Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neocortical GABA-containing interneurons form complex functional networks responsible for feedforward and feedback inhibition and for the generation of cortical oscillations associated with several behavioural functions. We previously reported that fast-spiking (FS), but not low-threshold-spiking (LTS), neocortical interneurons from rats generate a fast and precise self-inhibition mediated by inhibitory autaptic transmission. Here we show that LTS cells possess a different form of self-inhibition. LTS, but not FS, interneurons undergo a prominent hyperpolarization mediated by an increased K+-channel conductance. This self-induced inhibition lasts for many minutes, is dependent on an increase in intracellular [Ca2+] and is blocked by the cannabinoid receptor antagonist AM251, indicating that it is mediated by the autocrine release of endogenous cannabinoids. Endocannabinoid-mediated slow self-inhibition represents a powerful and long-lasting mechanism that alters the intrinsic excitability of LTS neurons, which selectively target the major site of excitatory connections onto pyramidal neurons; that is, their dendrites. Thus, modulation of LTS networks after their sustained firing will lead to long-lasting changes of glutamate-mediated synaptic strength in pyramidal neurons, with consequences during normal and pathophysiological cortical network activities.
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PMID:Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. 1537 34

Delta9-tetrahydrocannabinol (Delta9-THC), the major psychoactive component of marijuana, induces catalepsy-like immobilization and impairment of spatial memory in rats. Delta9-THC also induces aggressive behavior in isolated housing stress. These abnormal behaviors could be counteracted by SR141716A, a CB1 cannabinoid receptor antagonist. Also Delta9-THC inhibited release of glutamate in the dorsal hippocampus, but this inhibition could be antagonized by SR141716A in an in vivo microdialysis study. Moreover, NMDA and AMPA-type glutamate receptor enhancers improved the Delta9-THC-induced impairment of spatial memory. On the other hand, Delta9-THC markedly inhibited the neurodegeneration in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis and reduced the elevated glutamate level of cerebrospinal fluid induced by EAE. These therapeutic effects on EAE were reversed by SR141716A. Taken together, our results demonstrate that the inhibition of glutamate release via activation of the CB1-cannabinoid receptor is one mechanism involved in Delta9-THC-induced impairment of spatial memory, and the therapeutic effect of Delta9-THC on EAE, and a Delta9-THC analog might provide an effective treatment for psychosis and neurodegenerative diseases.
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PMID:New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. 1559 3

The wake-promoting neuropeptides orexins (hypocretins) play a crucial role in controlling neuronal excitability and synaptic transmission in the CNS. In this study, using whole-cell patch-clamp recordings in an acute dorsal raphe nucleus (DRN) slice preparation, we report that orexin B (Orx-B) depresses the evoked glutamate-mediated synaptic currents in DRN 5-HT neurons. The Orx-B-induced depression is accompanied by an increase in the paired-pulse ratio and the coefficient of variance, suggesting a presynaptic site of action. Orx-B also reduces the frequency but not the amplitude of miniature EPSCs, indicating that depression of glutamatergic transmission is mediated by a decrease in glutamate release. Surprisingly, the Orx-B-induced inhibition of glutamatergic transmission is abolished by postsynaptic inhibition of G-protein signaling with GDPbetaS, suggesting that this effect is signaled by postsynaptic orexin receptors and expressed presynaptically, presumably through a retrograde messenger. Interestingly, the Orx-B-induced depression of glutamate release is mimicked and occluded by the cannabinoid receptor agonist WIN 55,212-2, and is abolished by the CB1 cannabinoid receptor antagonist AM 251. These results imply that the Orx-B-induced depression of glutamatergic transmission to DRN 5-HT neurons is mediated by retrograde endocannabinoid release. Examination of downstream signaling pathways involved in this response indicates that the effect of Orx-B requires the activation of phospholipase C and DAG lipase enzymatic pathways but not a rise in postsynaptic intracellular calcium. Therefore, our findings reveal a previously unsuspected mechanism by which postsynaptic orexin receptors can modulate glutamatergic synaptic transmission to DRN 5-HT neurons.
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PMID:The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signaling. 1567 70

