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Special Issue "Cannabinoid Signaling in Nervous System"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular and Cellular Biology".

Deadline for manuscript submissions: closed (30 September 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Daniela Parolaro

Department of Biotechnology and Life Sciences, and Neuroscience Center, University of Insubria, Busto Arsizi, Italy
Website | E-Mail
Interests: endocannabinoisd system; adolescence; psychiatric disorders; autism
Guest Editor
Prof. Dr. Tiziana Rubino

Department of Biotechnology and Life Sciences, and Neuroscience Center, University of Insubria, Busto Arsizi, Italy
Website | E-Mail
Interests: endocannabinoisd system; adolescence; psychiatric disorders; epigenetics

Special Issue Information

Dear Colleagues,

The discovery in 1990 that the effects of delta-9 tetrahydrocannabinol (THC), the main psychoactive component present in Cannabis sativa, were mediated by its interaction with a specific receptor, represented the starting point for the characterization of what is now called the endocannabinoid system (ECS).

The initial picture showed that the ECS comprised two main receptors, CB1 and CB2, the endocannabinoids (the best known are anandamide and 2-arachidonoylglycerol) as well as the enzymes responsible for their synthesis and degradation. In the last few years, additional receptors and enzymes have been discovered, adding complexity to the system. In the meantime, growing evidence indicates that dysregulation of the ECS plays a key role in several pathologies of the nervous system, thus opening the way to the possibility of targeting ECS for therapeutic purposes.

Therefore, this Special Issue will provide an updated knowledge of both the physiology of the ECS signaling and its involvement in the neurobiology of several disorders of the nervous system.

Prof. Dr. Daniela Parolaro
Prof. Dr. Tiziana Rubino
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

 

Keywords

  • cannabinoid receptors
  • endocannabinoids
  • CNS development
  • epigenetics
  • emotionality
  • autism spectrum disorder
  • neurodegenerative diseases
  • psychosis
  • addiction
  • sex differences

Published Papers (10 papers)

