Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia

Štark, Tibor; Rudá-Kučerová, Jana; Iannotti, Fabio Arturo; D’Addario, Claudio; Marco, Roberta Di; Pekařík, Vladimír; Dražanová, Eva; Piscitelli, Fabiana; Bari, Monica; Babinská, Zuzana; Giurdanella, Giovanni; Bartolomeo, Martina Di; Salomone, Salvatore; Šulcová, Alexandra; Maccarrone, Mauro; Wotjak, Carsten T.; Starčuk, Zenon; Drago, Filippo; Mechoulam, Raphael; Marzo, Vincenzo Di; Micale, Vincenzo

doi:10.1016/j.neuropharm.2018.11.035

Cited by 77 publications

(74 citation statements)

References 89 publications

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“…Our findings are similar to a recent study that reported social interaction and recognition memory deficits in male offspring following gestational methylazoxymethanol (MAM) exposure, with concurrent alterations in CB1R protein and mRNA expression (albeit increases) in the PFC, but not the HPC of male offspring (Stark et al, 2019). It is unknown how CBD rescues changes in CB1R expression in neurodevelopmental models.…”

Section: Discussionsupporting

confidence: 89%

“…Similarly, in other neurodevelopmental rodent models of schizophrenia, studies report alterations in CB1R protein and mRNA expression in the PFC following gestational methylazoxymethanol (MAM) administration (Stark et al, 2019;Gomes et al, 2018), with no change in CB1R binding, protein or mRNA expression in the HPC of male lipopolysaccharide-or MAM-exposed (in utero) offspring (Stark et al, 2019;Gomes et al, 2018;Zavitsanou et al, 2013). However, this is the first study to report a corresponding reduction in CB1R binding density in the PFC, a region critical to memory and social behaviour, in male poly I:C offspring that also exhibit negative and cognitive phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia

Osborne¹,

Solowij

Babic³

et al. 2019

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Timemated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for postmortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:Cinduced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect Nmethyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid, anandamide. Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure. These findings provide novel evidence for the potential mechanisms underlying the therapeutic effects of CBD treatment in the poly I:C model.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia

Osborne¹,

Solowij

Babic³

et al. 2019

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…i) anxiety, PTSD, and depression in: a) animal models, in a manner attenuated by either 5-HT 1a or CB 1 /CB 2 receptor antagonists depending on the model and the potential role therein of chronic pain and stress, substance abuse, defective neurogenesis, and neuroinflammation [65][66][67] ; and b) humans, particularly in patients with neurological or other neuropsychiatric conditions that are accompanied by anxiety. 68,69 The capability of CBD to activate TRPV1 might somehow reduce its efficacy against anxiety and possibly explain why bell-shaped dose-response curves are often observed in preclinical studies 70 ; ii) schizophrenia, where the effects in animal models have been suggested to be due to reversal of overexpression of CB 1 receptors, 71 activation of 5-HT 1A receptors, 65 or activation/desensitization of TRPV1 channels 72 ; whereas the beneficial effect of CBD per se in a clinical trial carried out with a 800 mg/day dose of the compound was found to be accompanied by elevation of anandamide (and NAE) levels (in a manner that, for anandamide, correlated with positive and negative symptom amelioration), 73 in agreement with CBD weak inhibitory action on FAAH and the putative EMT. A subsequent clinical study, carried out with CBD (1 g/day) as an adjunct therapy, also showed beneficial effects on positive and cognitive symptoms.…”

Section: The Ecbome Mediates In Part the Therapeutic Effects Of Phytomentioning

confidence: 99%

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

Marzo

2020

Dialogues in Clinical Neuroscience

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The endocannabinoid (eCB) system encompasses the eCBs anandamide and 2-arachidonoylglycerol, their anabolic/catabolic enzymes, and the cannabinoid CB1 and CB2 receptors. Its expansion to include several eCB-like lipid mediators, their metabolic enzymes, and their molecular targets, forms the endocannabinoidome (eCBome). This complex signaling system is deeply involved in the onset, progress, and symptoms of major neuropsychiatric disorders and provides a substrate for future therapeutic drugs against these diseases. Such drugs may include not only THC, the major psychotropic component of cannabis, but also other, noneuphoric plant cannabinoids. These compounds, unlike THC, possess a wide therapeutic window, possibly due to their capability of hitting several eCBome and non-eCBome receptors. This is particularly true for cannabidiol, which is one of the most studied cannabinoids and shows promise for the treatment of a wide range of mental and mood disorders. The eCBome plays a role also in the microbiota-gut-brain axis, which is emerging as an important actor in the control of affective and cognitive functions and in their pathological alterations.

