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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the cannabinoid receptor agonist WIN 55,212-2 on endogenous extracellular glutamate levels in the prefrontal cortex of the awake rat and in primary cultures of rat cerebral cortex neurons were investigated. In the prefrontal cortex WIN 55,212-2 (0.1 and 1 mg/kg i.p.) increased dialysate glutamate levels from of the awake rat, while the lower (0.01 mg/kg) and the higher (2 mg/kg) doses were ineffective. Furthermore, the WIN 55,212-2 (0.1 mg/kg)- induced increase of dialysate glutamate levels was counteracted by pretreatment with the selective CB(1) receptor antagonist SR141716A (0.1 mg/kg i.p.) and by the local perfusion with a low-calcium Ringer solution (Ca(2+) 0.2 mM). In primary cultures of rat cerebral cortex neurons, WIN 55,212-2 (0.01--100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration-response curve. The facilitatory effect of WIN 55,212-2 (1 nM) was fully counteracted by SR141716A (10 nM), by the replacement of the normal Krebs Ringer-bicarbonate buffer with a low Ca(2+) medium (0.2 mM) and by the IP(3) receptor antagonist xestospongin C (1 microM). These in vivo and in vitro findings suggest an increase in cortical glutamatergic transmission by CB(1) receptors, an effect that may underlie some of the psychoactive and behavioural actions of acute exposure to marijuana.
Cereb Cortex 2001 Aug
PMID:The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study. 1145 62

We reported earlier that closed head injury (CHI) in mice causes a sharp elevation of brain 2-arachidonoylglycerol (2-AG) levels, and that exogenous 2-AG reduces brain edema, infarct volume and hippocampal death and improved clinical recovery after CHI. The beneficial effect of 2-AG was attenuated by SR141716A, a CB1 cannabinoid receptor antagonist, albeit at relatively high doses. In the present study, we further explored the role of CB1 receptors in mediating 2-AG neuroprotection. CB1 receptor knockout mice (CB1-/-) showed minor spontaneous recovery at 24 h after CHI, in contrast to the significant improvement in neurobehavioral function seen in wild-type (WT) mice. Moreover, administration of 2-AG did not improve neurological performance and edema formation in the CB1-/- mice. In addition, 2-AG abolished the three- to four-fold increase of nuclear factor kappaB (NF-kappa B) transactivation, at 24 h after CHI in the WT mice, while it had no effect on NF-kappaB in the CB1-/- mice, which was as high as in the WT vehicle-treated mice. We thus propose that 2-AG exerts its neuroprotection after CHI, at least in part, via CB1 receptor-mediated mechanisms that involve inhibition of intracellular inflammatory signaling pathways.
J Cereb Blood Flow Metab 2005 Apr
PMID:CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. 1572 96

Delta-9-tetrahydrocannabinol (Delta9-THC) has profound effects on higher cognitive functions, and exposure to Delta9-THC has been associated with the appearance or exacerbation of the clinical features of schizophrenia. These actions appear to be mediated via the CB1 receptor, the principal cannabinoid receptor expressed in the brain. However, the distribution of the CB1 receptor in neocortical regions of the primate brain that mediate cognitive functions is not known. We therefore investigated the immunocytochemical localization of the CB1 receptor in the brains of macaque monkeys and humans using antibodies that specifically recognize the N- or C-terminus of the CB1 receptor. In monkeys, intense CB1 immunoreactivity was observed primarily in axons and boutons. Across neocortical regions of the monkey brain, CB1-immunoreactive (IR) axons exhibited considerable heterogeneity in density and laminar distribution. Neocortical association regions, such as the prefrontal and cingulate cortices, demonstrated a higher density, and exhibited a unique laminar pattern of CB1-IR axons, compared with primary sensory and motor cortices. Similar regional and laminar distributions of CB1-IR axons were also present in the human neocortex. CB1-IR axons had more prominent varicosities in human tissue, but this difference appeared to represent a postmortem effect as similar morphological features increased in unperfused monkey tissue as a function of postmortem interval. In electron microscopy studies of perfused monkey prefrontal cortex, CB1 immunoreactivity was predominantly found in axon terminals that exclusively formed symmetric synapses. The high density, distinctive laminar distribution, and localization to inhibitory terminals of CB1 receptors in primate higher-order association regions suggests that the CB1 receptor may play a critical role in the circuitry that subserves cognitive functions such as those that are disturbed in schizophrenia.
Cereb Cortex 2007 Jan
PMID:Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. 1646 63