While cannabinoid receptors activate multiple signaling pathways in the brain, it remains unclear what influence the inhibition of adenylylcyclase has on the inhibition of glutamate release. In cerebrocortical nerve terminals, the cannabinoid receptor agonist WIN55,212-2 reduced KCl-evoked glutamate release through a mechanism that restricted the rise of cytoplasmic free Ca2+, but not the changes in plasma membrane depolarization. These effects were consistent with the inhibition of Ca2+ channels. Furthermore, WIN55,212-2 reduced 4-aminopyridine (4AP) evoked glutamate release to a larger extent by modulating the behavior of both Ca2+ and K(+)-channels. The inhibition of 4AP-evoked release was associated with a decrease in cytoplasmic free Ca2+ and in plasma membrane depolarization that was reverted by the potassium channel blocker, tetraethylammonium. Interestingly, the reduction of KCl- and 4AP-evoked release by WIN55,212-2 was independent of adenylylcyclase activity and did not affect cAMP. Forskolin and the beta-adrenergic receptor increase intrasynaptosomal cAMP and promote a PKA-dependent tetrodotoxin (TTX)-sensitive increase in the spontaneous release of glutamate. These two responses were reduced by WIN55,212-2. However, the glutamate release induced by Sp-8-Br-cAMPS, which directly activated PKA without affecting cAMP, was also similarly reduced by WIN55,212-2. Hence, we conclude that the inhibition of glutamate release by WIN55,212-2 is unrelated to changes in cAMP and that the inhibition of release that a decrease in cAMP might produce is occluded by the activation of additional pathways such as the inhibition of Ca2+ channels and/or the activation of K(+)-channels that strongly depress glutamate release.
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PMID:The modulation of Ca2+ and K+ channels but not changes in cAMP signaling contribute to the inhibition of glutamate release by cannabinoid receptors in cerebrocortical nerve terminals. 1575 82

This study was undertaken to analyze the involvement of periaqueductal gray (PAG) cannabinoid or group I metabotropic glutamate receptors in the formalin-induced changes on the rostral ventromedial medulla (RVM) ON- and OFF-cells activities. S.c. injection of formalin into the hind paw produced a transient decrease (4-6 min) followed by a longer increase (25-35 min) in tail flick latencies. Formalin also increased basal activity in RVM ON-cells (42+/-7%) and decreased it in OFF-cells (35+/-4%). Intra-PAG microinjection of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) (2 nmol/rat), a cannabinoid receptor agonist, prevented the formalin-induced changes in RVM cell activities. Higher dosages of WIN 55,212-2 (4-8 nmol/rat) increased the tail flick latencies, delayed the tail flick-related onset to ON-cell burst, and decreased the duration of OFF-cell pause. Furthermore, WIN 55,212-2 at a dosage of 8 nmol/rat decreased RVM ON-cell (57+/-7%) and increased OFF-cell ongoing activities (26+/-4%). These effects were prevented by N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide SR141716A, (1 pmol/rat), a CB1 cannabinoid receptor antagonist, or by 2-methyl-6-(phenylethynyl)pyridine (MPEP 20 nmol/rat), a selective mGlu5 glutamate receptor antagonist. T7-(hydroxyimino) cyclopropa[b]chromen-1alpha-carboxylate ethyl ester (CPCOOE/50 nmol/rat) and (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385, 20 nmol/rat), selective mGlu1 glutamate receptor antagonists, were ineffective in preventing the WIN-induced effects. This study suggests that s.c. injection of formalin modifies RVM neuronal activities and this effect is prevented by PAG cannabinoid receptor stimulation. Moreover, the physiological stimulation of PAG mGlu5, but not mGlu1 glutamate receptors, seems to be required for the cannabinoid-mediated effect.
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PMID:Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat. 1595 87