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Research

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Open AccessArticle Chronic Δ9-THC Exposure Differently Affects Histone Modifications in the Adolescent and Adult Rat Brain
Int. J. Mol. Sci. 2017, 18(10), 2094; doi:10.3390/ijms18102094
Received: 20 July 2017 / Revised: 29 September 2017 / Accepted: 30 September 2017 / Published: 4 October 2017
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Abstract
Adolescence represents a vulnerable period for the psychiatric consequences of delta9-tetrahydrocannabinol (Δ9-THC) exposure, however, the molecular underpinnings of this vulnerability remain to be established. Histone modifications are emerging as important epigenetic mechanisms involved in the etiopathogenesis of psychiatric diseases, thus, we
[...] Read more.
Adolescence represents a vulnerable period for the psychiatric consequences of delta9-tetrahydrocannabinol (Δ9-THC) exposure, however, the molecular underpinnings of this vulnerability remain to be established. Histone modifications are emerging as important epigenetic mechanisms involved in the etiopathogenesis of psychiatric diseases, thus, we investigated the impact of chronic Δ9-THC exposure on histone modifications in different brain areas of female rats. We checked histone modifications associated to both transcriptional repression (H3K9 di- and tri-methylation, H3K27 tri-methylation) and activation (H3K9 and H3K14 acetylation) after adolescent and adult chronic Δ9-THC exposure in the hippocampus, nucleus accumbens, and amygdala. Chronic exposure to increasing doses of Δ9-THC for 11 days affected histone modifications in a region- and age-specific manner. The primary effect in the adolescent brain was represented by changes leading to transcriptional repression, whereas the one observed after adult treatment led to transcriptional activation. Moreover, only in the adolescent brain, the primary effect was followed by a homeostatic response to counterbalance the Δ9-THC-induced repressive effect, except in the amygdala. The presence of a more complex response in the adolescent brain may be part of the mechanisms that make the adolescent brain vulnerable to Δ9-THC adverse effects. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Open AccessArticle Cannabinoid Receptor 1 and Fatty Acid Amide Hydrolase Contribute to Operant Sensation Seeking in Mice
Int. J. Mol. Sci. 2017, 18(8), 1635; doi:10.3390/ijms18081635
Received: 19 June 2017 / Revised: 21 July 2017 / Accepted: 25 July 2017 / Published: 27 July 2017
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Abstract
A large body of evidence in humans and preclinical models supports a role for the endocannabinoid system in the proper execution of motivated or goal-directed behaviors. Operant sensation seeking (OSS) is a task that uses varied sensory stimuli as a reinforcer to maintain
[...] Read more.
A large body of evidence in humans and preclinical models supports a role for the endocannabinoid system in the proper execution of motivated or goal-directed behaviors. Operant sensation seeking (OSS) is a task that uses varied sensory stimuli as a reinforcer to maintain operant responding in mice. The purpose of the studies in this report was to begin to explore the role of endocannabinoid signaling in OSS utilizing cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) knock out mice. Compared to wild type littermate controls, CB1R knock out mice exhibited significantly fewer active responses and earned significantly fewer reinforcers in fixed ratio and progressive ratio schedules. On the other hand, FAAH knock out mice exhibited increased active responses and earned more reinforcers than wild type littermates in fixed ratio but not progressive ratio schedules. These findings support the role of endocannabinoid signaling in motivated behaviors and also expand our understanding of the signaling processes involved in OSS. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Open AccessArticle Adolescent Exposure to the Synthetic Cannabinoid WIN 55212-2 Modifies Cocaine Withdrawal Symptoms in Adult Mice
Int. J. Mol. Sci. 2017, 18(6), 1326; doi:10.3390/ijms18061326
Received: 21 April 2017 / Revised: 6 June 2017 / Accepted: 16 June 2017 / Published: 21 June 2017
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Abstract
Chronic cannabinoid consumption is an increasingly common behavior among teenagers and has been shown to cause long-lasting neurobehavioral alterations. Besides, it has been demonstrated that cocaine addiction in adulthood is highly correlated with cannabis abuse during adolescence. Cocaine consumption and subsequent abstinence from
[...] Read more.
Chronic cannabinoid consumption is an increasingly common behavior among teenagers and has been shown to cause long-lasting neurobehavioral alterations. Besides, it has been demonstrated that cocaine addiction in adulthood is highly correlated with cannabis abuse during adolescence. Cocaine consumption and subsequent abstinence from it can cause psychiatric symptoms, such as psychosis, cognitive impairment, anxiety, and depression. The aim of the present research was to study the consequences of adolescent exposure to cannabis on the psychiatric-like effects promoted by cocaine withdrawal in adult mice. We pre-treated juvenile mice with the cannabinoid CB1 receptor agonist WIN 55212-2 (WIN) and then subjected them to a chronic cocaine treatment during adulthood. Following these treatments, animals were tested under cocaine withdrawal in the following paradigms: pre-pulse inhibition, object recognition, elevated plus maze, and tail suspension. The long-term psychotic-like actions induced by WIN were not modified after cocaine cessation. Moreover, the memory impairments induced by cocaine withdrawal were not altered by previous adolescent WIN intake. However, WIN pre-treatment prevented the anxiogenic effects observed after cocaine abstinence, and led to greater depressive-like symptoms following cocaine removal in adulthood. This study is the first to show the long-lasting behavioral consequences of juvenile exposure to WIN on cocaine withdrawal in adult mice. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Open AccessArticle A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy
Int. J. Mol. Sci. 2017, 18(5), 900; doi:10.3390/ijms18050900
Received: 19 February 2017 / Revised: 12 April 2017 / Accepted: 19 April 2017 / Published: 25 April 2017
Cited by 1 | PDF Full-text (3664 KB) | HTML Full-text | XML Full-text
Abstract
Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side
[...] Read more.
Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side effects, and impact on the formation of new neurons. The aim of the study was to conduct an in vivo evaluation of the relationship between treatments with synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone or in combination with valproic acid (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All studies were performed on adolescent male CB57/BL mice with using the following drugs: VPA (10 mg/kg), ACEA (10 mg/kg), phenylmethylsulfonyl fluoride (PMSF—a substance protecting ACEA against degradation by fatty acid hydrolase, 30 mg/kg), pilocarpine (PILO, a single dose of 290 mg/kg) and methylscopolamine (30 min before PILO to stop peripheral cholinergic effects of pilocarpine, 1 mg/kg). We evaluated the process of neurogenesis after a 10-day treatment with ACEA and VPA, alone and in combination. We observed a decrease of neurogenesis in the PILO control group as compared to the healthy control mice. Furthermore, ACEA + PMSF alone and in combination with VPA significantly increased neurogenesis compared to the PILO control group. In contrast, VPA 10-day treatment had no impact on the level of neurons in comparison to the PILO control group. The combination of ACEA, PMSF and VPA considerably stimulated the process of creating new cells, particularly neurons, while chronic administration of VPA itself had no influence on neurogenesis in the mouse pilocarpine model of epilepsy. The obtained results enabled an in vivo evaluation of neurogenesis after treatment with antiepileptic drugs in an experimental model of epilepsy. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Open AccessArticle Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington’s Disease
Int. J. Mol. Sci. 2017, 18(4), 684; doi:10.3390/ijms18040684
Received: 22 February 2017 / Revised: 15 March 2017 / Accepted: 17 March 2017 / Published: 23 March 2017
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Abstract
Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆9-tetrahydrocannabinol (∆9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®
[...] Read more.
Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆9-tetrahydrocannabinol (∆9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®, is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆9-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H+-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/N-acetylaspartate, and N-acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6/2 mice at the onset of motor symptoms produced certain benefits on the progression of striatal deterioration in these mice, which supports the interest of this cannabinoid-based medicine for the treatment of disease progression in HD patients. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Review

