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Monory K, de Azua IR, Lutz B. Genetic Tools in Rodents to Study Cannabinoid Functions. Curr Top Behav Neurosci 2024. [PMID: 39680319 DOI: 10.1007/7854_2024_550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
During the past 30 years, the endocannabinoid system (ECS) has emerged as a major signalling system in the mammalian brain regulating neurotransmission in numerous brain regions and in various cell populations. Endocannabinoids are able to regulate specific physiological functions and thus modify their behavioural manifestations and allostatic alterations of the ECS linked to different pathological conditions. As discussed in detail in other chapters of this book, endocannabinoids are involved in learning and memory, stress, and anxiety, feeding, energy balance, development, and ageing. Likewise, many CNS disorders (e.g. schizophrenia, epilepsy, substance use disorders, and multiple sclerosis) are associated with dysregulation of the ECS. Discerning the physiological functions of the synthetic and degrading enzymes of endocannabinoids and their receptors is a challenging task because of their distinct and complex expression patterns. Techniques of genetic engineering have been able to shed light on a number of complex ECS-related tasks during the past years. In this chapter, first, we take a critical look at the toolbox available to researchers who would like to investigate cannabinoid effects using genetic engineering techniques, then we comprehensively discuss genetically modified rodent models in various neuronal and non-neuronal cell populations, both within and outside the nervous system.
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Affiliation(s)
- Krisztina Monory
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | | | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
- Leibniz Institute for Resilience Research (LIR) gGmbH, Mainz, Germany.
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2
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Lulek CF, Maulik M, Mitra S, Guindon J, Morgan DJ, Henderson-Redmond AN. Sex differences in acute delta-9-tetrahydrocannabinol (Δ 9-THC) response and tolerance as a function of mouse strain. Psychopharmacology (Berl) 2023; 240:1987-2003. [PMID: 37516707 PMCID: PMC10471687 DOI: 10.1007/s00213-023-06421-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/06/2023] [Indexed: 07/31/2023]
Abstract
Cannabinoids are increasingly used to alleviate pain; however, tolerance to their antinociceptive effects, including those of delta-9-tetrahydrocannabinol (Δ9-THC), may limit their therapeutic utility. With more women than men using medical cannabis for pain relief, it is crucial to understand how sex influences cannabinoid-mediated antinociception and tolerance. Though studies in rats consistently find females are more sensitive to the acute antinociceptive effects of cannabinoids, our work with mice consistently finds the converse. The present study examined whether our observed sex differences in Δ9-THC-induced antinociception and tolerance are consistent across multiple mouse strains or are strain-dependent. Male and female C57BL/6J (B6), DBA/2, AKR, and CBA/J mice were assessed for differences in acute Δ9-THC-induced antinociception and hypothermia prior to and following seven days of once-daily Δ9-THC administration. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ9-THC than female littermates, an effect which dissipated with age. B6 males had decreased cannabinoid expression in the PAG compared to females. While DBA and CBA female mice showed increased Δ9-THC-antinociception compared to male littermates at 30 and 10 mg/kg Δ9-THC, respectively, these differences were less pronounced at higher doses, revealing that dose of Δ9-THC may also be important. Overall, CBA mice were more sensitive to Δ9-THC-induced antinociception while AKR mice were less responsive. These studies highlight the therapeutic potential of Δ9-THC in pain management and underscore the importance of considering not only Δ9-THC dose as a function of sex, but potentially genetic differences when evaluating their clinical utility.
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Affiliation(s)
- Courtney F Lulek
- Department of Biomedical Sciences, Marshall University, Huntington, WV, 25755, USA
| | - Malabika Maulik
- Department of Biomedical Sciences, Marshall University, Huntington, WV, 25755, USA
| | - Swarup Mitra
- Department of Biomedical Sciences, Marshall University, Huntington, WV, 25755, USA
| | - Josée Guindon
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Daniel J Morgan
- Department of Biomedical Sciences, Marshall University, Huntington, WV, 25755, USA
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3
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Wolf RC, Werler F, Schmitgen MM, Wolf ND, Wittemann M, Reith W, Hirjak D. Functional correlates of neurological soft signs in heavy cannabis users. Addict Biol 2023; 28:e13270. [PMID: 36825488 DOI: 10.1111/adb.13270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 12/03/2022] [Accepted: 01/20/2023] [Indexed: 02/17/2023]
Abstract
Sensorimotor dysfunction has been previously reported in persons with cannabis dependence. Such individuals can exhibit increased levels of neurological soft signs (NSS), particularly involving motor coordination, sensorimotor integration and complex motor task performance. Abnormal NSS levels can also be detected in non-dependent individuals with heavy cannabis use (HCU), yet very little is known about the functional correlates underlying such deficits. Here, we used resting-state functional magnetic resonance imaging (MRI) to investigate associations between NSS and intrinsic neural activity (INA) in HCU (n = 21) and controls (n = 26). Compared with controls, individuals with HCU showed significantly higher NSS across all investigated subdomains. Three of these subdomains, that is, motor coordination, sensorimotor integration and complex motor task behaviour, were associated with specific use-dependent variables, particularly age of onset of cannabis use and current cannabis use. Between-group comparisons of INA revealed lower regional homogeneity (ReHo) in left precentral gyrus, left inferior occipital gyrus, right triangular pat of the inferior frontal gyrus and right precentral gyrus in HCU compared with controls. In addition, HCU showed also higher ReHo in right cerebellum and left postcentral gyrus compared with controls. Complex motor task behaviour in HCU was significantly related to INA in postcentral, inferior frontal and occipital cortices. Our findings indicate abnormal ReHo in HCU in regions associated with sensorimotor, executive control and visuomotor-integration processes. Importantly, we show associations between ReHo, cannabis-use behaviour and execution of complex motor tasks. Given convergent findings in manifest psychotic disorders, this study suggests an HCU endophenotype that may present with a cumulative risk for psychosis.
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Affiliation(s)
- Robert Christian Wolf
- Department of General Psychiatry at the Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany
| | - Florian Werler
- Department of General Psychiatry at the Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany
| | - Mike M Schmitgen
- Department of General Psychiatry at the Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany
| | - Nadine D Wolf
- Department of General Psychiatry at the Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany
| | - Miriam Wittemann
- Department of Psychiatry and Psychotherapy, Saarland University, Saarbrücken, Germany
| | - Wolfgang Reith
- Department of Neuroradiology, Saarland University, Saarbrücken, Germany
| | - Dusan Hirjak
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Costas‐Insua C, Guzmán M. Endocannabinoid signaling in glioma. Glia 2023; 71:127-138. [PMID: 35322459 PMCID: PMC9790654 DOI: 10.1002/glia.24173] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/16/2022] [Accepted: 03/17/2022] [Indexed: 12/30/2022]
Abstract
High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB1 and CB2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling pathways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvironment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.
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Affiliation(s)
- Carlos Costas‐Insua
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain,Department of Biochemistry and Molecular BiologyInstituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityMadridSpain,Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
| | - Manuel Guzmán
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain,Department of Biochemistry and Molecular BiologyInstituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityMadridSpain,Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
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Henriquez JE, Bach AP, Matos-Fernandez KM, Crawford RB, Kaminski NE. Δ 9-Tetrahydrocannabinol (THC) Impairs CD8 + T Cell-Mediated Activation of Astrocytes. J Neuroimmune Pharmacol 2020; 15:863-874. [PMID: 32215844 PMCID: PMC7529688 DOI: 10.1007/s11481-020-09912-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/02/2020] [Indexed: 10/24/2022]
Abstract
CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8+ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10+, MCP-1+, and IL-6+ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8+ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8+ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.
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Affiliation(s)
- Joseph E Henriquez
- Michigan State University, East Lansing, MI, USA
- Department of Pharmacology and Toxicology, East Lansing, MI, USA
- Institute for Integrative Toxicology, Michigan State University, 1129 Farm Lane, Rm 165G, Food Safety and Toxicology Building, East Lansing, MI, 48824, USA
| | - Anthony P Bach
- Michigan State University, East Lansing, MI, USA
- Center for Research on Ingredient Safety, East Lansing, MI, USA
| | | | - Robert B Crawford
- Michigan State University, East Lansing, MI, USA
- Institute for Integrative Toxicology, Michigan State University, 1129 Farm Lane, Rm 165G, Food Safety and Toxicology Building, East Lansing, MI, 48824, USA
| | - Norbert E Kaminski
- Michigan State University, East Lansing, MI, USA.
- Department of Pharmacology and Toxicology, East Lansing, MI, USA.
- Institute for Integrative Toxicology, Michigan State University, 1129 Farm Lane, Rm 165G, Food Safety and Toxicology Building, East Lansing, MI, 48824, USA.
- Center for Research on Ingredient Safety, East Lansing, MI, USA.
