Species differences in cannabinoid receptor 2 (CNR2) gene: identification of novel human and rodent CB2 isoforms, differential tissue expression, and regulation by cannabinoid receptor ligands

Liu, Qingrong; Pan, Chun‐Hung; Hishimoto, Akitoyo; Li, Chuan-Yun; Xi, Zheng‐Xiong; Llorente-Berzal, Álvaro; Viveros, M.P.; Ishiguro, Hiroki; Arinami, Tadao; Onaivi, Emmanuel S.; Uhl, George R.

doi:10.1111/j.1601-183x.2009.0498.x

Cited by 63 publications

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“…Preliminary data also addressed CB 2 as a potential target for autism. Indeed, genomic studies have highlighted an upregulation of mRNA levels of the CB 2 A, but not the CB 2 B, isoform in the cerebellum of BTBR T+tF/ J mice [105], which have an autism-like behavioral phenotype [106]. Also, an independent clinical study performed on young (3-9-year-old) children demonstrated that CB 2 is highly expressed, both at transcriptional and translational levels, in peripheral blood mononuclear cells of patients with autism, compared with matched healthy controls [107].…”

Section: Alterations Of the Ecb System In Autismmentioning

confidence: 99%

Endocannabinoid Signaling in Autism

et al. 2015

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Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the Bendocannabinoid (eCB) system^, a rather complex ensemble of lipid signals (Bendocannabinoids^), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.Key Words Autism spectrum disorder . endocannabinoid system . fragile X syndrome . metabolic regulation . reward system The Endocannabinoid SystemTwenty-five years after the cloning and expression of a complementary DNA that encoded a G protein-coupled receptor, named type-1 cannabinoid (CB 1 ) receptor [1], there is a good deal of information on the main components of the so-called Bendocannabinoid (eCB) system^, as well as on its role in controlling cannabinergic signaling in human health and disease [2][3][4]. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most active eCBs as yet identified, although this family of bioactive lipids includes other arachidonic acid (AA) derivatives with cannabimimetic properties (i.e., noladin ether, virodhamine, N-arachidonoyldopamine, to name but a few). The classical dogma that eCBs are synthesized and released Bon demand^upon (patho)physiological stimuli has been recently revisited on the basis of unexpected evidence for intracellular reservoirs and transporters of eCBs. These new entities have been shown to drive intracellular trafficking of eCBs, adding a new dimension to the regulation of their biological activity [5]. To date, several metabolic routes have B. Chakrabarti, A. Persico and N. Battista are equal first authors.

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Section: Alterations Of the Ecb System In Autismmentioning

confidence: 99%

Endocannabinoid Signaling in Autism

et al. 2015

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“…Endocannabinoids and exogenous cannabinoids have been implicated in CB 1 R up-regulation in hepatocytes and T cells, respectively (Börner et al, 2007;Mukhopadhyay et al, 2010), and long-term CB 1 R antagonism has been found to counter increases in hepatic and adipose CB 1 R expression in response to high-fat diet (Jourdan et al, 2010). In addition, administration of a mixed CB 1 R/ CB 2 R agonist increases expression of the CB 2 A isoform (see section IV.B) in mouse cerebellum (Liu et al, 2009). Because endocannabinoids are often increased along with cannabinoid receptors in disease (Mitrirattanakul et al, 2006;Jeong et al, 2008), such autoinduction is probably common to many diseases.…”

Section: Rat Chronic Constriction Injury Model Of Neuropathic Painmentioning

confidence: 99%

The Highs and Lows of Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications

2011

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“…Male WT, CB 1 qRT-PCR. The qRT-PCR assay of brain CB 2 mRNA levels was performed as described previously (10). Because immune cells in blood contain a high density of CB 2 Rs, all mice used for qRT-PCR were perfused transcardially with 30-50 mL 0.9% saline under deep anesthesia, to prevent contamination of brain tissue by blood cells.…”

Section: Methodsmentioning

confidence: 99%

“…More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9)(10)(11)(12)(13)(14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cannabinoid CB 2 receptors (CB 2 Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB 2 Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB 2 mRNA and CB 2 R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB 2 Rs by JWH133 or other CB 2 R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB 1 −/− mice are blocked by CB 2 R antagonist and absent in CB 2 −/− mice. These data suggest that CB 2 R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.T he presence of functional cannabinoid CB 2 receptors (CB 2 Rs) in the brain has been controversial. When CB 2 Rs were first cloned, in situ hybridization (ISH) failed to detect CB 2 mRNA in brain (1). Similarly, Northern blot and polymerase chain reaction (PCR) assays failed to detect CB 2 mRNA in brain (2-5). Therefore, CB 2 Rs were considered "peripheral cannabinoid receptors" (1, 6).In contrast, other studies using ISH and radioligand binding assays detected CB 2 mRNA and receptor binding in rat retina (7), mouse cerebral cortex (8), and hippocampus and striatum of nonhuman primates (9). More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21). A currently accepted view is that brain CB 2 Rs are expressed predominantly in activated microglia during neuroinflammation, whereas brain neurons, except for a very small number in the brainstem, lack CB 2 R expression (21).On the other hand, we recently reported that brain CB 2 Rs modulate cocaine self-administration and cocaine-induced increases in locomotion and extracellular dopamine (DA) in the nucleus accumbens in mice (22). This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27). The cellular mechanisms underlying CB 2 R modulation of DA-related behav...

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Species differences in cannabinoid receptor 2 (CNR2) gene: identification of novel human and rodent CB2 isoforms, differential tissue expression, and regulation by cannabinoid receptor ligands

Cited by 63 publications

References 0 publications

Endocannabinoid Signaling in Autism

Endocannabinoid Signaling in Autism

The Highs and Lows of Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

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Species differences in cannabinoid receptor 2 (CNR2) gene: identification of novel human and rodent CB2 isoforms, differential tissue expression, and regulation by cannabinoid receptor ligands

Cited by 63 publications

References 0 publications

Endocannabinoid Signaling in Autism

Endocannabinoid Signaling in Autism

The Highs and Lows of Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

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Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice