Brain Cannabinoid CB2 Receptor in Schizophrenia

Ishiguro, Hiroki; Horiuchi, Yasue; Ishikawa, Maya; Koga, Minoru; Imai, Keiko; Suzuki, Yoshimi; Morikawa, Miyuki; Inada, Toshiya; Watanabe, Yuichiro; Takahashi, Makoto; Someya, Toshiyuki; Ujike, Hiroshi; Iwata, Nakao; Ozaki, Norio; Onaivi, Emmanuel S.; Kunugi, Hiroshi; Sasaki, Tsukasa; Itokawa, Masanari; Arai, Makoto; Niizato, Kazuhiro; Iritani, Shyuji; Naka, Izumi; Ohashi, Jun; Kakita, Akiyoshi; Takahashi, Hitoshi; Nawa, Hiroyuki; Arinami, Tadao

doi:10.1016/j.biopsych.2009.09.024

Cited by 166 publications

(137 citation statements)

References 42 publications

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“…Data reported so far indicate a dysregulation in the ECS (both in terms of ligands and receptors) in patients with schizophrenia and in animal models of psychosis (OrtegaAlvaro et al, 2011;Zamberletti et al, 2012). Our results agree with the described relationship between a diminished CB2 function (polymorphism Q63R) and an increased susceptibility to schizophrenia (Ishiguro et al, 2010), although from our data we cannot ensure whether its reduced expression is previous or concomitant to the psychotic episode. The ECS has been implicated as a neuroprotective system activated in certain neurodegenerative and neuroinflammatory damage (Wolf et al, 2008;Zoppi et al, 2011).…”

Section: Discussionsupporting

confidence: 81%

“…Reduced CB1 expression and activity have been found in different brain areas of patients with schizophrenia (Eggan et al, 2008). A close relationship has also been reported between a diminished CB2 function (polymorphism Q63R) and an increased susceptibility to schizophrenia, together with other risk factors (Ishiguro et al, 2010). Schizophrenia symptom remission has been linked to significant changes in CB2 mRNA transcripts in peripheral blood mononuclear cells (PBMC;De Marchi et al, 2003).…”

Section: Introductionmentioning

confidence: 98%

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Peripheral Endocannabinoid System Dysregulation in First-Episode Psychosis

Bioque

García‐Bueno

MacDowell

et al. 2013

Neuropsychopharmacol

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Several hypotheses involving alterations of the immune system have been proposed among etiological explanations for psychotic disorders. The endocannabinoid system (ECS) has a homeostatic role as an endogenous neuroprotective and anti-inflammatory system. Alterations of this system have been associated with psychosis. Cannabis use is a robust risk factor for these disorders that could alter the ECS signalling. In this study, 95 patients with a first episode of psychosis (FEP) and 90 healthy controls were recruited. Protein expression of cannabinoid receptor 2 (CB2), the protein levels of the main endocannabinoid synthesizing enzymes N-acyl phosphatidylethanolamine phospholipase (NAPE) and diacylglycerol lipase (DAGL), and of degradation enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) were determined by western blot analysis in peripheral blood mononuclear cells (PBMCs). Patients with a FEP showed a decreased expression of CB2 and of both endocannabinoids synthesizing enzymes (NAPE and DAGL) in comparison to healthy controls. After controlling for age, gender, body mass index, and cannabis use, NAPE and DAGL expression remained significantly decreased, whereas FAAH and MAGL expression were increased. On the other hand, FEP subjects with history of severe cannabis use showed a larger ECS dysregulation compared with healthy controls. These results indicate an ECS dysregulation in PBMC of FEP patients. The alteration of the ECS presented at the initial phases of psychosis could be contributing to the pathophysiology of the disease and constitutes a possible biomarker of psychotic disorders and an interesting pharmacological target to take into account for therapeutic purposes.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 98%

Peripheral Endocannabinoid System Dysregulation in First-Episode Psychosis

Bioque

García‐Bueno

MacDowell

et al. 2013

Neuropsychopharmacol

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“…Interestingly, a close relation between diminished CB 2 r function (polymorphism Q63R) and increased susceptibility to schizophrenia in the presence of other risk factors has been reported (Ishiguro et al, 2010). This observation supports the notion of a relationship between the cannabinoid system and the development of schizophrenia.…”

supporting

confidence: 76%

“…In addition, recent studies have sketched out the potential role of cannabinoid CB 2 r in the neurobiology of psychiatric disorders (Ishiguro et al, 2010;Onaivi, 2009). Interestingly, a close relation between diminished CB 2 r function (polymorphism Q63R) and increased susceptibility to schizophrenia in the presence of other risk factors has been reported (Ishiguro et al, 2010).…”

mentioning

confidence: 99%

Deletion of CB2 Cannabinoid Receptor Induces Schizophrenia-Related Behaviors in Mice

