Liu QS

References (16)

Title : Role of endocannabinoid signaling in a septohabenular pathway in the regulation of anxiety- and depressive-like behavior - Vickstrom_2021_Mol.Psychiatry_26_3178
Author(s) : Vickstrom CR , Liu X , Liu S , Hu MM , Mu L , Hu Y , Yu H , Love SL , Hillard CJ , Liu QS
Ref : Mol Psychiatry , 26 :3178 , 2021
Abstract : Enhancing endocannabinoid signaling produces anxiolytic- and antidepressant-like effects, but the neural circuits involved remain poorly understood. The medial habenula (MHb) is a phylogenetically-conserved epithalamic structure that is a powerful modulator of anxiety- and depressive-like behavior. Here, we show that a robust endocannabinoid signaling system modulates synaptic transmission between the MHb and its sole identified GABA input, the medial septum and nucleus of the diagonal band (MSDB). With RNAscope in situ hybridization, we demonstrate that key enzymes that synthesize or degrade the endocannabinoids 2-arachidonylglycerol (2-AG) or anandamide are expressed in the MHb and MSDB, and that cannabinoid receptor 1 (CB1) is expressed in the MSDB. Electrophysiological recordings in MHb neurons revealed that endogenously-released 2-AG retrogradely depresses GABA input from the MSDB. This endocannabinoid-mediated depolarization-induced suppression of inhibition (DSI) was limited by monoacylglycerol lipase (MAGL) but not by fatty acid amide hydrolase. Anatomic and optogenetic circuit mapping indicated that MSDB GABA neurons monosynaptically project to cholinergic neurons of the ventral MHb. To test the behavioral significance of this MSDB-MHb endocannabinoid signaling, we induced MSDB-specific knockout of CB1 or MAGL via injection of virally-delivered Cre recombinase into the MSDB of Cnr1(loxP/loxP) or Mgll(loxP/loxP) mice. Relative to control mice, MSDB-specific knockout of CB1 or MAGL bidirectionally modulated 2-AG signaling in the ventral MHb and led to opposing effects on anxiety- and depressive-like behavior. Thus, depression of synaptic GABA release in the MSDB-ventral MHb pathway may represent a potential mechanism whereby endocannabinoids exert anxiolytic and antidepressant-like effects.
ESTHER : Vickstrom_2021_Mol.Psychiatry_26_3178
PubMedSearch : Vickstrom_2021_Mol.Psychiatry_26_3178
PubMedID: 33093652

Title : Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice - Schurman_2019_J.Neurosci_39_5949
Author(s) : Schurman LD , Carper MC , Moncayo LV , Ogasawara D , Richardson K , Yu L , Liu X , Poklis JL , Liu QS , Cravatt BF , Lichtman AH
Ref : Journal of Neuroscience , 39 :5949 , 2019
Abstract : Diacylglycerol lipase-alpha (DAGL-alpha), the principal biosynthetic enzyme of the endogenous cannabinoid 2-arachidonylglycerol (2-AG) on neurons, plays a key role in CB(1) receptor-mediated synaptic plasticity and hippocampal neurogenesis, but its contribution to global hippocampal-mediated processes remains unknown. Thus, the present study examines the role that DAGL-alpha plays on LTP in hippocampus, as well as in hippocampal-dependent spatial learning and memory tasks, and on the production of endocannabinoid and related lipids through the use of complementary pharmacologic and genetic approaches to disrupt this enzyme in male mice. Here we show that DAGL-alpha gene deletion or pharmacological inhibition disrupts LTP in CA1 of the hippocampus but elicits varying magnitudes of behavioral learning and memory deficits in mice. In particular, DAGL-alpha(-/-) mice display profound impairments in the Object Location assay and Morris Water Maze (MWM) acquisition engaging in nonspatial search strategies. In contrast, WT mice administered the DAGL-alpha inhibitor DO34 show delays in MWM acquisition and reversal learning, but no deficits in expression, extinction, forgetting, or perseveration processes in this task, as well as no impairment in Object Location. The deficits in synaptic plasticity and MWM performance occur in concert with decreased 2-AG and its major lipid metabolite (arachidonic acid), but increases of a 2-AG diacylglycerol precursor in hippocampus, PFC, striatum, and cerebellum. These novel behavioral and electrophysiological results implicate a direct and perhaps selective role of DAGL-alpha in the integration of new spatial information.SIGNIFICANCE STATEMENT Here we show that genetic deletion or pharmacologic inhibition of diacylglycerol lipase-alpha (DAGL-alpha) impairs hippocampal CA1 LTP, differentially disrupts spatial learning and memory performance in Morris water maze (MWM) and Object Location tasks, and alters brain levels of endocannabinoids and related lipids. Whereas DAGL-alpha(-/-) mice exhibit profound phenotypic spatial memory deficits, a DAGL inhibitor selectively impairs the integration of new information in MWM acquisition and reversal tasks, but not memory processes of expression, extinction, forgetting, or perseveration, and does not affect performance in the Objection Location task. The findings that constitutive or short-term DAGL-alpha disruption impairs learning and memory at electrophysiological and selective in vivo levels implicate this enzyme as playing a key role in the integration of new spatial information.
ESTHER : Schurman_2019_J.Neurosci_39_5949
PubMedSearch : Schurman_2019_J.Neurosci_39_5949
PubMedID: 31127001
Gene_locus related to this paper: mouse-q6wqj1

