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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The striatum functions critically in movement control and habit formation. The development and function of cortical input to the striatum are thought to be regulated by activity-dependent plasticity of corticostriatal glutamatergic synapses. Here we show that the induction of a form of striatal synaptic plasticity, long-term depression (LTD), is dependent on activation of the CB1 cannabinoid receptor. LTD was facilitated by blocking cellular endocannabinoid uptake, and postsynaptic loading of anandamide (AEA) produced presynaptic depression. The endocannabinoid necessary for striatal LTD is thus likely to be released postsynaptically as a retrograde messenger. These findings demonstrate a new role for endocannabinoids in the induction of long-term synaptic plasticity in a circuit necessary for habit formation and motor control.
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PMID:Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. 1197 4

Anandamide (N -arachidonoyl-ethanolamine, AEA) was the first endogenous ligand of cannabinoid receptors to be discovered. Yet, since early studies, AEA appeared to exhibit also some effects that were not mediated by cannabinoid CB(1) or CB(2) receptors. Indeed, AEA exerts some behavioral actions also in mice with genetically disrupted CB(1) receptors, whereas in vitro it is usually a partial agonist at these receptors and a weak activator of CB(2) receptors. Nevertheless, several pharmacological effects of AEA are mediated by CB(1) receptors, which, by being coupled to G-proteins, can be seen as AEA "metabotropic" receptors. Furthermore, at least two different, and as yet uncharacterized, G-protein-coupled AEA receptors have been suggested to exist in the brain and vascular endothelium, respectively. AEA is also capable of directly inhibiting ion currents mediated by L-type Ca(2+) channels and TASK-1 K(+) channels. However, to date the only reasonably well characterized, non-cannabinoid site of action for AEA is the vanilloid receptor type 1 (VR1), a non-selective cation channel gated also by capsaicin, protons and heat. VR1 might be considered as an AEA "ionotropic" receptor and, under certain conditions, mediates effects ranging from vasodilation, broncho-constriction, smooth muscle tone modulation and nociception to stimulation of hippocampal pair-pulse depression, inhibition of tumor cell growth and induction of apoptosis.
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PMID:Anandamide receptors. 1205 51

Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB(1) and CB(2) receptors. CB(1) receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to Delta(9)-tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study, we looked at the possible role of the CB(1) receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP(8-37) was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB(1) receptor antagonist AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB(1) receptors seem to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a noncannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system.
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PMID:Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. 1471 91

Long-term changes in synaptic efficacy produced by high-frequency stimulation (HFS) of glutamatergic afferents to the rat dorsolateral striatum exhibit heterogeneity during early stages of postnatal development. Whereas HFS most often induces striatal long-term potentiation (LTP) in rats postnatal day 12 (P12)-P14, the same stimulation tends to induce long-term depression (LTD) at ages P16-P34. Previous studies have shown that striatal LTD induction depends on retrograde endocannabinoid signaling and activation of the CB1 cannabinoid receptor. It is also known that levels of one of the primary endogenous CB1 receptor agonists, anandamide (AEA), increases during development in whole-brain samples. In the present study, we sought to determine whether this developmental increase in AEA also takes place in striatal tissue and whether increased AEA levels contribute to the postnatal switch in the response to HFS. We observed a pronounced increase in striatal levels of AEA, but not the other major endogenous cannabinoid 2-arachidonoylglycerol (2-AG), during the postnatal period characterized by the switch from LTP to LTD. Furthermore, application of synthetic AEA during HFS in field recordings of slices from P12-P14 rats allowed for induction of LTD whereas blocking the CB1 receptor during HFS in animals P16-P34 resulted in expression of LTP. However, blocking 2-AG synthesis with the DAG-lipase inhibitor tetrahydrolipstatin did not alter HFS-induced striatal LTD. In addition, synaptic depression produced by a synthetic CB1 agonist was similar across development. Together, these findings suggest that the robust developmental increase in striatal AEA may be the key factor in the emergence of HFS-induced striatal LTD.
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PMID:Anandamide regulates postnatal development of long-term synaptic plasticity in the rat dorsolateral striatum. 1732 38

