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PubMed2002

Presynaptic factors in the regulation of DSI expression in hippocampus.

We studied the mechanisms by which GABA release is reduced in the retrograde signaling process called depolarization-induced suppression of inhibition (DSI). DSI is mediated by endocannabinoids in acute and cultured organotypic hippocampal slices. We examined a variety of K(+) channel antagonists to determine the nature of the K(+) channel that, when blocked, reduces DSI. Among 4-AP, TEA, dendrotoxin, Cs, margatoxin, and charybdotoxin, only 4-AP was highly effective in blocking DSI, suggesting that a K(+) channel composed in part of K(V1.4,) K(V1.5) or K(V1.7) subunits can readily regulate DSI. The inhibition of DSI by 4-AP is largely overcome by reducing [Ca(2+)](o), however, suggesting that DSI expression can be prevented by saturation of the release process when a K(V1.X) channel is inhibited. DSI of agatoxin- and TTX-insensitive mIPSCs was unaffected by 4-AP, but was largely occluded by omega-conotoxin GVIA, indicating that block of presynaptic N-type Ca(2+) channels is probably a major mechanism of DSI expression. Significant DSI of mIPSCs remained in omega-conotoxin, hence we infer that block of N-channels does not fully explain hippocampal DSI expression.

2-Amino-5-phosphonovalerate↗
PubMed2001

Proteins regulating the biosynthesis and inactivation of neuromodulatory fatty acid amides.

Fatty acid amides (FAAs) represent a growing family of biologically active lipids implicated in a diverse range of cellular and physiological processes. At present, two general types of fatty acid amides, the N-acylethanolamines (NAEs) and the fatty acid primary amides (FAPAs), have been identified as potential physiological neuromodulators/neurotransmitters in mammals. Representative members of these two subfamilies include the endocannabinoid NAE anandamide and the sleep-inducing FAPA oleamide. In this Chapter, molecular mechanisms proposed for the biosynthesis and inactivation of FAAs are critically evaluated, with an emphasis placed on the biochemical and cell biological properties of proteins thought to mediate these processes.

Amides↗
PubMed2002

Endocannabinoid hydrolases.

Endocannabinoids (endogenous ligands of cannabinoid receptors) such as anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG) are inactivated upon enzymatic hydrolysis. Recent progress in the enzymological and molecular biological studies on the 'endocannabinoid hydrolases' is reviewed in this article. Anandamide is hydrolyzed to arachidonic acid and ethanolamine by a membrane-bound amidase generally referred to as fatty acid amide hydrolase (FAAH). This enzyme has a broad substrate specificity, hydrolyzing oleamide (an endogenous sleep-inducing factor) and 2-AG as well as anandamide. cDNA cloning revealed that FAAH is composed of 579 amino acids and belongs to the amidase signature family. A serine residue functioning as a catalytic nucleophile and several other catalytically important residues were identified in its primary structure. Furthermore, recent generation and analysis of the FAAH gene-deficient mice demonstrated the central role of this enzyme in the metabolism of anandamide. Alternatively, an amidase, which is distinct from FAAH but also hydrolyzing anandamide and other N-acylethanolamines at acidic pH, was identified in human megakaryoblastic cells and rat organs such as lung and spleen. As for the 2-AG hydrolysis, in addition to the known monoacylglycerol lipase, other esterases and FAAH may be involved.

Amidohydrolases↗
PubMed2000

Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage.

BACKGROUND: Endocannabinoids such as anandamide are thought to have adverse effects on pregnancy and embryonic development. The activity of the degradative enzyme anandamide hydrolase may therefore be crucial for prevention of excessive concentrations of anandamide in the uterus, and thus prevention of pregnancy failure or female infertility. We tested this hypothesis in a preliminary study, and then used the results to find out whether anandamide hydrolase activity could predict miscarriage in a group of pregnant women. METHODS: We assessed anandamide hydrolase activity in peripheral lymphocytes from 50 healthy, pregnant women at weeks 6-11 of gestation by a specific radiochromatographic method. The expression of the enzyme at the protein level was measured by ELISA with specific polyclonal antibodies. In a further study, we measured anandamide hydrolase concentration in 120 women who were 7-8 weeks pregnant and compared these findings with subsequent pregnancy outcome. FINDINGS: In the first study, seven of the 50 women had a miscarriage. Anandamide hydrolase activity was lower in the seven women who miscarried than in the 43 who did not (60.43 pmol/min per mg protein [SD 29.34] vs 169.60 pmol/min per mg protein [30.20]; difference 109.17 pmol/min per mg protein [95% CI 26.64-191.70]; p<0.0001 by the Mann-Whitney test). Enzyme activity correlated with enzyme concentration, and a threshold concentration represented by an optical density (after ELISA) of 0.15 absorbance units at 450 nm separated the women who had miscarriages from those who did not. In the second study, 15 women had anandamide hydrolase concentrations below the threshold, and 105 had concentrations at or above the threshold. All 15 women in the low anandamide hydrolase group had miscarriages, compared with one of the 105 women with high concentrations (p<0.0001 by Fisher's exact test). INTERPRETATION: Decreased anandamide hydrolase activity and expression in peripheral lymphocytes is an early (<8 weeks of gestation) marker of spontaneous abortion, and may prove useful as a diagnostic tool for large-scale, routine monitoring of gestation. Our results also suggest that endocannabinoids might be critical in regulating the lymphocyte-dependent cytokine network associated with human fertility and successful pregnancy.

