El sistema endocannabinoide y su implicación en la depresión y en los procesos adictivos

Adicción y depresión.En esta conferencia se presentan los últimos trabajos del grupo de investigación en Neurobiología del Comportamiento de la Universidad Pompeu Fabra (Barcelona) dirigido por la Dra. Olga Valverde, sobre la implicación del sistema endocannabinoide en la adicción y la depresión

The pro-neurogenic effects of cannabidiol and its potential therapeutic implications in psychiatric disorders

During the last decades, researchers have investigated the functional relevance of adult hippocampal neurogenesis in normal brain function as well as in the pathogenesis of diverse psychiatric conditions. Although the underlying mechanisms of newborn neuron differentiation and circuit integration have yet to be fully elucidated, considerable evidence suggests that the endocannabinoid system plays a pivotal role throughout the processes of adult neurogenesis. Thus, synthetic, and natural cannabinoid compounds targeting the endocannabinoid system have been utilized to modulate the proliferation and survival of neural progenitor cells and immature neurons. Cannabidiol (CBD), a constituent of the Cannabis Sativa plant, interacts with the endocannabinoid system by inhibiting fatty acid amide hydrolase (FAAH) activity (the rate-limiting enzyme for anandamide hydrolysis), allosterically modulating CB1 and CB2 receptors, and activating components of the "extended endocannabinoid system." Congruently, CBD has shown prominent pro-neurogenic effects, and, unlike Δ9-tetrahydrocannabinol, it has the advantage of being devoid of psychotomimetic effects. Here, we first review pre-clinical studies supporting the facilitating effects of CBD on adult hippocampal neurogenesis and available data disclosing cannabinoid mechanisms by which CBD can induce neural proliferation and differentiation. We then review the respective implications for its neuroprotective, anxiolytic, anti-depressant, and anti-reward actions. In conclusion, accumulating evidence reveals that, in rodents, adult neurogenesis is key to understand the behavioral manifestation of symptomatology related to different mental disorders. Hence, understanding how CBD promotes adult neurogenesis in rodents could shed light upon translational therapeutic strategies aimed to ameliorate psychiatric symptomatology dependent on hippocampal function in humans.This study was supported by the Ministerio de Economia y Competitividad (SAF2016-75966-R-FEDER) and Ministerio de Sanidad (Plan Nacional sobre Drogas: 2018/007). The Department of Experimental and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX2018-000792-M)

The pharmacological reduction of hippocampal neurogenesis attenuates the protective effects of cannabidiol on cocaine voluntary intake

The administration of cannabidiol has shown promising evidence in the treatment of some neuropsychiatric disorders, including cocaine addiction. However, little information is available as to the mechanisms by which cannabidiol reduces drug use and compulsive seeking. We investigated the role of adult hippocampal neurogenesis in reducing cocaine voluntary intake produced by repeated cannabidiol treatment in mice. Cocaine intake was modelled using the intravenous cocaine self-administration procedure in CD1 male mice. Cannabidiol (20 mg/kg) reduced cocaine self-administration behaviour acquisition and total cocaine intake and enhanced adult hippocampal neurogenesis. Our results show that a 6-day repeated temozolomide treatment (25 mg/kg/day), a chemotherapy drug that blocks hippocampal neurogenesis, prevented cannabidiol-induced increment in the early stages of neuronal maturation and differentiation, without altering the basal levels of BrdU/NeuN and doublecortin immunostaining. The reduction of total cocaine intake and operant behaviour acquisition observed following cannabidiol exposure was attenuated by temozolomide treatment. Our results also show a similar effect of temozolamide on a cannabidiol-induced improvement of novel object recognition memory, a task influenced by the proneurogenic effects of cannabidiol (10 and 20 mg/kg). The anxiolytic effects of cannabidiol (10 and 20 mg/kg), however, remained unaffected after its proneurogenic effects decreased. The present study confirms that adult hippocampal neurogenesis is one of the mechanisms by which cannabidiol lowers cocaine reinforcement and demonstrates the functional implication of adult hippocampal neurogenesis in cocaine voluntary consumption in mice. Such findings highlight the possible use of cannabidiol for developing new pharmacotherapies to manage cocaine use disorders.This work was supported by Ministerio de Economía y Competitividad (grant number SAF2016-75966-R-FEDER), by the European Union's Horizon 2020 research andinnovation programme 2014–2020 under grant agreement no 634143. M.A.L. received FPU grant (15/02492) from the Ministeriode Educacion, Cultura y Deporte. L.C.received FPI grant(BES-2014-070657) from the Ministerio de Economía y Competitividad.The Department of Experimental and Health Sciences (UPF) is an“Unidad de Excelencia María de Maeztu” funded by the MINECO (Ref. MDM-2014-0370).The authors thank Gerald-Patrick Fannon for his English proofreading and editing of the manuscript, and Phytoplant Research S.L. for providing CBD compound.The authors declare no conflicts of interest. AUTHORS CONTRIBUTION M.A.L. and O.V. were responsible for the study concept and design.M.A.L .and L.C carried out the experimental studies. M.A.L. and O.V.drafted the manuscript and editing of the manuscript, and Phytoplant Research S.L. for providing CBD compound.The authors declare no conflicts of interest