Endocannabinoids are emerging as potent modulators of neuronal activity throughout the brain, and activation of the type-1 cannabinoid receptor (CB1R) reduces sensory-evoked cortical responses in vivo, presumably by decreasing excitatory transmission. In the neocortex, CB1R is differentially expressed across neocortical laminae, with highest levels of expression in layers 2/3 and 5. Although we have shown that cannabinoid signaling in layer 2/3 of somatosensory cortex targets both gamma-aminobutyric acid (GABA) and glutamate release, the predominant effect is a net increase in pyramidal neuron (PN) activity due to disinhibition. The role of endocannabinoid signaling in layer 5, the main output layer of the neocortex, remains unknown. We found that inducing activity in layer 5 PNs resulted in endocannabinoid-mediated depolarization-induced suppression of excitation (DSE), whereas the majority of inhibitory inputs were cannabinoid insensitive. Furthermore, in contrast to layer 2/3, the net effect of elevations in action potential firing of layer 5 PNs was an endocannabinoid-mediated decrease in PN spike probability. Interestingly, excitatory synaptic currents in layer 5 evoked by intralaminar stimulation were cannabinoid sensitive, whereas inputs evoked from layer 2/3 were insensitive, suggesting specificity of cannabinoid signaling across glutamatergic inputs. Thus, cannabinoids have differential effects on excitation and inhibition across cortical layers, and endocannabinoid signaling in layer 5 may serve to selectively decrease the efficacy of a subset of excitatory inputs.
Cereb Cortex 2007 Jan
PMID:Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons. 1646 64

In the present study we explored with a multidisciplinary approach, the role of anandamide (AEA) in the modulation of anxiety behavior at the level of the prefrontal cortex (PFC). Low doses of the metabolically stable AEA analog, methanandamide, microinjected into the PFC, produced an anxiolytic-like response in rats, whereas higher doses induced anxiety-like behaviors. Pretreatment with the selective antagonist of CB1 or TRPV1 receptors (AM251 and capsazepine, respectively) suggested that the anxiolytic effect evoked by AEA might be due to the interaction with the CB1 cannabinoid receptor, whereas vanilloid receptors seem to be involved in AEA anxiogenic action. When AEA contents in the PFC were increased by microinjecting the selective inhibitor of fatty acid amide hydrolase (FAAH), URB597, we observed an anxiolytic response only at low doses of the compound and no effect or even an anxiogenic profile at higher doses. In line with this, a marked decrease of AEA levels in the PFC, achieved by lentivirus-mediated local overexpression of FAAH, produced an anxiogenic response. These findings support an anxiolytic role for physiological increases in AEA in the PFC, whereas more marked increases or decreases of this endocannabinoid might lead to an anxiogenic response due to TRPV1 stimulation or the lack of CB1 activation, respectively.
Cereb Cortex 2008 Jun
PMID:Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. 1792 59

Distinct networks of gamma-aminobutyric acidergic interneurons connected by electrical synapses can promote different patterns of activity in the neocortex. Cannabinoids affect memory and cognition by powerfully modulating a subset of inhibitory synapses; however, very little is known about the synaptic properties of the cannabinoid receptor-expressing neurons (CB(1)-positive irregular spiking [CB(1)-IS]) in the neocortex. Using paired recordings in neocortical slices, we 1st report here that synapses of CB(1)-IS cells, but not synapses of fast-spiking (FS) cells, are suppressed by release of endocannabinoids from pyramidal neurons. CB(1)-IS synapses were characterized by a very high failure rate that contrasted with the high reliability of FS synapses. Furthermore, CB(1)-IS cells received excitatory inputs less frequently compared with FS cells and made significantly less frequent inhibitory contacts onto local pyramids. These distinct synaptic properties together with their characteristic irregular firing suggest that CB(1)-IS cells play different role in neocortical function than that of FS cells. Thus, whereas the synaptic properties of FS cells can allow them to impose high-frequency rhythmic oscillatory activity, those of CB(1)-IS cells may lead to disruption of fast rhythmic oscillations. Our results suggest that activity-dependent release of cannabinoids, by blocking CB(1)-IS synapses, may alter the role of inhibition in neocortical circuits.
Cereb Cortex 2008 Oct
PMID:Cannabinoid sensitivity and synaptic properties of 2 GABAergic networks in the neocortex. 1820 91

N-arachidonoyl-L-serine (AraS) is a brain component structurally related to the endocannabinoid family. We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto-parietal skull and the mechanisms involved. A single injection of AraS following injury led to a significant improvement in functional outcome, and to reduced edema and lesion volume compared with vehicle. Specific antagonists to CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) or large conductance calcium-activated potassium (BK) channels reversed these effects. Specific binding assays did not indicate binding of AraS to the GPR55 cannabinoid receptor. N-arachidonoyl-L-serine blocked the attenuation in phosphorylated extracellular-signal-regulated kinase 1/2 (ERK) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices. Increased levels of the prosurvival factor Bcl-xL were evident 24 hours after injury in AraS-treated mice, followed by a 30% reduction in caspase-3 activity, measured 3 days after injury. Treatment with a CB2 antagonist, but not with a CB1 antagonist, reversed this effect. Our results suggest that administration of AraS leads to neuroprotection via ERK and Akt phosphorylation and induction of their downstream antiapoptotic pathways. These protective effects are related mostly to indirect signaling via the CB2R and TRPV1 channels but not through CB1 or GPR55 receptors.
J Cereb Blood Flow Metab 2011 Aug
PMID:N-arachidonoyl-L-serine is neuroprotective after traumatic brain injury by reducing apoptosis. 2150 78