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Schiavi S, Manduca A, Segatto M, Campolongo P, Pallottini V, Vanderschuren LJMJ, Trezza V. Unidirectional opioid-cannabinoid cross-tolerance in the modulation of social play behavior in rats. Psychopharmacology (Berl) 2019; 236:2557-2568. [PMID: 30903212 DOI: 10.1007/s00213-019-05226-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 03/10/2019] [Indexed: 01/04/2023]
Abstract
RATIONALE The endocannabinoid and the endogenous opioid systems interact in the modulation of social play behavior, a highly rewarding social activity abundantly expressed in young mammals. Prolonged exposure to opioid or cannabinoid receptor agonists induces cross-tolerance or cross-sensitization to their acute behavioral effects. OBJECTIVES AND METHODS Behavioral and biochemical experiments were performed to investigate whether cross-tolerance or cross-sensitization occurs to the play-enhancing effects of cannabinoid and opioid drugs on social play behavior, and the possible brain substrate involved. RESULTS The play-enhancing effects induced by systemic administration of JZL184, which inhibits the hydrolysis of the endocannabinoid 2-AG, were suppressed in animals repeatedly pretreated with the opioid receptor agonist morphine. Conversely, acute morphine administration increased social play in rats pretreated with vehicle or with either JZL184 or the cannabinoid agonist WIN55,212-2. Acute administration of JZL184 increased the activation of both CB1 receptors and their effector Akt in the nucleus accumbens and prefrontal cortex, brain regions important for the expression of social play. These effects were absent in animals pretreated with morphine. Furthermore, only animals repeatedly treated with morphine and acutely administered with JZL184 showed reduced activation of CB1 receptors and Akt in the amygdala. CONCLUSIONS The present study demonstrates a dynamic opioid-cannabinoid interaction in the modulation of social play behavior, occurring in limbic brain areas strongly implicated in social play behavior. A better understanding of opioid-cannabinoid interactions in social play contributes to clarify neurobiological aspects of social behavior at young age, which may provide new therapeutic targets for social dysfunctions.
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Affiliation(s)
- Sara Schiavi
- Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Viale G. Marconi 446, 00146, Rome, Italy
| | - Antonia Manduca
- Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Viale G. Marconi 446, 00146, Rome, Italy
| | - Marco Segatto
- Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Viale G. Marconi 446, 00146, Rome, Italy
| | - Patrizia Campolongo
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
| | - Valentina Pallottini
- Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Viale G. Marconi 446, 00146, Rome, Italy
| | - Louk J M J Vanderschuren
- Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Viviana Trezza
- Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Viale G. Marconi 446, 00146, Rome, Italy.
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Endocannabinoid System and Alcohol Abuse Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1162:89-127. [PMID: 31332736 DOI: 10.1007/978-3-030-21737-2_6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Δ9-tetrahydrocannabinol (Δ9-THC), the primary active component in Cannabis sativa preparations such as hashish and marijuana, signals by binding to cell surface receptors. Two types of receptors have been cloned and characterized as cannabinoid (CB) receptors. CB1 receptors (CB1R) are ubiquitously present in the central nervous system (CNS) and are present in both inhibitory interneurons and excitatory neurons at the presynaptic terminal. CB2 receptors (CB2R) are demonstrated in microglial cells, astrocytes, and several neuron subpopulations and are present in both pre- and postsynaptic terminals. The majority of studies on these receptors have been conducted in the past two and half decades after the identification of the molecular constituents of the endocannabinoid (eCB) system that started with the characterization of CB1R. Subsequently, the seminal discovery was made, which suggested that alcohol (ethanol) alters the eCB system, thus establishing the contribution of the eCB system in the motivation to consume ethanol. Several preclinical studies have provided evidence that CB1R significantly contributes to the motivational and reinforcing properties of ethanol and that the chronic consumption of ethanol alters eCB transmitters and CB1R expression in the brain nuclei associated with addiction pathways. Additionally, recent seminal studies have further established the role of the eCB system in the development of ethanol-induced developmental disorders, such as fetal alcohol spectrum disorders (FASD). These results are augmented by in vitro and ex vivo studies, showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the eCB system during development and in the adult stage. This chapter provides a current and comprehensive review of the literature concerning the role of the eCB system in alcohol abuse disorders (AUD).
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8
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Murphy E, Benítez-Burraco A. Toward the Language Oscillogenome. Front Psychol 2018; 9:1999. [PMID: 30405489 PMCID: PMC6206218 DOI: 10.3389/fpsyg.2018.01999] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 09/28/2018] [Indexed: 12/20/2022] Open
Abstract
Language has been argued to arise, both ontogenetically and phylogenetically, from specific patterns of brain wiring. We argue that it can further be shown that core features of language processing emerge from particular phasal and cross-frequency coupling properties of neural oscillations; what has been referred to as the language ‘oscillome.’ It is expected that basic aspects of the language oscillome result from genetic guidance, what we will here call the language ‘oscillogenome,’ for which we will put forward a list of candidate genes. We have considered genes for altered brain rhythmicity in conditions involving language deficits: autism spectrum disorders, schizophrenia, specific language impairment and dyslexia. These selected genes map on to aspects of brain function, particularly on to neurotransmitter function. We stress that caution should be adopted in the construction of any oscillogenome, given the range of potential roles particular localized frequency bands have in cognition. Our aim is to propose a set of genome-to-language linking hypotheses that, given testing, would grant explanatory power to brain rhythms with respect to language processing and evolution.
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Affiliation(s)
- Elliot Murphy
- Division of Psychology and Language Sciences, University College London, London, United Kingdom.,Department of Psychology, University of Westminster, London, United Kingdom
| | - Antonio Benítez-Burraco
- Department of Spanish Language, Linguistics and Literary Theory, University of Seville, Seville, Spain
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9
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Labra VC, Santibáñez CA, Gajardo-Gómez R, Díaz EF, Gómez GI, Orellana JA. The Neuroglial Dialog Between Cannabinoids and Hemichannels. Front Mol Neurosci 2018; 11:79. [PMID: 29662436 PMCID: PMC5890195 DOI: 10.3389/fnmol.2018.00079] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/28/2018] [Indexed: 12/11/2022] Open
Abstract
The formation of gap junctions was initially thought to be the central role of connexins, however, recent evidence had brought to light the high relevance of unopposed hemichannels as an independent mechanism for the selective release of biomolecules during physiological and pathological conditions. In the healthy brain, the physiological opening of astrocyte hemichannels modulates basal excitatory synaptic transmission. At the other end, the release of potentially neurotoxic compounds through astroglial hemichannels and pannexons has been insinuated as one of the functional alterations that negatively affect the progression of multiple brain diseases. Recent insights in this matter have suggested encannabinoids (eCBs) as molecules that could regulate the opening of these channels during diverse conditions. In this review, we discuss and hypothesize the possible interplay between the eCB system and the hemichannel/pannexon-mediated signaling in the inflamed brain and during event of synaptic plasticity. Most findings indicate that eCBs seem to counteract the activation of major neuroinflammatory pathways that lead to glia-mediated production of TNF-α and IL-1β, both well-known triggers of astroglial hemichannel opening. In contrast to the latter, in the normal brain, eCBs apparently elicit the Ca2+-activation of astrocyte hemichannels, which could have significant consequences on eCB-dependent synaptic plasticity.
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Affiliation(s)
- Valeria C Labra
- Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes, Santiago, Chile
| | - Cristian A Santibáñez
- Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes, Santiago, Chile
| | - Rosario Gajardo-Gómez
- Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes, Santiago, Chile
| | - Esteban F Díaz
- Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes, Santiago, Chile
| | - Gonzalo I Gómez
- Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes, Santiago, Chile
| | - Juan A Orellana
- Departamento de Neurología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes, Santiago, Chile
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10
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Gamage TF, Farquhar CE, Lefever TW, Thomas BF, Nguyen T, Zhang Y, Wiley JL. The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB 1 receptor allosteric modulators. Neuropharmacology 2017; 125:365-375. [PMID: 28803965 DOI: 10.1016/j.neuropharm.2017.08.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 07/25/2017] [Accepted: 08/09/2017] [Indexed: 01/08/2023]
Abstract
While allosteric modulators of the cannabinoid type-1 receptor (CB1) continue to be developed and characterized, the gap between the in vitro and in vivo data is widening, raising questions regarding translatability of their effects and biological relevance. Among the CB1 allosteric modulators, PSNCBAM-1 has received little attention regarding its effects in vivo. Recently, pregnenolone was reported to act as an allosteric modulator of CB1, blocking THC's effects in vitro and in vivo, highlighting the potential of CB1 allosteric modulators for treatment of cannabis intoxication. We investigated the pharmacological effects of PSNCBAM-1 and two structural analogs, RTICBM-15 and -28, as well as pregnenolone, in both signaling and behavioral assays including [35S]GTPγS binding, the cannabinoid tetrad and drug discrimination. While the CB1 allosteric modulator PSNCBAM-1 attenuated THC-induced anti-nociception and its structural analog RTICBM-28 reduced THC's potency in drug discrimination, most cannabinoid effects in mice were unaffected. In contrast to the mouse studies, PSNCBAM-1 and analogs insurmountably antagonized CP55,940- and THC-stimulated [35S]GTPγS binding and exhibited negative binding cooperativity with [3H]SR141716 with similar apparent affinities. Notably, RTICBM-28, which contains a cyano substitution at the 4-chlorophenyl position of PSNCBAM-1, exhibited enhanced binding cooperativity with CP55,940. In contrast to previous findings, pregnenolone did not block THC's effects in drug discrimination or [35S]GTPγS. These data further highlight the difficulty in translating pharmacological effects of CB1 allosteric modulators in vivo but confirm the established pharmacology of PSNCBAM-1 and analogs in molecular assays of CB1 receptor function.