Title : Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex - McReynolds_2018_Biol.Psychiatry_84_85
Author(s) : McReynolds JR , Doncheck EM , Li Y , Vranjkovic O , Graf EN , Ogasawara D , Cravatt BF , Baker DA , Liu QS , Hillard CJ , Mantsch JR
Ref : Biological Psychiatry , 84 :85 , 2018
Abstract : BACKGROUND: Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone "set the stage" for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL). METHODS: We have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, intraperitoneal). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL microinfusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons. RESULTS: Corticosterone application attenuated inhibitory synaptic transmission in the PL via cannabinoid receptor type 1 (CB1R)- and 2-arachidonoylglycerol-dependent inhibition of gamma-aminobutyric acid release without altering postsynaptic responses. The ability of systemic stress-level corticosterone treatment to potentiate cocaine-primed reinstatement was recapitulated by intra-PL injection of corticosterone, the CB1R agonist WIN 55,212-2, or the monoacylglycerol lipase inhibitor URB602. Corticosterone effects on reinstatement were attenuated by intra-PL injections of either the CB1R antagonist, AM251, or the diacylglycerol lipase inhibitor, DO34. CONCLUSIONS: These findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-arachidonoylglycerol in the PL, resulting in CB1R-mediated attenuation of inhibitory transmission in this brain region.
ESTHER : McReynolds_2018_Biol.Psychiatry_84_85
PubMedSearch : McReynolds_2018_Biol.Psychiatry_84_85
PubMedID: 29100630

Title : Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum - Chen_2016_eNeuro_3_
Author(s) : Chen Y , Liu X , Vickstrom CR , Liu MJ , Zhao L , Viader A , Cravatt BF , Liu QS
Ref : eNeuro , 3 : , 2016
Abstract : Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knock-out of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation, because it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.
ESTHER : Chen_2016_eNeuro_3_
PubMedSearch : Chen_2016_eNeuro_3_
PubMedID: 27182552

Title : Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition - Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
Author(s) : Ogasawara D , Deng H , Viader A , Baggelaar MP , Breman A , den Dulk H , van den Nieuwendijk AM , Soethoudt M , van der Wel T , Zhou J , Overkleeft HS , Sanchez-Alavez M , Mori S , Nguyen W , Conti B , Liu X , Chen Y , Liu QS , Cravatt BF , van der Stelt M
Ref : Proc Natl Acad Sci U S A , 113 :26 , 2016
Abstract : Diacylglycerol lipases (DAGLalpha and DAGLbeta) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLalpha is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.
ESTHER : Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
PubMedSearch : Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
PubMedID: 26668358
Gene_locus related to this paper: human-DAGLA , human-DAGLB