Ortega-Álvaro

Aracil-Fernández

García-Gutiérrez

et al. 2011

Neuropsychopharmacol

178

134

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The possible role of the CB 2 receptor (CB 2 r) in psychiatric disorders has been considered. Several animal models use knockout (KO) mice that display schizophrenia-like behaviors and this study evaluated the role of CB 2 r in the regulation of such behaviors. Mice lacking the CB 2 r (CB 2 KO) were challenged in open field, light-dark box, elevated plus-maze, tail suspension, step down inhibitory avoidance, and pre-pulse inhibition tests (PPI). Furthermore, the effects of treatment with cocaine and risperidone were evaluated using the OF and the PPI test. Gene expression of dopamine D 2 (D 2 r), adrenergic-a 2C (a 2C r), serotonergic 5-HT 2A and 5-HT 2C receptors (5-HT 2A r and 5-HT 2C r) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB 2 r decreased motor activity in the OF test, but enhanced response to acute cocaine and produced mood-related alterations, PPI deficit, and cognitive impairment. Chronic treatment with risperidone tended to impair PPI in WT mice, whereas it 'normalized' the PPI deficit in CB 2 KO mice. CB 2 KO mice presented increased D 2 r and a 2C r gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT 2C r gene expression in the dorsal raphe (DR), and 5-HT 2A r gene expression in the PFC. Chronic risperidone treatment in WT mice left a 2C r gene expression unchanged, decreased D 2 r gene expression (15 mg/kg), and decreased 5-HT 2C r and 5-HT 2A r in PFC and DR. In CB 2 KO, the gene expression of D 2 r in the PFC, of a 2C r in the LC, and of 5-HT 2C r and 5-HT 2A r in PFC was reduced; 5-HT 2C r and 5-HT 2A r gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB 2 r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB 2 r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders.

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“…The authors suggested a role for CB2 receptors in the psychotic like behavioral alterations observed in this animal model. Moreover, Ishiguro and colleagues 23 described a polymorphism in the gene encoding for CB2 receptors associated with schizophrenia in a Japanese population. Additionally, administration of the CB2 receptor antagonist worsened disruption of PPI induced by the NMDA receptor antagonist MK-801 in rats.…”

Section: Animal Studiesmentioning

confidence: 99%

Consumo de cánnabis de los adolescentes y esquizofrenia: evidencias epidemiológicas y experimentales

Parolaro

2010

Adicciones

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Marijuana is consistently the most widely used illicit drug among teenagers and most users first experiment it in adolescence. Adolescence is a critical period between childhood and adulthood, including not only reproductive maturation, but also cognitive, emotional and social maturation. In this period adolescent brain is still in transition differing anatomically and neurochemically from the adult's one.The endocannabinoid system is an important determinant for cerebral maturation, therefore its strong stimulation by the delta-9-tetrahydrocannabinol, that acts through the endocannabinoid system, might lead to subtle but lasting neurobiological changes that can affect adult brain functions and behaviour. We summarize the more recent researches investigating the relationships between adolescent exposure to cannabinoids and increased risk for psychotic disease such as schizophrenia, as highlighted by both human and animal studies.Epidemiological evidence suggests that cannabis use is a risk factor for schizophrenia, and an exacerbation of symptoms and worsening of the schizophrenic prognosis may occur in individuals with a predisposition for schizophrenia. The characteristic of adolescent brain probably makes it more vulnerable to cannabis effect producing psychotic like symptoms and possibly cause schizophrenia.Key words: Cannabis, adolescence, psychosis, schizophrenia, brain RESUMEN ABSTRACTLa marihuana es la droga ilegal más utilizada entre los adolescentes. La mayoría de los usuarios comienzan además a experimentar con ella durante este período. La adolescencia es una etapa crítica, que incluye no sólo la maduración reproductiva,

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Brain Cannabinoid CB2 Receptor in Schizophrenia

Cited by 166 publications

References 42 publications

Peripheral Endocannabinoid System Dysregulation in First-Episode Psychosis

Peripheral Endocannabinoid System Dysregulation in First-Episode Psychosis

Deletion of CB2 Cannabinoid Receptor Induces Schizophrenia-Related Behaviors in Mice

Consumo de cánnabis de los adolescentes y esquizofrenia: evidencias epidemiológicas y experimentales

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