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Affiliation(s)
- Thomas F Gamage
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.
| | - Charlotte E Farquhar
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA
| | - Timothy W Lefever
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA
| | - Brian F Thomas
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA
| | - Thuy Nguyen
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA
| | - Yanan Zhang
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA
| | - Jenny L Wiley
- RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA
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11
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Cooper A, Singh S, Hook S, Tyndall JDA, Vernall AJ. Chemical Tools for Studying Lipid-Binding Class A G Protein-Coupled Receptors. Pharmacol Rev 2017; 69:316-353. [PMID: 28655732 DOI: 10.1124/pr.116.013243] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 05/15/2017] [Indexed: 12/16/2022] Open
Abstract
Cannabinoid, free fatty acid, lysophosphatidic acid, sphingosine 1-phosphate, prostanoid, leukotriene, bile acid, and platelet-activating factor receptor families are class A G protein-coupled receptors with endogenous lipid ligands. Pharmacological tools are crucial for studying these receptors and addressing the many unanswered questions surrounding expression of these receptors in normal and diseased tissues. An inherent challenge for developing tools for these lipid receptors is balancing the often lipophilic requirements of the receptor-binding pharmacophore with favorable physicochemical properties to optimize highly specific binding. In this study, we review the radioligands, fluorescent ligands, covalent ligands, and antibodies that have been used to study these lipid-binding receptors. For each tool type, the characteristics and design rationale along with in vitro and in vivo applications are detailed.
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Affiliation(s)
- Anna Cooper
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Sameek Singh
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Sarah Hook
- School of Pharmacy, University of Otago, Dunedin, New Zealand
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12
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Hungund BL. Drinking during pregnancy: Potential role of endocannabinoid signaling in fetal alcohol effects. World J Neurol 2017; 7:1-5. [DOI: 10.5316/wjn.v7.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 11/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Alcohol is a well-recognized teratogen that can cause variable physical and behavioral effects on the fetus. Alcohol use and abuse during pregnancy is one of the major health and societal problems and has been linked to a wide range of birth defects in the offspring collectively termed as fetal alcohol spectrum disorder (FASD). The severity of abnormalities may depend on a number of factors that include the amount, the frequency, the period during gestation and the route of alcohol administration. The current knowledge about the neurobiological basis of FASD is limited. However, recent studies have suggested that the membrane-derived lipids especially bioactive endogenous cannabinoids (eCB) such as arachidonyl ethanolamide and 2-arachidonyl glycerol resulting from alcohol exposure, may play a significant role in modulating neurophysiological and neurobehavioral effects in chronic alcohol exposed adult animals. Based on these findings and on reported studies on the role of eCB signaling in neurodevelopment and behavior, it is speculated that the eCB signaling may play a critical role in fetal alcohol syndrome and FASD-related behavioral effects. The current discussion will touch upon some of the mechanistic explanations about the role of eCB signaling system in FASD and provide further guidance for future direction.
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Olmo IG, Ferreira-Vieira TH, Ribeiro FM. Dissecting the Signaling Pathways Involved in the Crosstalk between Metabotropic Glutamate 5 and Cannabinoid Type 1 Receptors. Mol Pharmacol 2016; 90:609-619. [PMID: 27338080 DOI: 10.1124/mol.116.104372] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 06/16/2016] [Indexed: 02/06/2023] Open
Abstract
The metabotropic glutamate 5 receptor and the cannabinoid type 1 receptor are G protein-coupled receptors that are widely expressed in the central nervous system. Metabotropic glutamate 5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, whereas the cannabinoid type 1 receptor, mainly present at presynaptic terminals, is coupled to the Gi/o protein and triggers an inhibitory response. Recent studies suggest that the glutamatergic and endocannabinoid systems exhibit a functional interaction to modulate several neural processes. In this review, we discuss possible mechanisms involved in this crosstalk and its relationship with physiologic and pathologic conditions, including nociception, addiction, and fragile X syndrome.
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Affiliation(s)
- Isabella G Olmo
- Department of Biochemistry and Immunology, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Talita H Ferreira-Vieira
- Department of Biochemistry and Immunology, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Fabiola M Ribeiro
- Department of Biochemistry and Immunology, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling. Brain Sci 2015; 5:456-93. [PMID: 26529026 PMCID: PMC4701023 DOI: 10.3390/brainsci5040456] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/19/2015] [Accepted: 10/19/2015] [Indexed: 12/15/2022] Open
Abstract
One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS), which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD). Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD.
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Ortega A, Rangel-López E, Hidalgo-Miranda A, Morales A, Ruiz-García E, Meneses-García A, Herrera-Gómez A, Aguilar-Ponce JL, González-Herrera IG, Guevara-Salazar P, Prospero-García O, Del Angel SA. On the effects of CP 55-940 and other cannabinoid receptor agonists in C6 and U373 cell lines. Toxicol In Vitro 2015; 29:1941-51. [PMID: 26255146 DOI: 10.1016/j.tiv.2015.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 07/14/2015] [Accepted: 08/05/2015] [Indexed: 01/16/2023]
Abstract
Cannabinoid receptor (CBs) agonists affect the growth of tumor cells via activation of deadly cascades. The spectrum of action of these agents and the precise role of the endocannabinoid system (ECS) on oncogenic processes remain elusive. Herein we compared the effects of synthetic (CP 55-940 and WIN 55,212-2) and endogenous (anandamide or AEA) CBs agonists (10-20 μM) on morphological changes, cell viability, and induction of apoptosis in primary astrocytes and in two glioblastoma cell lines (C6 and U373 cells) in order to characterize their possible differential actions on brain tumor cells. None of the CBs agonist tested induced changes in cell viability or morphology in primary astrocytes. In contrast, CP 55-940 significantly decreased cell viability in C6 and U373 cells at 5 days of treatment, whereas AEA and WIN 55,212-2 moderately decreased cell viability in both cell lines. Treatment of U373 and C6 for 3 and 5 days with AEA or WIN 55,212-2 produced discrete morphological changes in cell bodies, whereas the exposure to CP 55-940 induced soma degradation. CP 55-940 also induced apoptosis in both C6 and U373 cell lines. Our results support a more effective action of CP 55-940 to produce cell death of both cell lines through apoptotic mechanisms. Comparative aspects between cannabinoids with different profiles are necessary for the design of potential treatments against glial tumors.
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Affiliation(s)
- A Ortega
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, SSA, Mexico City 14080, Mexico
| | - E Rangel-López
- Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City 14269, Mexico
| | - A Hidalgo-Miranda
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, SSA, Mexico City 14610, Mexico
| | - A Morales
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, SSA, Mexico City 14080, Mexico
| | - E Ruiz-García
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, SSA, Mexico City 14080, Mexico
| | - A Meneses-García
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, SSA, Mexico City 14080, Mexico
| | - A Herrera-Gómez
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, SSA, Mexico City 14080, Mexico
| | - J L Aguilar-Ponce
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, SSA, Mexico City 14080, Mexico
| | - I G González-Herrera
- Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City 14269, Mexico
| | - P Guevara-Salazar
- Departamento de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City 14269, Mexico
| | - O Prospero-García
- Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Mexico City 04510, Mexico
| | - S A Del Angel
- Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City 14269, Mexico.
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Epstein KA, Kumra S. White matter fractional anisotropy over two time points in early onset schizophrenia and adolescent cannabis use disorder: A naturalistic diffusion tensor imaging study. Psychiatry Res 2015; 232:34-41. [PMID: 25779033 DOI: 10.1016/j.pscychresns.2014.10.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 09/15/2014] [Accepted: 10/12/2014] [Indexed: 12/18/2022]
Abstract
Recurrent exposure to cannabis in adolescence increases the risk for later development of psychosis, but there are sparse data regarding the impact of cannabis use on brain structure during adolescence. This pilot study investigated the effect of cannabis use disorder (CUD) upon white matter fractional anisotropy (WM FA) values in non-psychotic treatment-seeking adolescents relative to adolescents with early onset schizophrenia-spectrum disorders (EOSS) and to healthy control (HC) participants. Diffusion tensor imaging (DTI) and tractography methods were used to examine fractional anisotropy (FA) of the cingulum bundle, superior longitudinal fasciculus (SLF), corticospinal tract (CST), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF) and uncinate fasciculus in adolescents with EOSS (n=34), CUD (n=19) and HC (n=29). Participants received DTI and substance use assessments at baseline and at 18-month follow-up. Using multivariate analysis of variance, a significant main effect of diagnostic group was observed. Post-hoc testing revealed that adolescents with CUD showed an altered change in FA values in the left ILF and in the left IFOF (trend level) compared with HC adolescents. Greater consumption of cannabis during the inter-scan interval predicted a greater decrease in left ILF FA in CUD. These preliminary longitudinal data suggest that heavy cannabis use during adolescence, or some factor associated with cannabis use, is associated with an altered change in WM FA values in a fiber bundle that has been implicated in the pathophysiology of EOSS (i.e., the left ILF). Additional studies are needed to clarify the clinical significance of these findings.