Title : Coordinated regulation of endocannabinoid-mediated retrograde synaptic suppression in the cerebellum by neuronal and astrocytic monoacylglycerol lipase - Liu_2016_Sci.Rep_6_35829
Author(s) : Liu X , Chen Y , Vickstrom CR , Li Y , Viader A , Cravatt BF , Liu QS
Ref : Sci Rep , 6 :35829 , 2016
Abstract : The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates retrograde synaptic depression including depolarization-induced suppression of excitation (DSE) and inhibition (DSI). 2-AG is degraded primarily by monoacylglycerol lipase (MAGL), which is expressed in neurons and astrocytes. Using knockout mice in which MAGL is deleted globally or selectively in neurons or astrocytes, we investigated the relative contribution of neuronal and astrocytic MAGL to the termination of DSE and DSI in Purkinje cells (PCs) in cerebellar slices. We report that neuronal MAGL plays a predominant role in terminating DSE at climbing fiber (CF) to PC synapses, while both neuronal and astrocytic MAGL significantly contributes to the termination of DSE at parallel fiber (PF) to PC synapses and DSI at putative Stellate cell to PC synapses. Thus, DSE and DSI at different synapses is not uniformly affected by global and cell type-specific knockout of MAGL. Additionally, MAGL global knockout, but not cell type-specific knockout, caused tonic activation and partial desensitization of the CB1 receptor at PF-PC synapses. This tonic CB1 activation is mediated by 2-AG since it was blocked by the diacylglycerol lipase inhibitor DO34. Together, these results suggest that both neuronal and astrocytic MAGL contribute to 2-AG clearance and prevent CB1 receptor over-stimulation in the cerebellum.
ESTHER : Liu_2016_Sci.Rep_6_35829
PubMedSearch : Liu_2016_Sci.Rep_6_35829
PubMedID: 27775008

Title : Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice - Ghosh_2015_J.Pharmacol.Exp.Ther_354_111
Author(s) : Ghosh S , Kinsey SG , Liu QS , Hruba L , McMahon LR , Grim TW , Merritt CR , Wise LE , Abdullah RA , Selley DE , Sim-Selley LJ , Cravatt BF , Lichtman AH
Ref : Journal of Pharmacology & Experimental Therapeutics , 354 :111 , 2015
Abstract : Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piper idinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Delta(9)-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition combined with partial MAGL inhibition reduces neuropathic and inflammatory pain states with minimal cannabimimetic effects.
ESTHER : Ghosh_2015_J.Pharmacol.Exp.Ther_354_111
PubMedSearch : Ghosh_2015_J.Pharmacol.Exp.Ther_354_111
PubMedID: 25998048

Title : Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity - Zhang_2015_Hippocampus_25_16
Author(s) : Zhang Z , Wang W , Zhong P , Liu SJ , Long JZ , Zhao L , Gao HQ , Cravatt BF , Liu QS
Ref : Hippocampus , 25 :16 , 2015
Abstract : The endocannabinoid ligand 2-arachidonoylglycerol (2-AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant- and anxiolytic-like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive-like behaviors and decreased the number of bromodeoxyuridine-labeled neural progenitor cells and doublecortin-positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long-term potentiation (LTP) in the DG known to be neurogenesis-dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS-exposed mice. These results suggest that enhanced adult neurogenesis and long-term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant- and anxiolytic-like behavioral effects of JZL184.
ESTHER : Zhang_2015_Hippocampus_25_16
PubMedSearch : Zhang_2015_Hippocampus_25_16
PubMedID: 25131612
Gene_locus related to this paper: human-MGLL

Title : Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling - Zhong_2014_Neuropsychopharmacology_39_1763
Author(s) : Zhong P , Wang W , Pan B , Liu X , Zhang Z , Long JZ , Zhang HT , Cravatt BF , Liu QS
Ref : Neuropsychopharmacology , 39 :1763 , 2014
Abstract : The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization-induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB1 receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling.
ESTHER : Zhong_2014_Neuropsychopharmacology_39_1763
PubMedSearch : Zhong_2014_Neuropsychopharmacology_39_1763
PubMedID: 24476943

