Depression‐resistant endophenotype in mice overexpressing cannabinoid CB<sub>2</sub> receptors

García-Gutiérrez,; Pérez‐Ortiz, José Manuel; Gutiérrez‐Adán, Alfonso; Manzanares, Jorge

doi:10.1111/j.1476-5381.2010.00819.x

Cited by 179 publications

(197 citation statements)

References 65 publications

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“…Furthermore, this opening of CaCCs is most likely responsible for the observed reduction in neuronal excitability upon CB 2 R activation. The presence of CB 2 R mRNA in the brain and CB 2 Rs in neurons of the brainstem, the cerebellum, and the hippocampus has been reported (12,13,18,(25)(26)(27)(28), but their presence in the cortex remained to be further characterized. The current view on the presence of functional CB 2 Rs in the CNS supports the expression of CB 2 Rs in neurons essentially upon brain stress and damage (19).…”

Section: Discussionmentioning

confidence: 99%

“…CB 2 Rs are found primarily in the immune system and were initially regarded as the "peripheral" cannabinoid receptor (10,11). This generally accepted idea is challenged by the description of CNS CB 2 R gene expression in rats and wild-type mice (12)(13)(14) and the identification of functional CB 2 Rs on glial cells and neurons (15)(16)(17)(18). In addition to the current view that supports the expression of functional CB 2 Rs in neurons upon brain stress or damage (19), it has been reported that CB 2 Rs could play a role in general CNS physiology (20)(21)(22).…”

mentioning

confidence: 99%

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Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors

Boon

Chameau

Schaafsma-Zhao

et al. 2012

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

161

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The endocannabinoid (eCB) system is widely expressed throughout the central nervous system (CNS) and the functionality of type-1 cannabinoid receptors in neurons is well documented. In contrast, there is little knowledge about type-2 cannabinoid receptors (CB 2 Rs) in the CNS. Here, we show that CB 2 Rs are located intracellularly in layer II/III pyramidal cells of the rodent medial prefrontal cortex (mPFC) and that their activation results in IP 3 Rdependent opening of Ca 2+ -activated Cl − channels. To investigate the functional role of CB 2 R activation, we induced neuronal firing and observed a CB 2 R-mediated reduction in firing frequency. The description of this unique CB 2 R-mediated signaling pathway, controlling neuronal excitability, broadens our knowledge of the influence of the eCB system on brain function.calcium-activated chloride current | firing rate | whole-cell current | voltage clamp | intracellular calcium stores T he endocannabinoid (eCB) system is involved in many functions of the CNS, including executive functions associated with the prefrontal cortex, such as decision-making and working memory (1). The eCB system consists of at least two G proteincoupled receptors (GPCRs), type-1 cannabinoid receptor (CB 1 R) and type-2 cannabinoid receptor (CB 2 R), lipid endogenous ligands (e.g., anandamide and 2-arachidonoylglycerol), and various enzymes responsible for the synthesis and degradation of the endogenous ligands (2-6). CB 1 Rs are among the most abundantly expressed GPCRs in the rat brain and their role, predominantly as presynaptic receptors, in modulating neurotransmission is clearly established (5,7,8). In contrast with CB 1 R, the presence and function of CB 2 R in the brain has long been a matter of debate (9). CB 2 Rs are found primarily in the immune system and were initially regarded as the "peripheral" cannabinoid receptor (10,11). This generally accepted idea is challenged by the description of CNS CB 2 R gene expression in rats and wild-type mice (12-14) and the identification of functional CB 2 Rs on glial cells and neurons (15)(16)(17)(18). In addition to the current view that supports the expression of functional CB 2 Rs in neurons upon brain stress or damage (19), it has been reported that CB 2 Rs could play a role in general CNS physiology (20)(21)(22). These developments emphasize the importance of understanding how CB 2 R activation affects neuronal functioning. To demonstrate the presence of functional CB 2 Rs in the rodent medial prefrontal cortex (mPFC) and to elucidate their functional role, we used Western blotting, a radioactive binding assay, and electrophysiological techniques (whole-cell current and voltage clamp) on layer II/III pyramidal neurons. ResultsFunctional CB 2 Rs in the mPFC. The presence of CB 2 Rs in the rat mPFC was demonstrated by a Western blot performed on homogenated mPFC samples (Fig. 1A). A band of the expected molecular weight for CB 2 R was detected, which was absent when the primary antibody was incubated with immunizing peptide (Fig. 1A)....

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors

Boon

Chameau

Schaafsma-Zhao

et al. 2012

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

161

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“…Coronal brain sections (500 mm) beginning at plates 19-20 (Paxinos and Franklin, 2001) were obtained in a cryostat (À101C). The PFC, LC, and DR were microdissected according to a modification of the Palkovits method (Palkovits, 1983) as described previously (Garcia-Gutierrez et al, 2010). Total RNA was isolated from brain tissue micropunches using Trizol reagent (Invitrogen, Madrid, Spain) and subsequently retrotranscribed to cDNA.…”

Section: Gene Expression Analysesmentioning

confidence: 99%

“…Further studies in rats have identified CB 2 r distributed extensively throughout different brain areas, including the spinal nucleus, hippocampus, olfactory nucleus, cerebral cortex, amygdala, striatum, thalamus, and cerebellum (Atwood and Mackie, 2010;Gong et al, 2006;Onaivi et al, 2006). In addition, CB 2 r gene expression has been identified in the thalamus, periaqueductal grey matter, cervical and thoracic spinal cord, and different brain nuclei, including the caudateputamen, nucleus accumbens, cingulate cortex, amygdala, hippocampus, ventromedial hypothalamic nucleus, arcuate nucleus, substantia nigra, and dorsal and medial raphe nuclei (Garcia-Gutierrez et al, 2010;Racz et al, 2008).…”

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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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“…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 behaviors and diseases are unclear, however.…”

mentioning

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.

310

353

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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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Depression‐resistant endophenotype in mice overexpressing cannabinoid CB₂ receptors

Cited by 179 publications

References 65 publications

Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors

Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors

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

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

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Depression‐resistant endophenotype in mice overexpressing cannabinoid CB2 receptors

Cited by 179 publications

References 65 publications

Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors

Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors

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

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

Contact Info

Product

Resources

About

Depression‐resistant endophenotype in mice overexpressing cannabinoid CB₂ receptors

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