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Affiliation(s)
- Katherine A Epstein
- Division of Child and Adolescent Psychiatry, University of Minnesota, Minneapolis, MN, USA
| | - Sanjiv Kumra
- Division of Child and Adolescent Psychiatry, University of Minnesota, Minneapolis, MN, USA.
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Turcotte C, Chouinard F, Lefebvre JS, Flamand N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol 2015; 97:1049-70. [PMID: 25877930 DOI: 10.1189/jlb.3ru0115-021r] [Citation(s) in RCA: 170] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 02/28/2015] [Indexed: 12/26/2022] Open
Abstract
2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids. In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions. This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.
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Affiliation(s)
- Caroline Turcotte
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - François Chouinard
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Julie S Lefebvre
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Nicolas Flamand
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
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Metna-Laurent M, Marsicano G. Rising stars: modulation of brain functions by astroglial type-1 cannabinoid receptors. Glia 2014; 63:353-64. [PMID: 25452006 DOI: 10.1002/glia.22773] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 11/13/2014] [Indexed: 01/03/2023]
Abstract
The type-1-cannabinoid (CB1 ) receptor is amongst the most widely expressed G protein-coupled receptors in the brain. In few decades, CB1 receptors have been shown to regulate a large array of functions from brain cell development and survival to complex cognitive processes. Understanding the cellular mechanisms underlying these functions of CB1 is complex due to the heterogeneity of the brain cell types on which the receptor is expressed. Although the large majority of CB1 receptors act on neurons, early studies pointed to a direct control of CB1 receptors over astroglial functions including brain energy supply and neuroprotection. In line with the growing concept of the tripartite synapse highlighting astrocytes as direct players in synaptic plasticity, astroglial CB1 receptor signaling recently emerged as the mediator of several forms of synaptic plasticity associated to important cognitive functions. Here, we shortly review the current knowledge on CB1 receptor-mediated astroglial functions. This functional spectrum is large and most of the mechanisms by which CB1 receptors control astrocytes, as well as their consequences in vivo, are still unknown, requiring innovative approaches to improve this new cannabinoid research field.
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Abstract
Isolation and structure elucidation of most of the major cannabinoid constituents--including Δ(9)-tetrahydrocannabinol (Δ(9)-THC), which is the principal psychoactive molecule in Cannabis sativa--was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.
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Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death. Toxicol Appl Pharmacol 2013; 274:17-23. [PMID: 24211273 DOI: 10.1016/j.taap.2013.10.028] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 10/17/2013] [Accepted: 10/28/2013] [Indexed: 01/28/2023]
Abstract
The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB1 receptor, but not by the CB2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain.
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Olango W, Géranton S, Roche M, Hunt S, Finn D. Novel molecular correlates of endocannabinoid-mediated fear-conditioned analgesia in rats. Eur J Pain 2013; 18:182-91. [DOI: 10.1002/j.1532-2149.2013.00369.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2013] [Indexed: 11/12/2022]
Affiliation(s)
- W.M. Olango
- Pharmacology and Therapeutics; School of Medicine; National University of Ireland Galway; Ireland
- NCBES Neuroscience Cluster; National University of Ireland Galway; Ireland
- Centre for Pain Research; National University of Ireland Galway; Ireland
| | - S.M. Géranton
- Department of Cell and Developmental Biology; University College London; UK
| | - M. Roche
- Physiology; School of Medicine; National University of Ireland Galway; Ireland
- NCBES Neuroscience Cluster; National University of Ireland Galway; Ireland
- Centre for Pain Research; National University of Ireland Galway; Ireland
| | - S.P. Hunt
- Department of Cell and Developmental Biology; University College London; UK
| | - D.P. Finn
- Pharmacology and Therapeutics; School of Medicine; National University of Ireland Galway; Ireland
- NCBES Neuroscience Cluster; National University of Ireland Galway; Ireland
- Centre for Pain Research; National University of Ireland Galway; Ireland
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Larrieu T, Madore C, Joffre C, Layé S. Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice. J Physiol Biochem 2012; 68:671-81. [PMID: 22707188 DOI: 10.1007/s13105-012-0179-6] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 05/16/2012] [Indexed: 01/14/2023]
Abstract
N-3 polyunsaturated fatty acids (PUFAs) cannot be synthesized de novo in mammals and need to be provided by dietary means. In the brain, the main n-3 PUFA is docosahexaenoic acid (DHA), which is a key component of neuronal membranes. A low dietary level of DHA has been associated with increased risk of developing neuropsychiatric diseases; however, the mechanisms involved remain to be determined. In this study, we found that long-term exposure to an n-3 deficient diet decreases the level of DHA in the brain and impairs the cannabinoid receptor signaling pathway in mood-controlling structures. In n-3 deficient mice, the effect of the cannabinoid agonist WIN55,212-2 in an anxiety-like behavior test was abolished. In addition, the cannabinoid receptor signaling pathways were altered in the prefrontal cortex and the hypothalamus. Consequently, our data suggest that behavioral changes linked to an n-3 dietary deficiency are due to an alteration in the endocannabinoid system in specific brain areas.
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Affiliation(s)
- Thomas Larrieu
- Nutrition et Neurobiologie Intégrée, INRA UMR 1286, Bâtiment UFR Pharmacie 2° tranche, 2° étage, Case courrier 34, Université Victor Ségalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
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Farkas S, Nagy K, Jia Z, Harkany T, Palkovits M, Donohou SR, Pike VW, Halldin C, Máthé D, Csiba L, Gulyás B. The decrease of dopamine D₂/D₃ receptor densities in the putamen and nucleus caudatus goes parallel with maintained levels of CB₁ cannabinoid receptors in Parkinson's disease: a preliminary autoradiographic study with the selective dopamine D₂/D₃ antagonist [³H]raclopride and the novel CB₁ inverse agonist [¹²⁵I]SD7015. Brain Res Bull 2012; 87:504-10. [PMID: 22421165 DOI: 10.1016/j.brainresbull.2012.02.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Accepted: 02/28/2012] [Indexed: 01/24/2023]
Abstract
Cannabinoid type-1 receptors (CB₁Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB₁Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB₁R and dopamine receptor density in case of Parkinson's disease (PD). Post mortem putamen, nucleus caudatus and medial frontal gyrus samples obtained from PD patients were used for CB₁R and dopamine D₂/D₃ receptor autoradiography. [¹²⁵I]SD7015, a novel selective CB₁R inverse agonist, developed by a number of the present co-authors, and [³H]raclopride, a dopamine D₂/D₃ antagonist, were used as radioligands. Our results demonstrate unchanged CB₁R density in the putamen and nucleus caudatus of deceased PD patients, treated with levodopa (L-DOPA). At the same time dopamine D₂/D₃ receptors displayed significantly decreased density levels in case of PD putamen (control: 47.97 ± 10.00 fmol/g, PD: 3.73 ± 0.07 fmol/g (mean ± SEM), p<0.05) and nucleus caudatus (control: 30.26 ± 2.48 fmol/g, PD: 12.84 ± 5.49 fmol/g, p<0.0005) samples. In contrast to the putamen and the nucleus caudatus, in the medial frontal gyrus neither receptor densities were affected. Our data suggest the presence of an unaltered CB₁R population even in late stages of levodopa treated PD. This further supports the presence of an intact CB₁R population which, in line with the conclusion of earlier publications, may be utilized as a pharmacological target in the treatment of PD. Furthermore we found discrepancy between a maintained CB₁R population and a decreased dopamine D₂/D₃ receptor population in PD striatum. The precise explanation of this conundrum requires further studies with simultaneous examination of the central cannabinoid and dopaminergic systems in PD using higher sample size.
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Affiliation(s)
- Szabolcs Farkas
- Department of Neurology, University of Debrecen, H-4012 Debrecen, Hungary
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Chung YC, Bok E, Huh SH, Park JY, Yoon SH, Kim SR, Kim YS, Maeng S, Park SH, Jin BK. Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation. THE JOURNAL OF IMMUNOLOGY 2011; 187:6508-17. [PMID: 22079984 DOI: 10.4049/jimmunol.1102435] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
This study examined whether the cannabinoid receptor type 1 (CB(1)) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB(1) receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB(1) receptor. The present in vivo and in vitro findings clearly indicate that the CB(1) receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson's disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage.