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“…Des études sont en cours pour étudier plus précisément les effets du CBD. Certains travaux réalisés chez des modèles animaux pour la schizophrénie [52,53] ou exposés au THC [54,55] ont montré que l'injection de CBD pendant l'adolescence peut prévenir l'apparition de certaines anomalies neurobiologiques et comportementales à court ou long terme telles que l'hyperactivité locomotrice, la baisse des performances mnésiques, la réduction des interactions sociales ou l'augmentation de l'anxiété des animaux. Cependant, ces résultats n'ont pas toujours été répliqués et il convient de rester prudent car certaines études ont mis en évidence des conséquences délétères telles qu'une aggravation des anomalies dans le groupe modèle, voire la diminution des interactions sociales dans le groupe contrôle exposé au CBD [55,56]…”

Section: Complications Psychiatriquesunclassified

Cannabis et neurodéveloppement

Krebs¹,

Demars²,

Frajerman³

et al. 2020

Bulletin de l'Académie Nationale de Médecine

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Le développement cérébral est un phénomène complexe, qui s'étend de la vie foetale à l'adolescence, pendant laquelle la maturation cérébrale suit une série d'événements ordonnés incluant des périodes critiques de plasticité. Le cerveau est particulièrement sensible à l'environnement pendant ces remaniements. Le système endocannabinoïde participe directement et indirectement à ces processus de plasticité et de maturation. Le delta-9tetrahydrocanabinol, principal composant psychoactif du cannabis, diffuse dans le placenta, le lait maternel et le cerveau. Il interagit avec le système endocannabinoïde, notamment par l'activation des récepteurs aux cannabinoïdes 1 CB1R, ce qui peut entraîner des altérations du neurodéveloppement et du fonctionnement des circuits neuronaux. Par conséquent, l'exposition au cannabis in utero, en période périnatale ainsi qu'à l'adolescence est susceptible d'entraîner des perturbations de la maturation cérébrale dont les conséquences, sur le plan cognitif, psychotique et addictif, persistent bien au-delà de la période d'exposition. Plusieurs facteurs modulent le risque de telles complications mais les études réalisées sur des modèles animaux ainsi que chez l'homme ont montré qu'une exposition durant les phases critiques, en particulier durant la phase de développement périnatal et à l'adolescence, constitue en soi un facteur de risque. Les données actuelles incitent à diffuser une information objective aux jeunes, pour prévenir et limiter les consommations précoces. © 2020 Publié par Elsevier Masson SAS au nom de l'Académie nationale de médecine. ଝ Étant donné le contexte sanitaire épidémique lié au Covid-19 du mois de mars 2020, la présentation orale de cette communication en séance à l'Académie a été reportée.Summary. -Brain development is a complex phenomenon, stretching from fetal life to adolescence, during which brain maturation proceeds through a series of ordered events including critical periods of plasticity. The brain is particularly sensitive to the environment during these changes. The endocannabinoid system participates directly and indirectly in these plasticity and maturation processes. The main psychoactive component of cannabis, the delta-9-tetrahydrocanabinol, can cross the placental barrier, is present in breastmilk and diffuses in the brain. It interacts with the endocannabinoid signaling, especially through the activation of cannabinoid receptors 1 CB1R, which can lead to abnormal neurodevelopmental processes and neuronal circuits functions. Therefore, exposure to cannabis in utero, in perinatal phase, as well as during the adolescence disrupts the brain maturation and can cause disturbances on the cognitive, psychotic and addictive levels that persist far beyond the period of exposure. Several factors modulate the risk of such complications, but studies performed in animal models as well as in human cohorts have shown that exposure during both the critical perinatal and adolescence phases is a risk factor per se. Current knowledge encourages the dissemination of obje...

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Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia

Cited by 77 publications

References 89 publications

Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia

Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

Cannabis et neurodéveloppement

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