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Results: 1 to 10 of 43

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Electrophysiological Measurement of Cannabinoid-Mediated Synaptic Modulation in Acute Mouse Brain Slices.
Báldi R, Ghosh D, Grueter BA, Patel S
(2016) Curr Protoc Neurosci 75: 6.29.1-6.29.19
MeSH Terms: Animals, Brain, Cannabinoid Receptor Modulators, Endocannabinoids, In Vitro Techniques, Mice, Neuronal Plasticity, Patch-Clamp Techniques, Synapses, Synaptic Transmission
Show Abstract · Added March 14, 2018
Endocannabinoids (eCBs) are a class of bioactive lipids that mediate retrograde synaptic modulation at central and peripheral synapses. The highly lipophilic nature of eCBs and the pharmacological tools available to interrogate this system require unique methodological consideration, especially when applied to ex vivo systems such as electrophysiological analysis in acute brain slices. This unit provides protocols for measuring cannabinoid and eCB-mediated synaptic signaling in mouse brain slices, including analysis of short-term, long-term, and tonic eCB signaling modes, and the unique considerations for working with eCBs and TRPV1/cannabinoid ligands in acute brain slices.
Copyright © 2016 John Wiley & Sons, Inc.
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10 MeSH Terms
Neurobiological Interactions Between Stress and the Endocannabinoid System.
Morena M, Patel S, Bains JS, Hill MN
(2016) Neuropsychopharmacology 41: 80-102
MeSH Terms: Animals, Arachidonic Acids, Cannabinoid Receptor Modulators, Endocannabinoids, Glycerides, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Polyunsaturated Alkamides, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Stress, Psychological
Show Abstract · Added March 14, 2018
Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.
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12 MeSH Terms
High times for low-frequency stimulation as endocannabinoids engage in hippocampal long-term depression.
Patel S
(2012) Neuropsychopharmacology 37: 583-5
MeSH Terms: Animals, Cannabinoid Receptor Modulators, Endocannabinoids, Hippocampus, Long-Term Synaptic Depression, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Receptors, N-Methyl-D-Aspartate
Added January 20, 2015
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8 MeSH Terms
(R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2.
Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, Banerjee S, Oates JA, Marnett LJ
(2011) Nat Chem Biol 7: 803-9
MeSH Terms: Arachidonic Acid, Arachidonic Acids, Cannabinoid Receptor Modulators, Catalytic Domain, Chemistry, Pharmaceutical, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Endocannabinoids, Glycerides, Models, Molecular, Oxidation-Reduction, Protein Binding, Protein Conformation, Substrate Specificity
Show Abstract · Added March 5, 2014
Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid and the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. Evaluation of a series of COX-2 inhibitors revealed that many weak competitive inhibitors of arachidonic acid oxygenation are potent inhibitors of endocannabinoid oxygenation. (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are considered to be inactive as COX-2 inhibitors, are potent 'substrate-selective inhibitors' of endocannabinoid oxygenation. Crystal structures of the COX-2–(R)-naproxen and COX-2–(R)-flurbiprofen complexes verified this unexpected binding and defined the orientation of the (R) enantiomers relative to (S) enantiomers. (R)-Profens selectively inhibited endocannabinoid oxygenation by lipopolysaccharide-stimulated dorsal root ganglion (DRG) cells. Substrate-selective inhibition provides new tools for investigating the role of COX-2 in endocannabinoid oxygenation and a possible explanation for the ability of (R)-profens to maintain endocannabinoid tone in models of neuropathic pain.
1 Communities
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14 MeSH Terms
Cannabinoids, endocannabinoids, and cancer.
Hermanson DJ, Marnett LJ
(2011) Cancer Metastasis Rev 30: 599-612
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Cannabinoid Receptor Agonists, Cannabinoid Receptor Antagonists, Cannabinoid Receptor Modulators, Cannabinoids, Cell Physiological Phenomena, Endocannabinoids, Humans, Neoplasms, Receptors, Cannabinoid, Signal Transduction
Show Abstract · Added March 7, 2014
The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid receptors. Although the primary focus of endocannabinoid biology has been on neurological and psychiatric effects, recent work has revealed several important interactions between the endocannabinoid system and cancer. Several different types of cancer have abnormal regulation of the endocannabinoid system that contributes to cancer progression and correlates to clinical outcomes. Modulation of the endocannabinoid system by pharmacological agents in various cancer types reveals that it can mediate antiproliferative and apoptotic effects by both cannabinoid receptor-dependent and -independent pathways. Selective agonists and antagonists of the cannabinoid receptors, inhibitors of endocannabinoid hydrolysis, and cannabinoid analogs have been utilized to probe the pathways involved in the effects of the endocannabinoid system on cancer cell apoptosis, proliferation, migration, adhesion, and invasion. The antiproliferative and apoptotic effects produced by some of these pharmacological probes reveal that the endocannabinoid system is a promising new target for the development of novel chemotherapeutics to treat cancer.
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13 MeSH Terms
Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways.
Rouzer CA, Marnett LJ
(2011) Chem Rev 111: 5899-921
MeSH Terms: Cannabinoid Receptor Modulators, Cytochrome P-450 Enzyme System, Eicosanoids, Endocannabinoids, Lipoxygenase, Oxygen, Prostaglandin-Endoperoxide Synthases
Added March 7, 2014
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7 MeSH Terms
Endocannabinoid signaling in the amygdala: anatomy, synaptic signaling, behavior, and adaptations to stress.