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Affiliation(s)
- Young C Chung
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea
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Marco EM, García-Gutiérrez MS, Bermúdez-Silva FJ, Moreira FA, Guimarães F, Manzanares J, Viveros MP. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects. Front Behav Neurosci 2011; 5:63. [PMID: 22007164 PMCID: PMC3186912 DOI: 10.3389/fnbeh.2011.00063] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2011] [Accepted: 09/09/2011] [Indexed: 01/19/2023] Open
Abstract
Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e., anxiety disorders, depression, and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB) system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R) in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD), the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation.
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Affiliation(s)
- Eva M. Marco
- Departamento de Fisiología (Fisiología Animal II), Facultad de Ciencias Biológicas, Universidad Complutense de MadridMadrid, Spain
- Instituto de Investigación Sanitaria del Hospital Clínico San CarlosMadrid, Spain
| | - María S. García-Gutiérrez
- Instituto de Neurociencias de Alicante, Universidad Miguel Hernández – CSICSan Juan de Alicante, Spain
| | - Francisco-Javier Bermúdez-Silva
- Laboratorio de Medicina Regenerativa, Hospital Carlos Haya de Malaga, Fundacion IMABISMalaga, Spain
- Neurocentre Magendie, INSERM, Université Bordeaux 2Bordeaux, France
| | - Fabricio A. Moreira
- Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas GeraisBelo Horizonte, MG, Brazil
| | - Francisco Guimarães
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São PauloRibeirão Preto, SP, Brazil
| | - Jorge Manzanares
- Instituto de Neurociencias de Alicante, Universidad Miguel Hernández – CSICSan Juan de Alicante, Spain
| | - María-Paz Viveros
- Departamento de Fisiología (Fisiología Animal II), Facultad de Ciencias Biológicas, Universidad Complutense de MadridMadrid, Spain
- Instituto de Investigación Sanitaria del Hospital Clínico San CarlosMadrid, Spain
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Goodfellow CE, Graham SE, Dragunow M, Glass M. Characterization of NTera2/D1 cells as a model system for the investigation of cannabinoid function in human neurons and astrocytes. J Neurosci Res 2011; 89:1685-97. [PMID: 21674570 DOI: 10.1002/jnr.22692] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2011] [Revised: 04/03/2011] [Accepted: 04/17/2011] [Indexed: 12/12/2022]
Abstract
The limited availability and potential to culture primary human brain cells means that there is still a need for cell lines that reliably model human neurons and glial cells. The human-derived NTera2/D1 (NT2) cell line is a promising tool from which both neuronal (NT2N) and astrocytic (NT2A) cells can be derived in vitro. Here we have investigated the potential to use this cell model to investigate the endocannabinoid system in the CNS. Through immunocytochemical characterization with a range of neuronal and glial markers, we found that these cell lines differentiate into cells with immature neuronal and astrocytic phenotypes, respectively. By real-time PCR, immunocytochemistry, and functional inhibition of cAMP accumulation, the cannabinoid 1 receptors were identified only on NT2N cells, consistent with high levels of expression of this receptor in neuronal cells of the CNS. No evidence of cannabinoid 2 receptor expression was found on any of the NT2 cell types. Both the precursors and the differentiated NT2N and NT2A cells demonstrated mRNA expression for the key enzymes involved in endocannabinoid synthesis and degradation. This work establishes a cannabinergic phenotype in NT2N and NT2A cells, providing an alternative human derived renewable cell model for investigation of cannabinoid receptor function and endocannabinoid synthesis and metabolism in the CNS.
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Affiliation(s)
- Catherine E Goodfellow
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Scotter EL, Abood ME, Glass M. The endocannabinoid system as a target for the treatment of neurodegenerative disease. Br J Pharmacol 2010; 160:480-98. [PMID: 20590559 DOI: 10.1111/j.1476-5381.2010.00735.x] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
The Cannabis sativa plant has been exploited for medicinal, agricultural and spiritual purposes in diverse cultures over thousands of years. Cannabis has been used recreationally for its psychotropic properties, while effects such as stimulation of appetite, analgesia and anti-emesis have lead to the medicinal application of cannabis. Indeed, reports of medicinal efficacy of cannabis can been traced back as far as 2700 BC, and even at that time reports also suggested a neuroprotective effect of the cultivar. The discovery of the psychoactive component of cannabis resin, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) occurred long before the serendipitous identification of a G-protein coupled receptor at which Delta(9)-THC is active in the brain. The subsequent finding of endogenous cannabinoid compounds, the synthesis of which is directed by neuronal excitability and which in turn served to regulate that excitability, further widened the range of potential drug targets through which the endocannabinoid system can be manipulated. As a result of this, alterations in the endocannabinoid system have been extensively investigated in a range of neurodegenerative disorders. In this review we examine the evidence implicating the endocannabinoid system in the cause, symptomatology or treatment of neurodegenerative disease. We examine data from human patients and compare and contrast this with evidence from animal models of these diseases. On the basis of this evidence we discuss the likely efficacy of endocannabinoid-based therapies in each disease context.
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Affiliation(s)
- Emma L Scotter
- Centre for Brain Research and Department of Pharmacology, University of Auckland, Auckland, New Zealand
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Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia 2010; 58:1017-30. [PMID: 20468046 DOI: 10.1002/glia.20983] [Citation(s) in RCA: 384] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
CB1 and CB2 receptors are activated by a plethora of cannabinoid compounds, be they endogenously-produced, plant-derived or synthetic. These receptors are expressed by microglia, astrocytes and astrocytomas, and their activation regulates these cells' differentiation, functions and viability. Recent studies show that glial cells also express cannabinoid-like receptors, and that their activation regulates different cell functions, but also control cell viability. This review summarizes this evidence, and discusses how selective compounds targeting cannabinoid-like receptors constitute promising therapeutics to manage neuroinflammation and eradicate malignant astrocytomas. Importantly, the selective targeting of cannabinoid-like receptors should provide therapeutic relieve without inducing the typical psychotropic effects and possible addictive properties associated with the use of Delta9-tetrahydrocannabinol, the main psychotropic ingredient produced by the plant Cannabis sativa.
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Affiliation(s)
- Nephi Stella
- Department of Pharmacology, Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195-7280, USA.
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Rational design of a novel peripherally-restricted, orally active CB(1) cannabinoid antagonist containing a 2,3-diarylpyrrole motif. Bioorg Med Chem Lett 2010; 20:4573-7. [PMID: 20584609 DOI: 10.1016/j.bmcl.2010.06.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 06/01/2010] [Accepted: 06/02/2010] [Indexed: 11/24/2022]
Abstract
A new series of 2,3-diarylpyrroles have been prepared and evaluated as CB(1) antagonists. Modulation of the topological polar surface area allowed the identification of high affinity peripherally-restricted CB(1) antagonists. Compound 11, obtained after further optimization of the metabolic profile displayed very low brain penetration, yet was able to reverse CP55940-induced gastrointestinal transit inhibition following oral administration.
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Bava S, Frank LR, McQueeny T, Schweinsburg BC, Schweinsburg AD, Tapert SF. Altered white matter microstructure in adolescent substance users. Psychiatry Res 2009; 173:228-37. [PMID: 19699064 PMCID: PMC2734872 DOI: 10.1016/j.pscychresns.2009.04.005] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Revised: 03/10/2009] [Accepted: 04/09/2009] [Indexed: 12/21/2022]
Abstract
Chronic marijuana use during adolescence is frequently comorbid with heavy alcohol consumption and associated with CNS alterations, yet the influence of early cannabis and alcohol use on microstructural white matter integrity is unclear. Building on evidence that cannabinoid receptors are present in myelin precursors and affect glial cell processing, and that excessive ethanol exposure is associated with persistently impaired myelination, we used diffusion tensor imaging (DTI) to characterize white matter integrity in heavy substance using and non-using adolescents. We evaluated 36 marijuana and alcohol-using (MJ+ALC) adolescents (ages 16-19) and 36 demographically similar non-using controls with DTI. The diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics (Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Watkins, K.E., Ciccarelli, O., Cader, M.Z., Matthews, P.M., Behrens, T.E., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505). MJ+ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ+ALC users. Findings suggest that fronto-parietal circuitry may be particularly impacted in adolescent users of the most prevalent intoxicants: marijuana and alcohol. Disruptions to white matter in this young group could indicate aberrant axonal and myelin maturation with resultant compromise of fiber integrity. Findings of increased anisotropic diffusion in alternate brain regions suggest possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing.