Title : Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice - Pan_2011_J.Neurosci_31_13420
Author(s) : Pan B , Wang W , Zhong P , Blankman JL , Cravatt BF , Liu QS
Ref : Journal of Neuroscience , 31 :13420 , 2011
Abstract : Endocannabinoid (eCB) signaling is tightly regulated by eCB biosynthetic and degradative enzymes. The eCB 2-arachidonoylglycerol (2-AG) is hydrolyzed primarily by monoacylglycerol lipase (MAGL). Here, we investigated whether eCB signaling, synaptic function, and learning behavior were altered in MAGL knock-out mice. We report that MAGL(-)/(-) mice exhibited prolonged depolarization-induced suppression of inhibition (DSI) in hippocampal CA1 pyramidal neurons, providing genetic evidence that the inactivation of 2-AG by MAGL determines the time course of the eCB-mediated retrograde synaptic depression. CB(1) receptor antagonists enhanced basal IPSCs in CA1 pyramidal neurons in MAGL(-)/(-) mice, while the magnitude of DSI or CB(1) receptor agonist-induced depression of IPSCs was decreased in MAGL(-)/(-) mice. These results suggest that 2-AG elevations in MAGL(-)/(-) mice cause tonic activation and partial desensitization of CB(1) receptors. Genetic deletion of MAGL selectively enhanced theta burst stimulation (TBS)-induced long-term potentiation (LTP) in the CA1 region of hippocampal slices but had no significant effect on LTP induced by high-frequency stimulation or long-term depression induced by low-frequency stimulation. The enhancement of TBS-LTP in MAGL(-)/(-) mice appears to be mediated by 2-AG-induced suppression of GABA(A) receptor-mediated inhibition. MAGL(-)/(-) mice exhibited enhanced learning as shown by improved performance in novel object recognition and Morris water maze. These results indicate that genetic deletion of MAGL causes profound changes in eCB signaling, long-term synaptic plasticity, and learning behavior.
ESTHER : Pan_2011_J.Neurosci_31_13420
PubMedSearch : Pan_2011_J.Neurosci_31_13420
PubMedID: 21940435
Gene_locus related to this paper: human-MGLL , mouse-MGLL

Title : Genetic deletion of monoacylglycerol lipase alters endocannabinoid-mediated retrograde synaptic depression in the cerebellum - Zhong_2011_J.Physiol_589_4847
Author(s) : Zhong P , Pan B , Gao XP , Blankman JL , Cravatt BF , Liu QS
Ref : Journal de Physiologie , 589 :4847 , 2011
Abstract : The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) is hydrolysed primarily by monoacylglycerol lipase (MAGL). Here, we investigated whether eCB-mediated retrograde synaptic depression in cerebellar slices was altered in MAGL knockout (MAGL(-/-)) mice. Depolarization-induced suppression of excitation (DSE) and metabotropic glutamate receptor (mGluR1)-mediated synaptic depression are mediated by 2-AG-induced activation of CB(1) receptors. We show that genetic deletion of MAGL prolonged DSE at parallel fibre (PF) or climbing fibre (CF) to Purkinje cell (PC) synapses. Likewise, mGluR1-mediated synaptic depression, induced either by high-frequency stimulation of PF or mGluR1 agonist DHPG, was prolonged in MAGL(-/-) mice. About 15% of 2-AG in the brain is hydrolysed by serine hydrolase alpha-beta-hydrolase domain 6 and 12 (ABHD6 and ABHD12). However, the selective ABHD6 inhibitor WWL123 had no significant effect on cerebellar DSE in MAGL(+/+) and (-/-) mice. The CB(1) receptor antagonist SR141716 significantly increased the amplitude of basal excitatory postsynaptic currents (EPSCs) in MAGL(-/-) mice but not in MAGL(+/+) mice. Conversely, the CB(1) agonist WIN55212 induced less depression of basal EPSCs in MAGL(-/-) mice than in MAGL(+/+) mice. These results provide genetic evidence that inactivation of 2-AG by MAGL determines the time course of eCB-mediated retrograde synaptic depression and that genetic deletion of MAGL causes tonic activation and consequential desensitization of CB(1) receptors.
ESTHER : Zhong_2011_J.Physiol_589_4847
PubMedSearch : Zhong_2011_J.Physiol_589_4847
PubMedID: 21911610
Gene_locus related to this paper: human-MGLL , mouse-MGLL