THC prevents MDMA neurotoxicity in mice

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB1 receptor antagonist AM251 and the CB2 receptor antagonist AM630, as well as in CB1, CB2 and CB1/CB2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB1 receptor antagonist AM251, neither in CB1 and CB1/CB2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB2 cannabinoid antagonist and in CB2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB1 receptor, although CB2 receptors may also contribute to attenuate neuroinflammation in this process

MDMA attenuates THC withdrawal syndrome in mice

3, 4-Methylenedioxymethamphetamine (MDMA) and cannabis are widely abused illicit drugs that are frequently consumed in combination. Interactions between these two drugs have been reported in several pharmacological responses observed in animals, such as body temperature, anxiety, cognition and reward. However, the interaction between MDMA and cannabis in addictive processes such as physical dependence has not been elucidated yet. In this study, the effects of acute and chronic MDMA were evaluated on the behavioral manifestations of Δ9-tetrahydrocannabinol (THC) abstinence in mice. THC withdrawal syndrome was precipitated by injecting the cannabinoid antagonist rimonabant (10 mg/kg, i.p.) in mice chronically treated with THC, and receiving MDMA (2.5, 5 and 10 mg/kg i.p.) or saline just before the withdrawal induction or chronically after the THC administration. Both, chronic and acute MDMA decreased in a dose-dependent manner the severity of THC withdrawal. In vivo microdialysis experiments showed that acute MDMA (5 mg/kg, i.p.) administration increased extracellular serotonin levels in the prefrontal cortex, but not dopamine levels in the nucleus accumbens. Our results also indicate that the attenuation of THC abstinence symptoms was not due to a direct interaction between rimonabant and MDMA nor to the result of the locomotor stimulating effects of MDMA. The modulation of the cannabinoid withdrawal syndrome by acute or chronic MDMA suggests a possible mechanism to explain the associated consumption of these two drugs in humans.This study was supported by grants from Spanish MCYT (SAF 2004/568; BFU 2004/920BFI), Generalitat de Catalunya (2005SGR00131), European Communities (GENADDICT LSHM–CT–2004–005166) and NIH (Extra-mural research project #DA016768). CT has a fellowship supported by the Department of Education and Universities from Generalitat de Catalunya and by the Social European Fund. Ms Dulce Real in this work is kindly acknowledged for her excellent technical assistance in the in vivo microdialysis experiments

CB1 cannabinoid receptor modulates MDMA acute responses and reinforcement

Background: 3, 4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug widely abused by young people. The endocannabinoid system is involved in the addictive processes induced by different drugs of abuse. However, the role of this system in the pharmacological effects of MDMA has not been yet clarified./nMethods: Locomotion, body temperature and anxiogenic-like responses were evaluated after acute MDMA administration in CB1 knockout mice. Additionally, MDMA rewarding properties were investigated in the place conditioning and the intravenous self-administration paradigms. Extracellular levels of DA in the nucleus accumbens were also analyzed after a single administration of MDMA by in vivo microdialysis. Results: Acute MDMA administration increased locomotor activity, body temperature and anxiogenic-like responses in wild type mice, but these responses were lower or abolished in knockout animals. MDMA produced similar conditioned place preference and increased dopamine extracellular levels in the nucleus accumbens in both genotypes. Nevertheless, CB1 knockout mice failed to self-administer MDMA at any of the doses used. Conclusions: These results indicate that CB1 cannabinoid receptors play an important role in the acute prototypical effects of MDMA, and are essential in the acquisition of an operant behavior to self-administer this drug.This study was supported by grants from Spanish MCYT (SAF 2004/568 to OV; BFU2004-00920/BFI and GEN2003-20651-C06-04 to RM), and MSC (Plan Nacional sobre Drogodependencias, conv-2006) to OV, Generalitat de Catalunya (2005SGR00141), European Communities (GENADDICT LSHM–CT–2004–005166) to RM. CT has a fellowship supported by the Department of Education and Universities from Generalitat de Catalunya and by the Social European Fund

Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice

The functional interactions between the endogenous cannabinoid and opioid systems were evaluated in pre-proenkephalin-deficient mice. Antinociception induced in the tail-immersion test by acute Delta9-tetrahydrocannabinol was reduced in mutant mice, whereas no difference between genotypes was observed in the effects induced on body temperature, locomotion, or ring catalepsy. During a chronic treatment with Delta9-tetrahydrocannabinol, the development of tolerance to the analgesic responses induced by this compound was slower in mice lacking enkephalin. In addition, cannabinoid withdrawal syndrome, precipitated in Delta9-tetrahydrocannabinol-dependent mice by the injection of SR141716A, was significantly attenuated in mutant mice. These results indicate that the endogenous enkephalinergic system is involved in the antinociceptive responses of Delta9-tetrahydrocannabinol and participates in the expression of cannabinoid abstinence.This work was supported by European Commission Grant BIOM ED-2/98–2227 and Fondo de Investigaciones Sanitaria Grant 99/0624 (R.M.), Dr. Esteve S.A. Laboratories, and La Fondation des Treilles, and by a grant from the Land Nordrhein-Westfalen (Innovationsprogramm Forschung) (A.Z.)