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Affiliation(s)
- Sunita Bava
- Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA,Department of Radiology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Lawrence R. Frank
- Department of Radiology, University of California, San Diego, La Jolla, CA 92093, USA,VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Tim McQueeny
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Brian C. Schweinsburg
- Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA,Department of Psychiatry, Yale University, New Haven, CT 06511, USA
| | | | - Susan F. Tapert
- Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA,VA San Diego Healthcare System, La Jolla, CA 92161, USA, Address correspondence to: Susan F. Tapert, Ph.D., VA San Diego Healthcare System, 3350 La Jolla Village Drive 116B, San Diego, CA 92161, USA, Telephone: (858) 552-8585 x2599, Fax: (858) 642-6474,
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Basavarajappa BS, Nixon RA, Arancio O. Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration. Mini Rev Med Chem 2009; 9:448-62. [PMID: 19356123 DOI: 10.2174/138955709787847921] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The endocannabinoid system, including endogenous ligands ('endocannabinoids' ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied ECs, and act as agonists of cannabinoid receptors. Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol (Delta(9)-THC), the psychoactive principle of cannabis sativa preparations like hashish and marijuana. Recently, however, several lines of evidence have suggested that the EC system may play an important role in early neuronal development as well as a widespread role in neurodegeneration disorders. Many of the effects of cannabinoids and ECs are mediated by two G protein-coupled receptors (GPCRs), CB1 and CB2, although additional receptors may be implicated. Both CB1 and CB2 couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. This new system is briefly presented in this review, in order to put in a better perspective the role of the EC pathway from neurodevelopment to neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, the potential exploitation of antagonists of CB1 receptors, or of inhibitors of EC metabolism, as next-generation therapeutics is discussed.
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Affiliation(s)
- Balapal S Basavarajappa
- Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY 10962, USA.
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Vignali M, Benfenati V, Caprini M, Anderova M, Nobile M, Ferroni S. The endocannabinoid anandamide inhibits potassium conductance in rat cortical astrocytes. Glia 2009; 57:791-806. [PMID: 19031444 DOI: 10.1002/glia.20807] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Endocannabinoids are a family of endogenous signaling molecules that modulate neuronal excitability in the central nervous system (CNS) by interacting with cannabinoid (CB) receptors. In spite of the evidence that astroglial cells also possess CB receptors, there is no information on the role of endocannabinoids in regulating CNS function through the modulation of ion channel-mediated homeostatic mechanisms in astroglial cells. We provide electrophysiological evidence that the two brain endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) markedly depress outward conductance mediated by delayed outward rectifier potassium current (IK(DR)) in primary cultured rat cortical astrocytes. Pharmacological experiments suggest that the effect of AEA does not result from the activation of known CB receptors. Moreover, neither the production of AEA metabolites nor variations in free cytosolic calcium are involved in the negative modulation of IK(DR). We show that the action of AEA is mediated by its interaction with the extracellular leaflet of the plasma membrane. Similar experiments performed in situ in cortical slices indicate that AEA downregulates IK(DR) in complex and passive astroglial cells. Moreover, IK(DR) is also inhibited by AEA in NG2 glia. Collectively, these results support the notion that endocannabinoids may exert their modulation of CNS function via the regulation of homeostatic function of the astroglial syncytium mediated by ion channel activity.
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Affiliation(s)
- M Vignali
- Department of Human and General Physiology, University of Bologna, 40127 Bologna, Italy
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Brighton PJ, McDonald J, Taylor AH, Challiss RAJ, Lambert DG, Konje JC, Willets JM. Characterization of anandamide-stimulated cannabinoid receptor signaling in human ULTR myometrial smooth muscle cells. Mol Endocrinol 2009; 23:1415-27. [PMID: 19477951 DOI: 10.1210/me.2009-0097] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Accumulating evidence highlights the importance of the endocannabinoid anandamide (AEA) as a key mediator in reproductive physiology. Current data suggest potential roles for AEA in gametogenesis, fertilization, and parturition. AEA exerts its actions through two G protein-coupled receptors, termed cannabinoid receptor 1 (CB1), and 2 (CB2), and the ligand-gated transient receptor potential vanilloid receptor type 1 (TRPV1) ion channel. At present, the cellular mechanism(s) and consequences of AEA signaling in reproductive tissues, especially the myometrium, are poorly understood. Here, we examine the expression of CB1, CB2, and TRPV1 in the human myometrial smooth muscle cell-line (ULTR) and characterize intracellular signaling after stimulation with AEA. Radioligand binding analysis revealed a total CB receptor expression of 76 +/- 24 fmol/mg protein, with both quantitative PCR and competition binding studies indicating a negligible CB2 component. AEA caused Galpha(i/o)-dependent inhibition of adenylate cyclase to reduce intracellular cAMP levels. In addition, AEA caused a 2.5- to 3.5-fold increase in ERK activation, which was ablated by inhibition of Galpha(i/o), phosphoinositide-3-kinase and Src-kinase activities, but not by inhibition of Ca(2+)/calmodulin-dependent protein kinase or protein kinase C activities. TRPV1 channel activation with capsaicin failed to activate ERK. Consistent with these findings, the selective agonists, arachidonyl-2-chloroethylamide (CB1) and L759656 (CB2), and selective antagonists AM251 (CB1) and JTE907 (CB2), provided pharmacological evidence that the ERK signaling pathway is activated through endogenously expressed CB1. These findings provide an insight into myometrial AEA signaling, highlighting a potential role for endocannabinoids in the regulation of gene expression in myometrial smooth muscle cells.
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Affiliation(s)
- Paul J Brighton
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies, University of Leicester, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom
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Widmer M, Hanemann CO, Zajicek J. High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells. J Neurosci Res 2009; 86:3212-20. [PMID: 18615640 DOI: 10.1002/jnr.21757] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Cannabinoids bind to two G-protein-coupled receptors, CB1 and CB2, expressed by neurons and cells of the immune system, respectively. Glioma cells (astrocyte-derived brain tumor cells) express cannabinoid receptors, and numerous in vitro and in vivo studies performed in rodents have concluded that apoptosis could be induced by cannabinoids in these cells. Whether this also applies to human cells is controversial; we, therefore, assessed the effect of cannabinoids on human glioma cell viability with the human astrocytoma cell line U373MG. We report here that U373MG human glioma cells are sensitive only to high concentrations of cannabinoids (>5 microg/ml for Delta(9)-THC). Similar concentrations of the compounds promoted a rapid activation of extracellular-regulated kinase and c-Jun NH2-terminal kinase, suggesting that cannabinoid receptors are functional in U373MG cells. Nevertheless, these kinases are not involved in cannabinoid-induced cell death in U373MG cells, insofar as blocking their activation with specific inhibitors does not reduce cell death. CB1 is expressed in U373MG cells and is involved in cannabinoid-induced cell death, in that blocking its activation with a specific antagonist (AM251) almost totally prevented cell death following incubation of the cells with Delta(9)-THC. In addition, as already reported, some cannabinoids may have modest proproliferative properties in U373MG cells. Human U373MG glioma cells are sensitive only to very high, pharmacologically irrelevant concentrations of cannabinoids, so it seems unlikely that cannabinoids would constitute promising molecules for treating malignant astrocytoma; they do not induce glioma cell death at doses that could be applied safely to humans.
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Affiliation(s)
- M Widmer
- Clinical Neurology, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Plymouth, Plymouth, UK
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Blázquez C, Salazar M, Carracedo A, Lorente M, Egia A, González-Feria L, Haro A, Velasco G, Guzmán M. Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression. Cancer Res 2008; 68:1945-52. [DOI: 10.1158/0008-5472.can-07-5176] [Citation(s) in RCA: 122] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Alexander SPH, Kendall DA. The complications of promiscuity: endocannabinoid action and metabolism. Br J Pharmacol 2007; 152:602-23. [PMID: 17876303 PMCID: PMC2190010 DOI: 10.1038/sj.bjp.0707456] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2007] [Revised: 08/15/2007] [Accepted: 08/16/2007] [Indexed: 01/27/2023] Open
Abstract
In this review, we present our understanding of the action and metabolism of endocannabinoids and related endogenous molecules. It is clear that the interactions between the multiple endocannabinoid-like molecules (ECLs) are highly complex, both at the level of signal transduction and metabolism. Thus, ECLs are a group of ligands active at 7-transmembrane and nuclear receptors, as well as transmitter-gated and ion channels. ECLs and their metabolites can converge on common endpoints (either metabolic or signalling) through contradictory or reinforcing pathways. We highlight the complexity of the endocannabinoid system, based on the promiscuous nature of ECLs and their metabolites, as well as the synthetic modulators of the endocannabinoid system.
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Affiliation(s)
- S P H Alexander
- School of Biomedical Sciences and Institute of Neuroscience, University of Nottingham Medical School, Nottingham NG7 7LP, UK.