Ramikie TS, Patel S
(2012) Neuroscience 204: 38-52
MeSH Terms: Adaptation, Physiological, Adaptation, Psychological, Amygdala, Animals, Behavior, Animal, Cannabinoid Receptor Modulators, Endocannabinoids, Signal Transduction, Stress, Psychological, Synapses
Show Abstract · Added January 20, 2015
The molecular constituents of endocannabinoid (eCB) signaling are abundantly expressed within the mammalian amygdaloid complex, consistent with the robust role of eCB signaling in the modulation of emotional behavior, learning, and stress-response physiology. Here, we detail the anatomical distribution of eCB signaling machinery in the amygdala and the role of this system in the modulation of excitatory and inhibitory neuroplasticity in this region. We also summarize recent findings demonstrating dynamic alternations in eCB signaling that occur in response to stress exposure, as well as known behavioral consequences of eCB-mediated modulation of amygdala function. Finally, we discuss how integrating anatomical and physiological data regarding eCB signaling in the amygdala could help elucidate common functional motifs of this system in relation to broader forebrain function.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation.
Sumislawski JJ, Ramikie TS, Patel S
(2011) Neuropsychopharmacology 36: 2750-61
MeSH Terms: Adaptation, Psychological, Amygdala, Animals, Anxiety Disorders, Arachidonic Acids, Benzodioxoles, Cannabinoid Receptor Modulators, Chronic Disease, Disease Models, Animal, Endocannabinoids, Glycerides, Male, Mice, Mice, Inbred ICR, Monoacylglycerol Lipases, Organ Culture Techniques, Piperidines, Stress, Psychological
Show Abstract · Added January 20, 2015
Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.
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18 MeSH Terms
Endocannabinoid (EC) receptor, CB1, and EC enzymes' expression in primary adipocyte cultures of lean and obese pre-pubertal children in relation to adiponectin and insulin.
Karvela A, Rojas-Gil AP, Samkinidou E, Papadaki H, Pappa A, Georgiou G, Spiliotis BE
(2010) J Pediatr Endocrinol Metab 23: 1011-24
MeSH Terms: Adipocytes, Adiponectin, Blood Pressure, Cannabinoid Receptor Modulators, Cells, Cultured, Child, Child, Preschool, Endocannabinoids, Female, Humans, Immunohistochemistry, Infant, Insulin, Insulin Resistance, Lipoprotein Lipase, Male, Obesity, RNA, Messenger, Receptor, Cannabinoid, CB1, Thinness
Show Abstract · Added April 10, 2014
AIM - The over-expression of CB1 in adult obesity is associated with insulin resistance (IR),but it is not elucidated in childhood obesity. We studied CB1 and endocannabinoid enzymes (EE), Adiponectin (Ad), and Insulin (SI) in lean and obese pre-pubertal (PP) children.
METHODS - CB1 mRNA and protein (Pr) expression were studied by RT-PCR, western immunoblotting and immunohistochemistry in primary cultures of adipose tissue. The EE(NAPE-PLD, DAGL-alpha, FAAH, MAGL) expression was assessed by Real-Time PCR. Ad and SI were measured by ELISA and IR by HOMA-IR index.
RESULTS - In the older obese vs older lean children: (1) CB1 Pr was decreased, (2) FAAHmRNA and DAGL-alpha mRNA were increased. Ad was decreased and SI and HOMA-IR increased in the older PP children.
CONCLUSIONS - Increased CB1 and decreased adiponectin in older lean PP children may facilitate fat deposition and "physiologic" IR necessary for the increased body growth of puberty. The reduced expression of CB1 in the older obese may be an attempt to reduce lipogenesis to avoid greater insulin resistance.
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20 MeSH Terms
Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo.
Simon GM, Cravatt BF
(2010) Mol Biosyst 6: 1411-8
MeSH Terms: Animals, Animals, Newborn, Cannabinoid Receptor Modulators, Endocannabinoids, Ethanolamines, Female, Lipid Metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Neurons, Phospholipase D, Phosphoric Diester Hydrolases, Signal Transduction
Show Abstract · Added April 10, 2014
The biosynthesis of the endocannabinoid anandamide (AEA) and related N-acyl ethanolamine (NAE) lipids is complex and appears to involve multiple pathways, including: (1) direct release of NAEs from N-acyl phosphatidyl ethanolamine (NAPE) precursors by the phosphodiesterase NAPE-PLD, and (2) double O-deacylation of NAPEs followed by phosphodiester bond hydrolysis of the resulting glycero-phospho (GP)-NAEs. We recently identified GDE1 as a GP-NAE phosphodiesterase that may be involved in the second pathway. Here, we report the generation and characterization of GDE1(-/-) mice, which are viable and overtly normal in their cage behavior. Brain homogenates from GDE1(-/-) mice exhibit a near-complete loss of detectable GP-NAE phosphodiesterase activity; however, bulk brain levels of AEA and other NAEs were unaltered in these animals. To address the possibility of compensatory pathways, we generated GDE1(-/-)/NAPE-PLD(-/-) mice. Conversion of NAPE to NAE was virtually undetectable in brain homogenates from these animals as measured under standard assay conditions, but again, bulk changes in brain NAEs were not observed. Interestingly, significant reductions in the accumulation of brain NAEs, including anandamide, were detected in GDE1(-/-)/NAPE-PLD(-/-) mice treated with a fatty acid amide hydrolase (FAAH) inhibitor that blocks NAE degradation. Finally, we determined that primary neurons from GDE1(-/-)/NAPE-PLD(-/-) mice can convert NAPEs to NAEs by a pathway that is not preserved following cell homogenization. In summary, combined inactivation of GDE1 and NAPE-PLD results in partial disruption of NAE biosynthesis, while also pointing to the existence of an additional enzymatic pathway(s) that converts NAPEs to NAEs. Characterization of this pathway should provide clarity on the multifaceted nature of NAE biosynthesis.
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15 MeSH Terms