Title : Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system - Schlosburg_2010_Nat.Neurosci_13_1113
Author(s) : Schlosburg JE , Blankman JL , Long JZ , Nomura DK , Pan B , Kinsey SG , Nguyen PT , Ramesh D , Booker L , Burston JJ , Thomas EA , Selley DE , Sim-Selley LJ , Liu QS , Lichtman AH , Cravatt BF
Ref : Nat Neurosci , 13 :1113 , 2010
Abstract : Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.
ESTHER : Schlosburg_2010_Nat.Neurosci_13_1113
PubMedSearch : Schlosburg_2010_Nat.Neurosci_13_1113
PubMedID: 20729846

Title : Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) Enhances retrograde endocannabinoid signaling - Pan_2009_J.Pharmacol.Exp.Ther_331_591
Author(s) : Pan B , Wang W , Long JZ , Sun D , Hillard CJ , Cravatt BF , Liu QS
Ref : Journal of Pharmacology & Experimental Therapeutics , 331 :591 , 2009
Abstract : Endocannabinoid (eCB) signaling mediates depolarization-induced suppression of excitation (DSE) and inhibition (DSI), two prominent forms of retrograde synaptic depression. N-Arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), two known eCBs, are degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Selective blockade of FAAH and MAGL is critical for determining the roles of the eCBs in DSE/DSI and understanding how their action is regulated. 4-Nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) is a recently developed, highly selective, and potent MAGL inhibitor that increases 2-AG but not AEA concentrations in mouse brain. Here, we report that JZL184 prolongs DSE in Purkinje neurons in cerebellar slices and DSI in CA1 pyramidal neurons in hippocampal slices. The effect of JZL184 on DSE/DSI is mimicked by the nonselective MAGL inhibitor methyl arachidonyl fluorophosphonate. In contrast, neither the selective FAAH inhibitor cyclohexylcarbamic acid 3'-carbomoylbiphenyl-3-yl ester (URB597) nor FAAH knockout has a significant effect on DSE/DSI. JZL184 produces greater enhancement of DSE/DSI in mouse neurons than that in rat neurons. The latter finding is consistent with biochemical studies showing that JZL184 is more potent in inhibiting mouse MAGL than rat MAGL. These results indicate that the degradation of 2-AG by MAGL is the rate-limiting step that determines the time course of DSE/DSI and that JZL184 is a useful tool for the study of 2-AG-mediated signaling.
ESTHER : Pan_2009_J.Pharmacol.Exp.Ther_331_591
PubMedSearch : Pan_2009_J.Pharmacol.Exp.Ther_331_591
PubMedID: 19666749

Title : Potentiation of alpha7-containing nicotinic acetylcholine receptors by select albumins - Conroy_2003_Mol.Pharmacol_63_419
Author(s) : Conroy WG , Liu QS , Nai Q , Margiotta JF , Berg DK
Ref : Molecular Pharmacology , 63 :419 , 2003
Abstract : Nicotinic receptors containing alpha7 subunits are ligand-gated ion channels widely distributed in the nervous system; they influence a diverse array of events because of their high relative calcium permeability. We show here that nicotine-induced whole-cell responses generated by such receptors can be dramatically potentiated in a rapidly reversible manner by some but not all albumins. The potentiation involves increases both in potency and efficacy with no obvious differences in rise and fall times of the response. The potentiation is not reduced by removing absorbed components; it is abolished by proteolysis, suggesting that the albumin protein backbone is essential. The fact that some albumins are ineffective indicates that minor differences in amino acid sequence may be critical. Experiments with open channel blockers indicate that the potentiation involves increased responses from active receptors rather than recruitment of receptors from a previously silent pool. Single channel recordings reveal that the potentiation correlates with increased single channel opening probability, reflected in increased frequency of channel opening and increased mean channel open time. The potentiation can be exploited to overcome blockade by noncompetitive inhibitors such as beta-amyloid peptide. The results raise the possibility that endogenous compounds use the site to modulate receptor function in vivo, and suggest that the receptors may represent useful targets for therapeutic intervention in cases where they have been implicated in neuropathologies such as Alzheimer's disease.
ESTHER : Conroy_2003_Mol.Pharmacol_63_419
PubMedSearch : Conroy_2003_Mol.Pharmacol_63_419
PubMedID: 12527814