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38
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Cudaback E, Stella N. Targeting Astrocytomas and Invading Immune Cells with Cannabinoids: A Promising Therapeutic Avenue. Mol Neurobiol 2007; 36:36-44. [DOI: 10.1007/s12035-007-0016-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2007] [Accepted: 05/11/2007] [Indexed: 01/07/2023]
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Khaspekov LG, Bobrov MY. The endocannabinoid system and its protective role in ischemic and cytotoxic injuries of brain neurons. NEUROCHEM J+ 2007. [DOI: 10.1134/s1819712407020018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Sánchez-Pastor E, Trujillo X, Huerta M, Andrade F. Effects of cannabinoids on synaptic transmission in the frog neuromuscular junction. J Pharmacol Exp Ther 2007; 321:439-45. [PMID: 17267583 DOI: 10.1124/jpet.106.116319] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This study aimed to investigate the function of the cannabinoid receptor in the neuromuscular junction of the frog (Rana pipiens). Miniature end-plate potentials were recorded using the intracellular electrode recording technique in the cutaneous pectoris muscle in the presence of the cannabinoid agonists WIN55212-2 (WIN; R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]-pyrolol[1,2,3de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone) and arachidonylcyclopropylamide [ACPA; N-(2-cyclopropyl)-5Z,8Z,11Z,147-eicosatetraenamide] and the cannabinoid antagonists 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281) and 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630). Adding WIN to the external medium decreased the frequency and amplitude of the miniature end-plate potentials (MEPPs); the WIN EC50 value was 5.8+/-1.0 microM. Application of ACPA, a selective agonist of cannabinoid receptor CB1, also decreased the frequency of the MEPPs; the ACPA EC50 value was 115.5+/-6.5 nM. The CB2 antagonist AM630 did not inhibit the effects of WIN, indicating that its action is not mediated through the CB2 receptor. However, the CB1 antagonist AM281 inhibited the effects of WIN and ACPA, suggesting that their actions are mediated through the CB1 receptor. Pretreatment with the pertussis toxin inhibited the effects of WIN and ACPA, suggesting that their effects are mediated through Gi/o protein activation. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTX) diminished the frequency of the MEPPs, with an omega-CgTX EC50 value of 2.5+/-0.40 microM. Blocking the N-type Ca2+ channels with 5 microM omega-CgTX before addition of ACPA to the bath had no additional inhibitory effect on the MEPPs, whereas in the presence of 1 microM omega-CgTX, ACPA had an additional inhibition effect. These results suggest that cannabinoids modulate transmitter release in the end-plate of the frog neuromuscular junction by activating CB1 cannabinoid receptors in the nerve ending.
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Affiliation(s)
- Enrique Sánchez-Pastor
- Unidad de Investigacion Enrico Stefani del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio #965, Colonia Villa San Sebastián, Apartado Postal 11, C.P. 28000-Colima, Colima, Mexico
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41
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Basavarajappa BS. Neuropharmacology of the endocannabinoid signaling system-molecular mechanisms, biological actions and synaptic plasticity. Curr Neuropharmacol 2007; 5:81-97. [PMID: 18084639 PMCID: PMC2139910 DOI: 10.2174/157015907780866910] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2006] [Revised: 02/07/2007] [Accepted: 02/14/2007] [Indexed: 11/22/2022] Open
Abstract
The endocannabinoid signaling system is composed of the cannabinoid receptors; their endogenous ligands, the endocannabinoids; the enzymes that produce and inactivate the endocannabinoids; and the endocannabinoid transporters. The endocannabinoids are a new family of lipidic signal mediators, which includes amides, esters, and ethers of long-chain polyunsaturated fatty acids. Endocannabinoids signal through the same cell surface receptors that are targeted by Delta(9)-tetrahydrocannabinol (Delta(9)THC), the active principles of cannabis sativa preparations like hashish and marijuana. The biosynthetic pathways for the synthesis and release of endocannabinoids are still rather uncertain. Unlike neurotransmitter molecules that are typically held in vesicles before synaptic release, endocannabinoids are synthesized on demand within the plasma membrane. Once released, they travel in a retrograde direction and transiently suppress presynaptic neurotransmitter release through activation of cannabinoid receptors. The endocannabinoid signaling system is being found to be involved in an increasing number of pathological conditions. In the brain, endocannabinoid signaling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in central nervous system (CNS) disease. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities. The present review is focused on new information regarding the endocannabinoid signaling system in the brain. First, the structure, anatomical distribution, and signal transduction mechanisms of cannabinoid receptors are described. Second, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. Finally, the role of the endocannabinoid signaling system in the CNS and its potential as a therapeutic target in various CNS disease conditions, including alcoholism, are discussed.
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Affiliation(s)
- Balapal S Basavarajappa
- Division of Analytical Psychopharmacology, New York State Psychiatric Institute, New York, NY 10032, USA.
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Ellert-Miklaszewska A, Grajkowska W, Gabrusiewicz K, Kaminska B, Konarska L. Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res 2006; 1137:161-9. [PMID: 17239827 DOI: 10.1016/j.brainres.2006.12.060] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2006] [Revised: 12/13/2006] [Accepted: 12/14/2006] [Indexed: 10/23/2022]
Abstract
The efficacy of cannabinoids against high-grade glioma in animal models, mediated by two specific receptors, CB1 and CB2, raised promises for targeted treatment of the most frequent and malignant primary brain tumors. Unlike the abundantly expressed CB1, the CB2 receptor shows a restricted distribution in normal brain. Although brain tumors constitute the second most common malignancy in children and the prevalence of histological types of brain tumors vary significantly between the adult and pediatric populations, cannabinoid receptor expression in pediatric tumors remains unknown. In the present study, we compared the expression of the CB2 receptor in paraffin-embedded sections from primary brain tumors of adult and pediatric patients. Most glioblastomas expressed very high levels of CB2 receptors and the expression correlated with tumor grade. Interestingly, some benign pediatric astrocytic tumors, such as subependymal giant cell astrocytoma (SEGA), which may occasionally cause mortality owing to progressive growth, also displayed high CB2 immunoreactivity. The high levels of CB2 expression would predestine those tumors to be vulnerable to cannabinoid treatment. In contrast, all examined cases of embryonal tumors (medulloblastoma and S-PNET), the most frequently diagnosed malignant brain tumors in childhood, showed no or trace CB2 immunoreactivity. Our results suggest that the CB2 receptor expression depends primarily on the histopathological origin of the brain tumor cells and differentiation state, reflecting the tumor grade.
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Jia W, Hegde VL, Singh NP, Sisco D, Grant S, Nagarkatti M, Nagarkatti PS. Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria. Mol Cancer Res 2006; 4:549-62. [PMID: 16908594 DOI: 10.1158/1541-7786.mcr-05-0193] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Plant-derived cannabinoids, including Delta9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells, although the precise mechanism remains unclear. In the current study, we investigated the effect of THC on the upstream and downstream events that modulate the extracellular signal-regulated kinase (ERK) module of mitogen-activated protein kinase pathways primarily in human Jurkat leukemia T cells. The data showed that THC down-regulated Raf-1/mitogen-activated protein kinase/ERK kinase (MEK)/ERK/RSK pathway leading to translocation of Bad to mitochondria. THC also decreased the phosphorylation of Akt. However, no significant association of Bad translocation with phosphatidylinositol 3-kinase/Akt and protein kinase A signaling pathways was noted when treated cells were examined in relation to phosphorylation status of Bad by Western blot and localization of Bad to mitochondria by confocal analysis. Furthermore, THC treatment decreased the Bad phosphorylation at Ser(112) but failed to alter the level of phospho-Bad on site Ser(136) that has been reported to be associated with phosphatidylinositol 3-kinase/Akt signal pathway. Jurkat cells expressing a constitutively active MEK construct were found to be resistant to THC-mediated apoptosis and failed to exhibit decreased phospho-Bad on Ser(112) as well as Bad translocation to mitochondria. Finally, use of Bad small interfering RNA reduced the expression of Bad in Jurkat cells leading to increased resistance to THC-mediated apoptosis. Together, these data suggested that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in THC-induced apoptosis in Jurkat cells.
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Affiliation(s)
- Wentao Jia
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, USA
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44
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Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzmán M, Galve-Roperh I. Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J 2006; 20:2405-7. [PMID: 17015409 DOI: 10.1096/fj.06-6164fje] [Citation(s) in RCA: 174] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB1 cannabinoid receptor. In contrast, the CB2 cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB2-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB1-mediated psychoactive effects. CB2 receptor expression in brain has been partially examined in differentiated cells, while its presence and function in neural progenitor cells remain unknown. Here we show that the CB2 receptor is expressed, both in vitro and in vivo, in neural progenitors from late embryonic stages to adult brain. Selective pharmacological activation of the CB2 receptor in vitro promotes neural progenitor cell proliferation and neurosphere generation, an action that is impaired in CB2-deficient cells. Accordingly, in vivo experiments evidence that hippocampal progenitor proliferation is increased by administration of the CB2-selective agonist HU-308. Moreover, impaired progenitor proliferation was observed in CB2-deficient mice both in normal conditions and on kainate-induced excitotoxicity. These findings provide a novel physiological role for the CB2 cannabinoid receptor and open a novel therapeutic avenue for manipulating neural progenitor cell fate.
