse exploration time and reduces variability compared to other arenas used before to assess NOR. As both long- and short-term NOR memory can be easily and accurately quantified using this paradigm, this improved methodology can be easily applied to study pharmacological, genetic or age-related modulation of cognitive function. Copyright © 2020 The Authors; exclusive licensee Bio-protocol LLC.Initiative d'excellence de l'Université de Bordeau

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Jardins per a la salut

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia. Assignatura: Botànica farmacèutica. Curs: 2014-2015. Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són el recull de les fitxes botàniques de 128 espècies presents en el Jardí Ferran Soldevila de l’Edifici Històric de la UB. Els treballs han estat realitzats manera individual per part dels estudiants dels grups M-3 i T-1 de l’assignatura Botànica Farmacèutica durant els mesos de febrer a maig del curs 2014-15 com a resultat final del Projecte d’Innovació Docent «Jardins per a la salut: aprenentatge servei a Botànica farmacèutica» (codi 2014PID-UB/054). Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pels professors de l’assignatura. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica. També s’ha pretès motivar els estudiants a través del retorn de part del seu esforç a la societat a través d’una experiència d’Aprenentatge-Servei, deixant disponible finalment el treball dels estudiants per a poder ser consultable a través d’una Web pública amb la possibilitat de poder-ho fer in-situ en el propi jardí mitjançant codis QR amb un smartphone

Nat Metab

The endocannabinoid system is considered one of the most important modulatory networks in the whole organism. Research has yielded great insight on the mechanisms that link endocannabinoids and several peripheral and brain metabolic functions. Here, we provide a brief overview of the metabolic roles of endocannabinoids in tissue-, cellular- and subcellular-dependent mechanisms. We highlight past discoveries and future open questions with a special focus on CB1 receptor-dependent astroglial and mitochondrial metabolic processes.Dissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes.Représentation sensorielle lors d'états psychotiquesBordeaux Region Aquitaine Initiative for NeuroscienceNeurocircuitry of endocannabinoid regulation of food intakeDevelopment of pregnenolone derivatives as allosteric inhibitors of CB1 cannabinoid receptors for thetreatment of schizophrenia and psychotic syndrome

Special issue editorial: Cannabinoid signalling in the brain: New vistas

International audienceThe endocannabinoid system is widely expressed both in the brain and in the periphery. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in their metabolic processes. In the last few years, the development of new imaging and molecular tools has demonstrated that these receptors are distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular or molecular effects are differentially mediated by cannabinoid receptors according to their specific localization in different cell-types or in different subcellular locations. Moreover, the endocannabinoid system is also expressed throughout the body where it can serve to modulate the connection between the brain and the periphery. Finally, better understanding of the cannabinoid receptors structure and pharmacology has led researchers to propose interesting and new allosteric modulators of synaptic communication. The latest advances and innovative research in the cannabinoid field will provide new insights and better approaches to improve its interesting potential therapeutic profile. This special issue intends to bring together a series of empirical papers, targeted reviews and opinions from leaders in the field that will highlight the new advances in cannabinoid research

Neural substrates of incidental associations and mediated learning: the role of Cannabinoid receptors

International audienceThe ability to form associations between different stimuli in the environment to guide adaptive behavior is a central element of learning processes, from perceptual learning in humans to Pavlovian conditioning in animals. Like so, classical conditioning paradigms that test direct associations between low salience sensory stimuli and high salience motivational reinforcers are extremely informative. However, a large part of everyday learning cannot be solely explained by direct conditioning mechanisms – this includes to a great extent associations between individual sensory stimuli, carrying low or null immediate motivational value. This type of associative learning is often described as incidental learning and can be captured in animal models through sensory preconditioning procedures. Here we summarize the evolution of research on incidental and mediated learning, overview the brain systems involved and describe evidence for the role of cannabinoid receptors in such higher-order learning tasks. This evidence favors a number of contemporary hypotheses concerning the participation of the endocannabinoid system in psychosis and psychotic experiences and provides a conceptual framework for understanding how the use of cannabinoid drugs can lead to altered perceptive states

Representation-mediated aversion as a model to study psychotic-like states in mice

Several paradigms for rodent models of the cognitive and negative endophenotypes found in schizophrenic patients have been proposed. However, significant efforts are needed in order to study the pathophysiology of schizophrenia-related positive symptoms. Recently, it has been shown that these positive symptoms can be studied in rats by using representation-mediated learning. This learning measure the accuracy of mental representations of reality, also called 'reality testing'. Alterations in 'reality testing' performance can be an indication of an impairment in perception which is a clear hallmark of positive psychotic-like states. Thus, we describe here a mouse task adapted from previous findings based on a sensory preconditioning task. With this task, associations made between different neutral stimuli (e.g., an odor and a taste) and subsequent selective devaluation of one of these stimuli have allowed us to study mental sensory representations. Thus, the interest of this task is that it can be used to model positive psychotic-like states in mice, as recently described