Title : Nicotinic regulation of CREB activation in hippocampal neurons by glutamatergic and nonglutamatergic pathways - Hu_2002_Mol.Cell.Neurosci_21_616
Author(s) : Hu M , Liu QS , Chang KT , Berg DK
Ref : Molecular & Cellular Neurosciences , 21 :616 , 2002
Abstract : Activity-dependent gene expression is essential for form and function in the nervous system. Best understood is the role of glutamatergic signaling in controlling such events, but nicotinic signaling can also regulate transcription. We show here that nicotine can alter gene expression in rat hippocampal neurons, as reflected by activation of the transcription factor CREB and appearance of the immediate early gene product c-Fos. The process depends on both CaM and MAP kinases and on calcium release from internal stores. Part of the nicotinic effect is mediated via glutamatergic transmission, even in the absence of action potentials. Voltage-gated calcium channels are not necessary for nicotine-induced activation of CREB in hippocampal neurons. The low levels of sustained nicotinic stimulation required for transcriptional effects are consistent with those likely to be achievable either by the normal septal cholinergic innervation of the hippocampus or by repeated tobacco usage.
ESTHER : Hu_2002_Mol.Cell.Neurosci_21_616
PubMedSearch : Hu_2002_Mol.Cell.Neurosci_21_616
PubMedID: 12504594

Title : Extracellular calcium regulates responses of both alpha3- and alpha7-containing nicotinic receptors on chick ciliary ganglion neurons - Liu_1999_J.Neurophysiol_82_1124
Author(s) : Liu QS , Berg DK
Ref : Journal of Neurophysiology , 82 :1124 , 1999
Abstract : Neuronal nicotinic receptors are generally both permeable to calcium and potentiated by it. We have examined acute calcium regulation of both native alpha7-containing and the less abundant alpha3-containing nicotinic receptors on chick ciliary ganglion neurons. Most of the receptors are concentrated on somatic spines tightly overlaid in situ by a large presynaptic calyx. Whole cell patch-clamp recording from dissociated neurons using perforated patch-clamp techniques indicates that the rapidly desensitizing nicotinic response of alpha7-containing receptors achieves maximum amplitude in 2 mM calcium; both lower and higher concentrations of calcium are less effective. Barium and strontium but not magnesium can substitute for calcium in potentiating the response. Neither calcium current through the receptors nor calcium action at intracellular sites is necessary. These latter conclusions are supported by current-voltage analysis of the nicotine-induced response, ion substitution experiments, and internal perfusion of the cells with 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA) via a conventional patch pipette. Varying the agonist concentration indicates that some of the calcium-dependent enhancement may involve a shift in the dose-response curve for agonist binding, but much of the effect is also likely to involve increased receptor responsiveness. Blockade of alpha7-containing receptors with alpha-bungarotoxin showed that the heteromeric alpha3-containing nicotinic receptors also undergo calcium-dependent potentiation. Calcium did not have a major effect on the desensitization rate of either receptor class but did have a selective effect on the rise time of alpha7-containing receptors. Analysis of stably transfected cells expressing an alpha7 gene construct showed that the calcium potentiation observed for native receptors did not require neuron-specific modifications or components and that it could be seen with the natural agonist acetylcholine. Receptor dependence on extracellular calcium may provide a regulatory mechanism for constraining synaptic signaling, avoiding local depletion of external calcium, and limiting calcium buildup in postsynaptic compartments.
ESTHER : Liu_1999_J.Neurophysiol_82_1124
PubMedSearch : Liu_1999_J.Neurophysiol_82_1124
PubMedID: 10482732