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MESH Headings
- Animals
- Cannabinoids/pharmacology
- Cell Differentiation/drug effects
- Cell Differentiation/physiology
- DNA Primers
- Embryo, Mammalian
- Hippocampus/cytology
- Hippocampus/drug effects
- Hippocampus/physiology
- Humans
- Kainic Acid/pharmacology
- Mice
- Mice, Knockout
- Neurons/cytology
- Neurons/drug effects
- Neurons/physiology
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/deficiency
- Receptor, Cannabinoid, CB2/genetics
- Receptor, Cannabinoid, CB2/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Stem Cells/drug effects
- Stem Cells/physiology
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Affiliation(s)
- Javier Palazuelos
- Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain
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45
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Nakamura-Palacios EM, Moerschbaecher JM, Barker LA. The Pharmacology of SR 141716A: A Review. CNS DRUG REVIEWS 2006. [DOI: 10.1111/j.1527-3458.1999.tb00085.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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46
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Ullrich O, Schneider-Stock R, Zipp F. Cell-cell communication by endocannabinoids during immune surveillance of the central nervous system. Results Probl Cell Differ 2006; 43:281-305. [PMID: 17068977 DOI: 10.1007/400_015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The immune system is designed to defend the organism from hazardous infection. The way by which cells of the immune system perform this function can be dangerous for the survival and function of the neuronal network in the brain. An attack of immune cells inside the brain includes the potential for severe neuronal damage or cell death and therefore impairment of CNS function. To avoid such undesirable action of the immune system, the CNS harbours an impressive arsenal of cellular and molecular mechanisms enabling strict control of immune reactions--the so-called "immune privilege". Under inflammatory and pathological conditions, loss of control of the CNS immune system results in the activation of neuronal damage cascades frequently associated with neurological disease. On the other hand, processes of neuroprotection and neurorepair after neuronal damage depend on a steady and tightly controlled immune surveillance. Accordingly, the immune system serves a highly specialized function in the CNS including negative feedback mechanisms that control immune reactions. Recent studies have revealed that endocannabinoids participate in one of the most important ones of the brain's negative feedback system. The CNS endocannabinoid system consists of cannabinoid receptors, their endogenous ligands and enzymes for the synthesis and degradation of endocannabinoids. It participates crucially in neuronal cell-cell-communication and signal transduction, e.g., by modulating synaptic input and protecting neurons from excitotoxic damage. Over the last decade, it has also become evident that endocannabinoids play an important role in the communication between immune cells, and in the interaction between nerve and immune system during CNS damage. Thus, therapeutic intervention in the CNS endocannabinoid system may help to restore the well-controlled and finely tuned balance of immune reactions in pathological conditions.
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Affiliation(s)
- Oliver Ullrich
- Institute of Immunology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Germany.
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47
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Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 2006; 49:67-79. [PMID: 16387640 DOI: 10.1016/j.neuron.2005.11.027] [Citation(s) in RCA: 331] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2005] [Revised: 09/17/2005] [Accepted: 11/02/2005] [Indexed: 11/23/2022]
Abstract
Endocannabinoids are released after brain injury and believed to attenuate neuronal damage by binding to CB(1) receptors and protecting against excitotoxicity. Such excitotoxic brain lesions initially result in primary destruction of brain parenchyma, which attracts macrophages and microglia. These inflammatory cells release toxic cytokines and free radicals, resulting in secondary neuronal damage. In this study, we show that the endocannabinoid system is highly activated during CNS inflammation and that the endocannabinoid anandamide (AEA) protects neurons from inflammatory damage by CB(1/2) receptor-mediated rapid induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) in microglial cells associated with histone H3 phoshorylation of the mkp-1 gene sequence. As a result, AEA-induced rapid MKP-1 expression switches off MAPK signal transduction in microglial cells activated by stimulation of pattern recognition receptors. The release of AEA in injured CNS tissue might therefore represent a new mechanism of neuro-immune communication during CNS injury, which controls and limits immune response after primary CNS damage.
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Affiliation(s)
- Eva Eljaschewitsch
- Institute of Immunology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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48
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Scrivens M, Dickenson JM. Pharmacological effects mediated by UDP-glucose that are independent of P2Y14 receptor expression. Pharmacol Res 2006; 51:533-8. [PMID: 15829433 DOI: 10.1016/j.phrs.2005.02.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2005] [Indexed: 11/28/2022]
Abstract
In transfected cells, the P2Y14 receptor reportedly couples to pertussis toxin-sensitive G(i/o)-proteins. However, the functional coupling of endogenously expressed P2Y14 receptors to the inhibition of adenylyl cyclase activity has not been reported. Therefore, the primary aim of this study was to investigate the effects of uridine 5'-diphosphoglucose (UDP-glucose) on forskolin-stimulated cyclic AMP (cAMP) accumulation in two cell lines that reportedly express P2Y14 receptor mRNA, namely human neuroblastoma SH-SY5Y cells and human astrocytoma U373 MG cells. In U373 MG cells, UDP-glucose inhibited forskolin-stimulated cAMP accumulation in a concentration-dependent manner (pEC50=4.5 +/- 0.3). Furthermore, treatment with pertussis toxin abolished the inhibitory effects of UDP-glucose on forskolin-stimulated cAMP accumulation in U373 MG cells. In SH-SY5Y cells, UDP-glucose had no significant effect on forskolin-stimulated cAMP accumulation. To confirm the expression of P2Y14 receptor mRNA in U373 MG and SH-SY5Y cells, we performed reverse transcriptase polymerase chain reaction (RT-PCR) analysis. However, RT-PCR did not detect the expression of P2Y14 receptor mRNA in SH-SY5Y cells or surprisingly in U373 MG cells. In conclusion, we have shown that although UDP-glucose inhibits forskolin-stimulated cAMP accumulation in human U373 MG astrocytoma cells, we did not detect P2Y14 receptor mRNA in these cells. These results would suggest that the effects of UDP-glucose in U373 MG cells are independent of P2Y14 receptor expression. Thus, results obtained with UDP-glucose should be interpreted with caution, since they clearly may not necessarily reflect the involvement of the P2Y14 receptor.
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Affiliation(s)
- Michelle Scrivens
- School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK
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49
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Beardsley PM, Thomas BF. Current evidence supporting a role of cannabinoid CB1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders. Behav Pharmacol 2006; 16:275-96. [PMID: 16148435 DOI: 10.1097/00008877-200509000-00003] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Since the discovery of the cannabinoid CB1 receptor (CB1R) in 1988, and subsequently of the CB2 receptor (CB2R) in 1993, there has been an exponential growth of research investigating the functions of the endocannabinoid system. The roles of CB1Rs have been of particular interest to behavioral pharmacologists because of their selective presence within the central nervous system (CNS) and because of their association with brain-reward circuits involving mesocorticolimbic dopamine systems. One potential role that has become of considerable recent focus is the ability of CB1Rs to modulate the effects of drugs of abuse. Many drugs of abuse elevate dopamine levels, and the ability of CB1R antagonists or inverse agonists to attenuate these elevations has suggested their potential application as pharmacotherapies for treating drug abuse disorders. With the identification of the selective CB1R antagonist, SR141716, in 1994, and its subsequent widespread availability, there has been a rapid expansion of research investigating its ability to modulate the effects of drugs of abuse. The preliminary clinical reports of its success in retarding relapse in tobacco users have accelerated this expansion. This report critically reviews preclinical and clinical studies involving the ability of CB1R antagonists to attenuate the effects of drugs of abuse, while providing an overview of the neuroanatomical and neurochemical points of contact between the endocannabinoid system and systems mediating abuse-related effects.
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Affiliation(s)
- P M Beardsley
- Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA.
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50
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Abstract
The cannabinoid receptor family currently includes two types: CB1, characterized in neuronal cells and brain, and CB2, characterized in immune cells and tissues. CB1 and CB2 receptors are members of the superfamily of seven-transmembrane-spanning (7-TM) receptors, having a protein structure defined by an array of seven membrane-spanning helices with intervening intracellular loops and a C-terminal domain that can associate with G proteins. Cannabinoid receptors are associated with G proteins of the Gi/o family (Gi1, 2 and 3, and Go1 and 2). Signal transduction via Gi inhibits adenylyl cyclase in most tissues and cells, although signaling via Gs stimulates adenylyl cyclase in some experimental models. Evidence exists for cannabinoid receptor-mediated Ca2+ fluxes and stimulation of phospholipases A and C. Stimulation of CB1 and CB2 cannabinoid receptors leads to phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK), p38 MAPK and Jun N-terminal kinase (JNK) as signaling pathways to regulate nuclear transcription factors. The CB1 receptor regulates K+ and Ca2+ ion channels, probably via Go. Ion channel regulation serves as an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to neuronal depolarization. Cannabinoid receptor signaling via G proteins results from interactions with the second, third and fourth intracellular loops of the receptor. Desensitization of signal transduction pathways that couple through the G proteins probably entails phosphorylation of critical amino acid residues on these intracellular surfaces.
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Affiliation(s)
- A C Howlett
- Neuroscience/Drug Abuse Research Program, 208 JLC-BBRI, North Carolina Central University, 700 George Street, Durham, NC 27707, USA.
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