Abortion, Habitual↗
PubMed2002

Tetrahydrocannabinol and endocannabinoids in feeding and appetite.

The physiological control of appetite and satiety, in which numerous neurotransmitters and neuropeptides play a role, is extremely complex. Here we describe the involvement of endocannabinoids in these processes. These endogenous neuromodulators enhance appetite in animals. The same effect is observed in animals and in humans with the psychotropic plant cannabinoid Delta(9)-tetrahydrocannabinol, which is an approved appetite-enhancing drug. The CB(1) cannabinoid receptor antagonist SR141716A blocks the effects on feeding produced by the endocannabinoids. If administered to mice pups, this antagonist blocks suckling. In obese humans, it causes weight reduction. Very little is known about the physiological and biochemical mechanisms involved in the effects of Delta(9)-tetrahydrocannabinol and the cannabinoids in feeding and appetite.

Animals↗
PubMed2003

It could be habit forming: drugs of abuse and striatal synaptic plasticity.

Drug addiction can take control of the brain and behavior, activating behavioral patterns that are directed excessively and compulsively toward drug usage. Such patterns often involve the development of repetitive and nearly automatic behaviors that we call habits. The striatum, a subcortical brain region important for proper motor function as well as for the formation of behavioral habits, is a major target for drugs of abuse. Here, we review recent studies of long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse can exert pronounced influences on these processes, both in the striatum and in the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears to play a prominent role in early stages of drug use, whereas dopamine- and endocannabinoid-dependent synaptic plasticity in the dorsal striatum could contribute to the formation of persistent drug-related habits when casual drug use progresses towards compulsive drug use and addiction.

Animals↗
PubMed2002

A rostro-caudal dissociation in the dorsal and ventral striatum of the juvenile SHR suggests an anterior hypo- and a posterior hyperfunctioning mesocorticolimbic system.

Functional molecular neuroimaging techniques have been applied to the study of the neural substrates of Attention-Deficit Hyperactivity Disorder (ADHD) in an animal model, the juvenile SHR rat. They include quantitative receptor autoradiography and immunocytochemistry for neuronal markers such as Ca2+/Calmodulin Dependent Kinase II (CaMKII) and transcription factors. Multiple evidence emerges for a rostro caudal dissociation within the dorsal (DS) and ventral striatum (VS) (n. accumbens) and olfactory tubercle (OT). It consists in (i) a higher density of dopamine (DA) D-1/D-5 receptor binding sites in a discrete segment of the anterior forebrain that comprises the DS, VS and OT, (ii) a lower density of DA D-2/D-3 autoreceptors in the caudal portion of the n. accumbens shell subterritory, (iii) a reduced number of CaMKII and c-FOS positive elements only in the anterior portion of DS and VS (iv) reversal by repeated injections of methylphenidate (MP) (3 mg/kg, 14 days) with 'downregulation' in SHR and 'up-regulation' in the WKY control rats of DS and VS of DA D-1/D-5 receptors. Thus, under basal conditions the mesocorticolimbic (MCL) DA system appears to be hyperfunctioning rather than hypofunctioning, as demonstrated (i) by subsensitivity of presynaptic D-3 autoreceptors and (ii) by phasic inhibition of MCL activity induced by acute blockade of endocannabinoid reuptake using AM404. Following MP treatment, the hyperfunctioning MCL DA system turns into a hypofunctioning one, as earlier suggested by Solanto. Since the target neurons of MCL fibers seem to be uncoupled to D-1 receptors, the medium spiny GABA neurons projecting to the ventral pallidum and ventral tegmental area (VTA) exert a weak feedback inhibition on the neurons of origin of MCL system. Therefore, MCL neurons maintain a high basal activity with consequences on the cortico-striato-pallido-thalamo-cortical system and amygdala complex through the 'extended amygdala system'. While the former explains the attention, motivation and activity alterations of this rat model of ADHD, the latter explains the emotional symptoms of the syndrome. It remains to be ascertained the starting point in the network leading eventually to the segmental defect as well as its significance in humans.

