Molecular mechanisms underlying the effects of cannabinoids in the brain

The endocannabinoid system is an endogenous neuromodulatory system that regulates a plethora of physiological functions, including the control of movement, memory, anxiety, and pain, among others. Cannabinoid compounds are mainly found in the Cannabis sativa plant and exert their effects by acting at the endocannabinoid system. Cannabinoids are potential therapeutic agents, mainly for multiple sclerosis, pain, and emesis, although an important caveat to their use is the possible adverse effects, such as memory impairment and anxiety. This thesis mainly addresses the molecular mechanisms underlying some of the physiological processes controlled by the endocannabinoid system as well as specific pharmacological effects triggered by 9-tetrahydrocannabinol, the main psychoactive compound of marijuana plant. The combination of biochemical, pharmacological, and behavioral approaches allowed the elucidation of certain signaling cascades responsible for particular effects induced by cannabinoids.El sistema endocannabinoid és un sistema neuromodulador endogen que regula diverses funcions fisiològiques, incloent el control del moviment, la memòria, l’ansietat i el dolor, entre altres. Els compostos cannabinoids es troben principalment a la planta Cannabis sativa i exerceixen els seus efectes actuant al sistema endocannabinoid. Els cannabinoids tenen potencial terapèutic, principalment per l’esclerosi múltiple, el dolor i l’èmesi, tot i que una limitació important pel seu ús recau en els possibles efectes adversos, tal com l’alteració de la memòria i l’ansietat. Aquesta tesi exposa principalment els mecanismes moleculars responsables d’alguns processos fisiològics controlats pel sistema endocannabinoid així com efectes farmacològics desencadenats pel 9-tetrahidrocannabinol, el principal compost psicoactiu de la planta de marihuana. La combinació d’aproximacions bioquímiques, farmacològiques i comportamentals ha permès revelar algunes cascades de senyalització responsables de determinats efectes induïts pels cannabinoids

Ribosomal Protein S6 Phosphorylation in the Nervous System: From Regulation to Function

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Organisation spatio-moléculaire des neurones D2R du striatum dévoilée par le séquençage d’ARN à haut débit

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Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

As central nervous system (CNS)-related disorders present an increasing cause of global morbidity, mortality, and high pressure on our healthcare system, there is an urgent need for new insights and treatment options. The endocannabinoid system (ECS) is a critical network of endogenous compounds, receptors, and enzymes that contribute to CNS development and regulation. Given its multifaceted involvement in neurobiology and its significance in various CNS disorders, the ECS as a whole is considered a promising therapeutic target. Despite significant advances in our understanding of the ECS's role in the CNS, its complex architecture and extensive crosstalk with other biological systems present challenges for research and clinical advancements. To bridge these knowledge gaps and unlock the full therapeutic potential of ECS interventions in CNS-related disorders, a plethora of molecular-genetic tools have been developed in recent years. Here, we review some of the most impactful tools for investigating the neurological aspects of the ECS. We first provide a brief introduction to the ECS components, including cannabinoid receptors, endocannabinoids, and metabolic enzymes, emphasizing their complexity. This is followed by an exploration of cutting-edge imaging tools and genetic models aimed at elucidating the roles of these principal ECS components. Special emphasis is placed on their relevance in the context of CNS and its associated disorders

Mammalian Target of Rapamycin-RhoA Signaling Impairments in Direct Striatal Projection Neurons Induce Altered Behaviors and Striatal Physiology in Mice

Background: As an integrator of molecular pathways, mTOR (mammalian target of rapamycin) has been associated with diseases including neurodevelopmental, psychiatric, and neurodegenerative disorders such as autism spectrum disorder, schizophrenia, and Huntington's disease. An important brain area involved in all these diseases is the striatum. However, the mechanisms behind how mTOR is involved in striatal physiology and its relative role in distinct neuronal populations in these striatal-related diseases still remain to be clarified. Methods: Using Drd1-Cre mTOR-conditional knockout male mice, we combined behavioral, biochemical, electrophysiological, and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons and how this would impact on striatal physiology. Results: Our results indicate deep behavioral changes in absence of mTOR in Drd1-expressing neurons such as decreased spontaneous locomotion, impaired social interaction, and decreased marble-burying behavior. These alterations were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and coincident decreased distal spine density in striatal direct pathway striatal projection neurons. The physiological changes were mechanistically independent of protein synthesis but sensitive to pharmacological blockade of transforming protein RhoA activity. Conclusions: These results identify mTOR signaling as an important regulator of striatal functions through an intricate mechanism involving RhoA and culminating in Kv1.1 overfunction, which could be targeted to treat striatal-related monogenic disorders associated with the mTOR signaling pathway.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system.EP is a recipient of an EMBO Fellowship with the support of European Commission (EMBOCOFUND2010, GA-2010-267146) and Marie Curie Actions. AB-G is a recipient of a predoctoral fellowship, Spanish Ministry of Education and Culture. This study was supported by grants from La Marató de TV3 (#090910 to AO), Grants from the Spanish Ministry of Science and Innovation (#SAF2009-07309 to AO and/n#SAF2011-29864 to RM); Instituto de Salud Carlos III (RD06/0001/0001 to RM); PLAN E (Plan Español para el Estímulo de la Economía y el Empleo); Generalitat de Catalunya (SGR-2009-00731 to RM and SGR-2009-00718 to RdlT); ICREA (Institució Catalana de Recerca i Estudis Avançats) Academia to R

Hypothalamic dopamine signaling regulates brown fat thermogenesis

Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance

Anatomical and molecular characterization of dopamine D1 receptor-expressing neurons of the mouse CA1 dorsal hippocampus

International audienceIn the hippocampus, a functional role of dopa-mine D1 receptors (D1R) in synaptic plasticity and memory processes has been suggested by electrophysiological and pharmacological studies. However, comprehension of their function remains elusive due to the lack of knowledge on the precise localization of D1R expression among the diversity of interneuron populations. Using BAC trans-genic mice expressing enhanced green fluorescent protein under the control of D1R promoter, we examined the molecular identity of D1R-containing neurons within the CA1 subfield of the dorsal hippocampus. In agreement with previous findings, our analysis revealed that these neurons are essentially GABAergic interneurons, which express several neurochemical markers, including calcium-binding proteins, neuropeptides, and receptors among others. Finally, by using different tools comprising cell type-specific isolation of mRNAs bound to tagged-ribosomes, we provide solid data indicating that D1R is present in a large proportion of interneurons expressing dopamine D2 receptors. Altogether, our study indicates that D1Rs are expressed by different classes of interneurons in all layers examined and not by pyramidal cells, suggesting that CA1 D1R mostly acts via modulation of GABAergic interneurons