Glucocorticoids secreted in response to stress activation of the hypothalamic-pituitary-adrenal axis feed back onto the brain to rapidly suppress neuroendocrine activation, including oxytocin and vasopressin secretion. Here we show using whole-cell patch clamp recordings that glucocorticoids elicit a rapid, opposing action on synaptic glutamate and gamma-aminobutyric acid (GABA) release onto magnocellular neurons of the hypothalamic supraoptic nucleus and paraventricular nucleus, suppressing glutamate release and facilitating GABA release by activating a putative membrane receptor. The glucocorticoid effect on both glutamate and GABA release was blocked by inhibiting postsynaptic G protein activity, suggesting a dependence on postsynaptic G protein signaling and the involvement of a retrograde messenger. Biochemical analysis of hypothalamic slices treated with dexamethasone revealed a glucocorticoid-induced rapid increase in the levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The glucocorticoid suppression of glutamate release was blocked by the type I cannabinoid receptor cannabinoid receptor antagonist, AM251, and was mimicked and occluded by AEA and 2-AG, suggesting it was mediated by retrograde endocannabinoid release. The glucocorticoid facilitation of GABA release was also blocked by AM251 but was not mimicked by AEA, 2-AG, or a synthetic cannabinoid, WIN 55,212-2, nor was it blocked by vanilloid or ionotropic glutamate receptor antagonists, suggesting that it was mediated by a retrograde messenger acting at an AM251-sensitive, noncannabinoid/nonvanilloid receptor at presynaptic GABA terminals. The combined, opposing actions of glucocorticoids mediate a rapid inhibition of the magnocellular neuroendocrine cells, which in turn should mediate rapid feedback inhibition of the secretion of oxytocin and vasopressin by glucocorticoids during stress activation of the hypothalamic-pituitary-adrenal axis.
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PMID:Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons. 1599 43

Glycinergic synapses are implicated in the coordination of reflex responses, sensory signal processing and pain sensation. Their activity is pre- and postsynaptically regulated, although mechanisms are poorly understood. Using patch-clamp recording and Ca2+ imaging in hypoglossal motoneurones from rat and mouse brainstem slices, we address here the role of cytoplasmic Ca2+ (Ca(i)) in glycinergic synapse modulation. Ca2+ influx through voltage-gated or NMDA receptor channels caused powerful transient inhibition of glycinergic IPSCs. This effect was accompanied by an increase in both the failure rate and paired-pulse ratio, as well as a decrease in the frequency of mIPSCs, suggesting a presynaptic mechanism of depression. Inhibition was reduced by the cannabinoid receptor antagonist SR141716A and occluded by the agonist WIN55,212-2, indicating involvement of endocannabinoid retrograde signalling. Conversely, in the presence of SR141716A, glycinergic IPSCs were potentiated postsynaptically by glutamate or NMDA, displaying a Ca2(+)-dependent increase in amplitude and decay prolongation. Both presynaptic inhibition and postsynaptic potentiation were completely prevented by strong Ca(i) buffering (20 mm BAPTA). Our findings demonstrate two independent mechanisms by which Ca2+ modulates glycinergic synaptic transmission: (i) presynaptic inhibition of glycine release and (ii) postsynaptic potentiation of GlyR-mediated responses. This dual Ca2(+)-induced regulation might be important for feedback control of neurotransmission in a variety of glycinergic networks in mammalian nervous systems.
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PMID:Dual Ca2+ modulation of glycinergic synaptic currents in rodent hypoglossal motoneurones. 1612 5

Endocannabinoid release from a single neuron has been shown to cause presynaptic inhibition of transmitter release at many different sites. Here, we demonstrate that hypothalamic proopiomelanocortin (POMC) neurons release endocannabinoids continuously under basal conditions, unlike other release sites at which endocannabinoid production must be stimulated. The basal endocannabinoid release selectively inhibited GABA release onto POMC neurons, although exogenous administration of cannabinoid agonists also inhibited glutamate release. The CB1 cannabinoid receptor antagonist AM 251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] blocked endocannabinoid-mediated inhibition of GABA release without affecting excitatory synaptic currents, whereas the CB1 receptor agonist WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] inhibited both inhibitory and excitatory synaptic currents in POMC neurons. These data demonstrate that endogenously released cannabinoids and exogenously applied CB1 receptor agonists can have markedly different effects on synaptic inputs. Furthermore, the data suggest a novel form of endocannabinoid-mediated retrograde inhibition, whereby the regulation of a subset of inputs requires either the removal of tonic presynaptic inhibition caused by endocannabinoids or the engagement of a mechanism that actively inhibits endocannabinoid production.
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PMID:Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids. 1623 78