Endocannabinoids (eCBs) mediate short- and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies have suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it is not known whether this release process occurs automatically upon eCB synthesis or whether it is regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM11 and UCM707, but did not require activation of metabotropic glutamate receptors, l-calcium channels, nitric oxide, voltage-activated Na(+) channels, or intracellular calcium. Application of the CB(1)R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB(1) receptor by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. These findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.
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PMID:Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step. 1807 76

During immuno-mediated attack of the brain, activation of endocannabinoids represents a protective mechanism, aimed at reducing both neurodegenerative and inflammatory damage through various and partially converging mechanisms that involve neuronal and immune cells. Here, we review the main alterations of the endocannabinoid system (ECS) within the central nervous system and in peripheral blood mononuclear cells, in order to discuss the intriguing observation that elements of the peripheral ECS mirror central dysfunctions of endocannabinoid signaling. As a consequence, elements of blood ECS might serve as novel, non-invasive diagnostic tools of several neurological disorders, and targeting the ECS might be useful for therapeutic purposes. In addition, we discuss the appealing working hypothesis that the presence of type-1 cannabinoid receptors on the luminal side, and that of type-2 cannabinoid receptors on the abluminal side of the blood-brain barrier, could drive a unidirectional transport of AEA in the luminal --> abluminal direction (i.e., from blood to brain), thus implying that blood may be a reservoir of AEA for the brain. On this basis, it can be expected that an unbalance of the endogenous tone of AEA in the blood may sustain a similar unbalance of its level within the brain, as demonstrated in Huntington's disease, Parkinson's disease, multiple sclerosis, attention-deficit/hyperactivity disorder, schizophrenia, depression and headache.
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PMID:The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases. 1878 87

Epilepsy is one of the most common diseases in neurology department. It is caused by many different kinds of perturbances of normal balance of excitation and inhibition within the central nervous system. Current clinical antiepileptic drugs (AEDs) targets include ion channels, neurotransmitter transporters and neurotransmitter metabolic enzymes. They could control about 70-80% of the patients' symptoms; 20-30% patients develop to be intractable epilepsy sufferers. Moreover, antiepileptic drugs could not prevent formation of foci and disease process, but only alleviate symptoms of seizures at risk of different adverse effects as the consequences of large doses. Recently, impressive data on the actions of transient receptor potential vanilloid receptor 1 (TRPV1) prove it to be an inspiring antiepileptogenic target. TRPV1 activation modulates activity-dependent synaptic efficacy: (i) facilitating long-term potentiation (LTP) and suppressing long-term depression (LTD) of hippocampal neurons (ii) selectively inhibiting excitatory synapses onto hippocampal interneurons, which is expected to increase the excitability of innervated pyramidal cells. Nerve growth factor (NGF) can acutely and chronically upregulates TRPV1 expression, suggesting that TRPV1 channels would play an important role in the course of NGF regulated epileptogenesis. Endocannabinoid anandamide (AEA) is one of the TRPV1 endogenous agonists. It has been proved that, in the course of epilepsy, AEA levels increases due to enhanced formation and both exogenously administered and endogenously produced AEA display proconvulsant activity. Moreover, TRPV1 activation triggers apoptotic neuronal death of rat cortical cultures, which may be responsible, at least in part, for the volume loss of neocortex in chronic epilepsy. Our hypothesis may broaden the drug screening and designing for clinical strategies for epilepsy treatment.
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PMID:TRPV1: a potential target for antiepileptogenesis. 1932 32

Adenosine A(2A) receptor antagonists are psychomotor stimulants that also hold therapeutic promise for movement disorders. However, the molecular mechanisms underlying their stimulant properties are not well understood. Here, we show that the robust increase in locomotor activity induced by an A(2A) antagonist in vivo is greatly attenuated by antagonizing cannabinoid CB(1) receptor signaling or by administration to CB(1)(-/-) mice. To determine the locus of increased endocannabinoid signaling, we measured the amount of anandamide [AEA (N-arachidonoylethanolamine)] and 2-arachidonoylglycerol (2-AG) in brain tissue from striatum and cortex. We find that 2-AG is selectively increased in striatum after acute blockade of A(2A) receptors, which are highly expressed by striatal indirect-pathway medium spiny neurons (MSNs). Using targeted whole-cell recordings from direct- and indirect-pathway MSNs, we demonstrate that A(2A) receptor antagonists potentiate 2-AG release and induction of long-term depression at indirect-pathway MSNs, but not direct-pathway MSNs. Together, these data outline a molecular mechanism by which A(2A) antagonists reduce excitatory synaptic drive on the indirect pathway through CB(1) receptor signaling, thus leading to increased psychomotor activation.
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PMID:Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists. 2014 43