Reviewing the role of the endocannabinoid system in the pathophysiology of depression

Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.This work was supported by Ministerio de Economía y Competitividad: PID 2019-104077-RB-100/AEI/10.3389/fphar.2021.762738, Ministerio de Sanidad, Asuntos Sociales e Igualdad (Retic-ISCIII-RD/16/0017/0010-FEDER and Plan Nacional Sobre Drogas (#2018/007). AG-B received a FI-AGAUR grant from the Generalitat de Catalunya (2019FI_B0081). The Department of Experimental and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX 2018-000792-M)

Altered brain functional connectivity and behaviour in a mouse model of maternal alcohol binge-drinking

Prenatal and perinatal alcohol exposure caused by maternal alcohol intake during gestation and lactation periods can have long-lasting detrimental effects on the brain development and behaviour of offspring. Children diagnosed with Foetal Alcohol Spectrum Disorders (FASD) display a wide range of cognitive, emotional and motor deficits, together with characteristic morphological abnormalities. Maternal alcohol binge drinking is particularly harmful for foetal and early postnatal brain development, as it involves exposure to high levels of alcohol over short periods of time. However, little is known about the long-term effects of maternal alcohol binge drinking on brain function and behaviour. To address this issue, we used pregnant C57BL/6 female mice with time-limited access to a 20% v/v alcohol solution as a procedure to model alcohol binge drinking during gestation and lactational periods. Male offspring were behaviourally tested during adolescence (30 days) and adulthood (60 days), and baseline neural metabolic capacity of brain regions sensitive to alcohol effects were also evaluated in adult animals from both groups. Our results show that prenatal and postnatal alcohol exposure caused age-dependent changes in spontaneous locomotor activity, increased anxiety-like behaviour and attenuated alcohol-induced conditioned place preference in adults. Also, significant changes in neural metabolic capacity using cytochrome c oxidase (CCO) quantitative histochemistry were found in the hippocampal dentate gyrus, the mammillary bodies, the ventral tegmental area, the lateral habenula and the central lobules of the cerebellum in adult mice with prenatal and postnatal alcohol exposure. In addition, the analysis of interregional CCO activity correlations in alcohol-exposed adult mice showed disrupted functional brain connectivity involving the limbic, brainstem, and cerebellar regions. Finally, increased neurogenesis was found in the dentate gyrus of the hippocampus of alcohol-exposed offspring, suggesting neuroadaptive effects due to early alcohol exposure. Our results demonstrate that maternal binge-like alcohol drinking causes long-lasting effects on motor and emotional-related behaviours associated with impaired neuronal metabolic capacity and altered functional brain connectivity.This study was supported by grants from the EuropeanUnion's Horizon 2020 research and innovation programme 2014-2020under Grant Agreement No 634143, the Spanish Ministry of Economy,Innovation and Competitiveness (SAF2016-75966-R), the SpanishMinistryof Education and Science and Innovation and EuropeanRegional Development Fund (PSI2013-45924-P, PSI2015-73111-EXP, PSI2017-83038-P, PSI2017-83893-R, the Plan Nacional sobre Drogas(#2014/020), and the Plan de Ciencia, Tecnología e Innovación delPrincipado de Asturias (FC-15-GRUPIN14-088). Department ofExperimental and Health Sciences is a“Unidad de Excelencia María deMaeztu”funded by the MINECO (MDM-2014-0370). The authors de-clare no potential conflicts of interest

Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice

The functional interactions between the endogenous cannabinoid and opioid systems were evaluated in pre-proenkephalin-deficient mice. Antinociception induced in the tail-immersion test by acute Delta9-tetrahydrocannabinol was reduced in mutant mice, whereas no difference between genotypes was observed in the effects induced on body temperature, locomotion, or ring catalepsy. During a chronic treatment with Delta9-tetrahydrocannabinol, the development of tolerance to the analgesic responses induced by this compound was slower in mice lacking enkephalin. In addition, cannabinoid withdrawal syndrome, precipitated in Delta9-tetrahydrocannabinol-dependent mice by the injection of SR141716A, was significantly attenuated in mutant mice. These results indicate that the endogenous enkephalinergic system is involved in the antinociceptive responses of Delta9-tetrahydrocannabinol and participates in the expression of cannabinoid abstinence.This work was supported by European Commission Grant BIOM ED-2/98–2227 and Fondo de Investigaciones Sanitaria Grant 99/0624 (R.M.), Dr. Esteve S.A. Laboratories, and La Fondation des Treilles, and by a grant from the Land Nordrhein-Westfalen (Innovationsprogramm Forschung) (A.Z.)