A novel, non-CB1 cannabinoid receptor has been defined by the persistence of inhibition of glutamatergic EPSPs by the cannabinoid receptor agonist WIN55,212-2 in mice lacking the cloned CB1 receptor (CB1-/-) (Hajos et al., 2001). This novel receptor was also distinguished from CB1 by its sensitivity to the antagonist SR141716A and its insensitivity to the antagonist AM251 (Hajos & Freund, 2002). We have chosen to refer to this putative receptor as CBsc due to its identification on Schaffer collateral axon terminals in the hippocampus. We examined properties of CBsc receptors in Sprague Dawley (SD) rats and two strains of wild-type (WT) mice (C57BL/6J and CD1) used as backgrounds for two independent lines of CB1-/- mice (Ledent et al., 1999; Zimmer et al., 1999). The inhibition of synaptic glutamate release by WIN55,212-2 was observed in hippocampal slices from WT CD1 mice and SD rats but was absent in WT C57 mice. We also found that AM251 and SR141716A antagonized the effect of WIN55,212-2 in hippocampal slices from CD1 mice and SD rats demonstrating a lack of selectivity of these ligands for CB1 and CBsc receptors in these animals. The results indicate that the glutamate-modulating CBsc cannabinoid receptor is present in the hippocampi of CD1 mice and SD rats but not in C57BL/6J mice. Thus, we have identified animal models that may permit the study of cannabinoids independently of the novel CBsc receptor (C57CB1+/+), the CBsc receptor independently of the cloned CB1 receptor (CD1CB1-/-), or in the absence of both receptors (C57CB1-/-).
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PMID:Species and strain differences in the expression of a novel glutamate-modulating cannabinoid receptor in the rodent hippocampus. 1626 78

We recently showed that central injections of alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits oxytocin cells and reduces peripheral release of oxytocin, but induces oxytocin release from dendrites. Dendritic oxytocin release can be triggered by agents that mobilize intracellular calcium. Oxytocin, like alpha-MSH, mobilizes intracellular calcium stores in oxytocin cells and triggers presynaptic inhibition of afferent inputs that is mediated by cannabinoids. We hypothesized that this mechanism might underlie the inhibitory effects of alpha-MSH. To test this, we recorded extracellularly from identified oxytocin and vasopressin cells in the anesthetized rat supraoptic nucleus (SON). Retrodialysis of a CB1 cannabinoid receptor antagonist to the SON blocked the inhibitory effects of intracerebroventricular injections of alpha-MSH on the spontaneous activity of oxytocin cells. We then monitored synaptically mediated responses of SON cells to stimulation of the organum vasculosum of the lamina terminalis (OVLT); this evoked a mixed response comprising an inhibitory component mediated by GABA and an excitatory component mediated by glutamate, as identified by the effects of bicuculline and 6-cyano-7-nitroquinoxaline-2,3-dione applied to the SON by retrodialysis. Application of CB1 receptor agonists to the SON attenuated the excitatory effects of OVLT stimulation in both oxytocin and vasopressin cells, whereas alpha-MSH attenuated the responses of oxytocin cells only. Thus alpha-MSH can act as a "switch"; it triggers oxytocin release centrally, but at the same time through initiating endocannabinoid production in oxytocin cells inhibits their electrical activity and hence, peripheral secretion.
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PMID:Presynaptic actions of endocannabinoids mediate alpha-MSH-induced inhibition of oxytocin cells. 1626 71


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