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Open AccessReview The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models
Int. J. Mol. Sci. 2017, 18(9), 1916; doi:10.3390/ijms18091916
Received: 24 July 2017 / Revised: 22 August 2017 / Accepted: 4 September 2017 / Published: 7 September 2017
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Abstract
Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of
[...] Read more.
Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact to the society, no effective treatment for ASD is yet available, possibly because its neurobiological basis is not clearly understood hence specific drugs have not yet been developed. The endocannabinoid (EC) system represents a major neuromodulatory system involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. Furthermore, the EC system is also affected in conditions often present in subsets of patients diagnosed with ASD, such as seizures, anxiety, intellectual disabilities, and sleep pattern disturbances. Despite the indirect evidence suggestive of an involvement of the EC system in ASD, only a few studies have specifically addressed the role of the EC system in the context of ASD. This review describes the available data on the investigation of the presence of alterations of the EC system as well as the effects of its pharmacological manipulations in animal models of ASD-like behaviors. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Open AccessReview Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid
Int. J. Mol. Sci. 2017, 18(8), 1669; doi:10.3390/ijms18081669
Received: 10 July 2017 / Revised: 26 July 2017 / Accepted: 26 July 2017 / Published: 31 July 2017
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Abstract
The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising
[...] Read more.
The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies. The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Open AccessReview Interactions between the Kynurenine and the Endocannabinoid System with Special Emphasis on Migraine
Int. J. Mol. Sci. 2017, 18(8), 1617; doi:10.3390/ijms18081617
Received: 30 June 2017 / Revised: 18 July 2017 / Accepted: 21 July 2017 / Published: 30 July 2017
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Abstract
Both the kynurenine and the endocannabinoid systems are involved in several neurological disorders, such as migraine and there are increasing number of reports demonstrating that there are interactions of two systems. Although their cooperation has not yet been implicated in migraine, there are
[...] Read more.
Both the kynurenine and the endocannabinoid systems are involved in several neurological disorders, such as migraine and there are increasing number of reports demonstrating that there are interactions of two systems. Although their cooperation has not yet been implicated in migraine, there are reports suggesting this possibility. Additionally, the individual role of the endocannabinoid and kynurenine system in migraine is reviewed here first, focusing on endocannabinoids, kynurenine metabolites, in particular kynurenic acid. Finally, the function of NMDA and cannabinoid receptors in the trigeminal system—which has a crucial role in the pathomechanisms of migraine—will also be discussed. The interaction of the endocannabinoid and kynurenine system has been demonstrated to be therapeutically relevant in a number of pathological conditions, such as cannabis addiction, psychosis, schizophrenia and epilepsy. Accordingly, the cross-talk of these two systems may imply potential mechanisms related to migraine, and may offer new approaches to manage the treatment of this neurological disorder. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Open AccessReview Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations
Int. J. Mol. Sci. 2017, 18(7), 1425; doi:10.3390/ijms18071425
Received: 19 May 2017 / Revised: 23 June 2017 / Accepted: 23 June 2017 / Published: 3 July 2017
PDF Full-text (555 KB) | HTML Full-text | XML Full-text
Abstract
Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2)
[...] Read more.
Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. In addition to autism, the EC system is also involved in several other psychiatric disorders (i.e., anxiety, major depression, bipolar disorder and schizophrenia). This system is a key regulator of metabolic and cellular pathways involved in autism, such as food intake, energy metabolism and immune system control. Early studies in autism animal models have demonstrated alterations in the brain’s EC system. Autism is also characterized by immune system dysregulation. This alteration includes differential monocyte and macrophage responses, and abnormal cytokine and T cell levels. EC system dysfunction in a monocyte and macrophagic cellular model of autism has been demonstrated by showing that the mRNA and protein for CB2 receptor and EC enzymes were significantly dysregulated, further indicating the involvement of the EC system in autism-associated immunological disruptions. Taken together, these new findings offer a novel perspective in autism research and indicate that the EC system could represent a novel target option for autism pharmacotherapy. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Other

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Open AccessCase Report Speechlessness in Gilles de la Tourette Syndrome: Cannabis-Based Medicines Improve Severe Vocal Blocking Tics in Two Patients
Int. J. Mol. Sci. 2017, 18(8), 1739; doi:10.3390/ijms18081739
Received: 25 May 2017 / Revised: 24 June 2017 / Accepted: 3 August 2017 / Published: 10 August 2017
PDF Full-text (180 KB) | HTML Full-text | XML Full-text
Abstract
We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1
[...] Read more.
We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1 × 0.1 g cannabis daily. Case 2: a 16-year old patient initially received dronabinol at a maximum dose of 22.4–33.6 mg daily. Both treatments provided significant symptom improvement of vocal blocking tics as well as of comorbid conditions and were well tolerated. Thus, cannabis-based medicine appears to be effective in treatment-resistant TS patients with vocal blocking tics. Full article
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)

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