We studied, in behaving mice, the contribution of CB1 receptors to the activity-dependent changes induced at the hippocampal CA3-CA1 synapse by associative learning and following experimentally evoked long-term potentiation (LTP). Mice were classically conditioned to evoke eyelid responses with a trace paradigm using a tone as conditioned stimulus (CS) and an electric shock as unconditioned stimulus (US). Field excitatory postsynaptic potentials (fEPSPs) were evoked at the CA3-CA1 synapse during the CS-US interval across training. Conditioning was performed in presence of an agonist (WIN55,212-2) alone or with an antagonist (AM251) of the CB1 receptor, injected either systemically or locally. Conditioned responses (CRs) and fEPSP potentiation were depressed by WIN55,212-2. LTP was evoked by high-frequency stimulation of Schaffer collaterals after systemic or local WIN55,212-2 and AM251 injections. WIN55,212-2 affected the induction phase of LTP, mainly when injected locally. The addition of AM251 canceled out the effects of WIN55,212-2. Similar experiments were carried out in animals lacking the CB1 receptor (CB1(-/-) mice) and following silencing of hippocampal CB1 receptors (CB1R-siRNA-injected animals). In this case, CRs (CB1(-/-) mice) and LTP (CB1(-/-) and CB1R-siRNA-injected mice) reached lower values than their respective controls. Results offer new insights for understanding CB1 receptor contribution to associative learning and to CA3-CA1 synaptic plasticity.
Cereb Cortex 2012 Mar
PMID:Involvement of cannabinoid CB1 receptor in associative learning and in hippocampal CA3-CA1 synaptic plasticity. 2167 70

Chronic cannabinoid exposure results in tolerance due to region-specific desensitization and down-regulation of CB1 cannabinoid receptors (CB1Rs). For most G-protein-coupled receptors, internalization closely follows rapid desensitization as an important component of long-term down-regulation. However, in vivo patterns of CB1R internalization are not known. Here we investigate the subcellular redistribution of CB1Rs in the rat forebrain following activation by agonist CP55 940 or inhibition by antagonist/inverse agonist AM251. At steady state, CB1Rs are mainly localized to the cell membrane of preterminal axon shafts and, to a lesser degree, to synaptic terminals. A high proportion of CB1Rs is also localized to somatodendritic endosomes. Inhibition of basal activation by acute AM251 administration decreases the number of cell bodies containing CB1R-immunoreactive endosomes, suggesting that CB1Rs are permanently activated and internalized at steady state. On the contrary, acute agonist treatment induces rapid and important increase of endosomal CB1R immunolabeling, likely due to internalization and retrograde transport of axonal CB1Rs. Repeated agonist treatment is necessary to significantly reduce initially high levels of axonal CB1R labeling, in addition to increasing somatodendritic endosomal CB1R labeling in cholecystokinin-positive interneurons. This redistribution displays important region-specific differences; it is most pronounced in the neocortex and hippocampus and absent in basal ganglia.
Cereb Cortex 2013 Nov
PMID:Activation-dependent subcellular distribution patterns of CB1 cannabinoid receptors in the rat forebrain. 2289 24

The CB1 cannabinoid receptor regulates cortical progenitor proliferation during embryonic development, but the molecular mechanism of this action remains unknown. Here, we report that CB1-deficient mouse embryos show premature cell cycle exit, decreased Pax6- and Tbr2-positive cell number, and reduced mammalian target of rapamycin complex 1 (mTORC1) activation in the ventricular and subventricular cortical zones. Pharmacological stimulation of the CB1 receptor in cortical slices and progenitor cell cultures activated the mTORC1 pathway and increased the number of Pax6- and Tbr2-expressing cells. Likewise, acute CB1 knockdown in utero reduced mTORC1 activation and cannabinoid-induced Tbr2-positive cell generation. Luciferase reporter and chromatin immunoprecipitation assays revealed that the CB1 receptor drives Tbr2 expression downstream of Pax6 induction in an mTORC1-dependent manner. Altogether, our results demonstrate that the CB1 receptor tunes dorsal telencephalic progenitor proliferation by sustaining the transcriptional activity of the Pax6-Tbr2 axis via the mTORC1 pathway, and suggest that alterations of CB1 receptor signaling, by producing the missexpression of progenitor identity determinants may contribute to neurodevelopmental alterations.
Cereb Cortex 2015 Sep
PMID:CB1 Cannabinoid Receptor-Dependent Activation of mTORC1/Pax6 Signaling Drives Tbr2 Expression and Basal Progenitor Expansion in the Developing Mouse Cortex. 2461 Jan 19


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