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are hydrolytic enzymes which degrade the endogenous cannabinoids (endocannabinoids) N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), respectively. Endocannabinoids are an important class of lipid messenger molecules that are produced on demand in response to elevated intracellular calcium levels. They recognize and activate the cannabinoid CB(1) and CB(2) receptors, the molecular targets for Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in marijuana evoking several beneficial therapeutic effects. However, in vivo the cannabimimetic effects of AEA and 2-AG remain weak owing to their rapid inactivation by FAAH and MGL, respectively. The inactivation of FAAH and MGL by specific enzyme inhibitors increases the levels of AEA and 2-AG, respectively, producing therapeutic effects such as pain relief and depression of anxiety.
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PMID:Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors. 2037 Jul 10

Endogenous ethanolamides (fatty acid amides), including arachidonyl ethanolamide (anandamide, AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA), are substrates of fatty acid amide hydrolase (FAAH). FAAH may play an important role for pain, anxiety/depression, and metabolic disorders. Ethanolamides are considered to be potential pharmacodynamic biomarkers to determine target engagement for FAAH inhibition by novel pharmaceutical agents. A highly selective, sensitive, and high-throughput liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantitation of AEA, OEA, and PEA in human plasma. The method employed D(4)-AEA, D(4)-OEA, and (13)C(2)-PEA as "surrogate analytes" to establish the concentration-mass response relationship, i.e. a regression equation. The concentrations of AEA, OEA, and PEA were calculated based on the regression equations derived from the surrogate analytes. This approach made it possible to prepare calibration standard and quality control (QC) samples in plasma devoid of interferences from the endogenous analytes. The analytical methodology required 150 microL of human plasma that was processed via liquid-liquid extraction (LLE) using a 96-well plate format. Chromatographic separation was achieved with a reversed-phase high performance liquid chromatography (HPLC) column using gradient elution, and the run time was 3 min. The method was fully validated and it demonstrated acceptable accuracy, precision, linearity, and specificity. The lower limit of quantitation (LLOQ) was 0.1/0.5/0.5 ng/mL for AEA/OEA/PEA, which was sensitive enough to capture the basal plasma levels in healthy subjects. Bench-top stability in plasma, freeze-thaw stability in plasma, frozen long-term stability in plasma, autosampler stability, and stock solution stability all met acceptance criteria (%Bias within +/-12.0%). Characterization of stability in purchased/aged blood indicated that ethanolamides are subject to degradation mediated by intracellular membrane-bound FAAH, which has been shown to be inhibited by phenylmethylsulfonyl fluoride (PMSF). In the presence of PMSF, ethanolamide levels increased slightly over time, suggesting that blood cells release ethanolamides into plasma. Whole blood stability conducted in fresh blood immediately following collection revealed that there was significant elevation of ethanolamide concentrations (approximately 1.3-2.0-fold on ice and approximately 1.5-3.0-fold at room temperature by 2h), indicating that de novo synthesis and release from blood cells were the predominant factors affecting ethanolamide concentrations ex vivo. Accordingly, conditions that ensured rapid separation of plasma from blood cells and consistency in the blood harvesting procedures were established and implemented for clinical studies to minimize the ex vivo elevation of plasma ethanolamide concentrations. The variability (intra-subject and inter-subject) of plasma ethanolamide levels was evaluated in healthy subjects during a Phase 0 study (no drug administration) that simulated the design of single-ascending dose and multiple-ascending dose clinical trials in terms of sample collection time points, population, food, and activity. The data indicated there was relatively large inter- and intra-subject variation in plasma ethanolamide concentrations. In addition, apparent variations due to time of day and/or food effects were also revealed. Understanding the variability of ethanolamide levels in humans is very important for study design and data interpretation when changes in ethanolamide levels are used as target engagement biomarkers in clinical trials.
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PMID:Validation and application of an LC-MS/MS method for quantitation of three fatty acid ethanolamides as biomarkers for fatty acid hydrolase inhibition in human plasma. 2046 10


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