Animals↗
PubMed2002

Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids.

This review covers recent developments in the cellular neurophysiology of retrograde signaling in the mammalian central nervous system. Normally at a chemical synapse a neurotransmitter is released from the presynaptic element and diffuses to the postsynaptic element, where it binds to and activates receptors. In retrograde signaling a diffusible messenger is liberated from the postsynaptic element, and travels "backwards" across the synaptic cleft, where it activates receptors on the presynaptic cell. Receptors for retrograde messengers are usually located on or near the presynaptic nerve terminals, and their activation causes an alteration in synaptic transmitter release. Although often considered in the context of long-term synaptic plasticity, retrograde messengers have numerous roles on the short-term regulation of synaptic transmission. The focus of this review will be on a group of molecules from different chemical classes that appear to act as retrograde messengers. The evidence supporting their candidacy as retrograde messengers is considered and evaluated. Endocannabinoids have recently emerged as one of the most thoroughly investigated, and widely accepted, classes of retrograde messenger in the brain. The study of the endocannabinoids can therefore serve as a model for the investigation of other putative messengers, and most attention is devoted to a discussion of systems that use these new messenger molecules.

Animals↗
PubMed2001

Characterization of the 5'-sequence of the mouse fatty acid amide hydrolase.

Fatty acid amide hydrolase (FAAH) is critical for degradation of several important fatty acid amides including anandamide, an endocannabinoid, as well as oleamide, a sleep-inducing factor. These compounds play roles in diverse physiological processes ranging from memory and learning to the regulation of blood pressure. The mechanisms that regulate FAAH expression have not been characterized. A 5'-region of the mouse FAAH with promoter activity was isolated from 1.8 kbp of genomic sequence. Characterization of +1 of transcription of FAAH by RNA ligase mediated-rapid amplification of cDNA ends showed that FAAH mRNA is transcribed from multiple transcription start sites lacking a TATA-box element. Functional analysis of the FAAH upstream sequence fused to a luciferase reporter gene revealed a FAAH-promoter construct with tissue specific activity. A 674-bp FAAH-promoter construct was active in N18TG2 (N18) neuroblastoma cells and C6 glioma cells, lines that have endogenous FAAH activity. The same 674-bp FAAH-promoter construct was not active in C2C12 or L6 myogenic cells, two lines that do not have FAAH activity.

Amides↗
PubMed2002

Neonatal anandamide treatment results in prolonged mitochondrial damage in the vanilloid receptor type 1-immunoreactive B-type neurons of the rat trigeminal ganglion.

Capsaicin acting on the vanilloid type 1 receptor (VR1) excites a subset of primary sensory neurons. Systemic capsaicin treatment of adult or neonatal rats results in selective damage of the B-type neurons in the rat sensory ganglia by causing a long-lasting mitochondrial lesion that has been described in detail in previous studies. The endocannabinoid, anandamide, exhibits an agonist effect on VR1 receptors. The physiological role of anandamide as a VR1 agonist is still uncertain. This study addresses whether high doses of anandamide induce similar ultrastructural changes to those described for capsaicin. The effect of neonatally administered anandamide (1 mg/kg) on neurons of the trigeminal ganglia and the hippocampal formation was examined in the light and electron microscope from the first day after injections to the 20th week after treatment. Anandamide was found to cause mitochondrial damage of the B-type neurons of trigeminal ganglia similar to what has been described for capsaicin. The time course of damage was also comparable. In addition to the cells of the trigeminal ganglia, B-type cells of dorsal root ganglia were also damaged. A-type neurons and satellite glial cells were not affected either in the trigeminal or in the dorsal root ganglia. In the hippocampal formation, where a subpopulation of local circuit neurons is known to contain cannabinoid type 1 (CB1) but not VR1 receptors, anandamide did not cause morphological changes of mitochondria either in the dentate gyrus or in Ammon's horn. At 3 weeks of age, all VR1-immunoreactive neurons in the trigeminal ganglia of animals treated neonatally with anandamide displayed swollen mitochondria. The results suggest that anandamide, at pharmacologically relevant doses, acts on the VR1 receptor and causes prolonged and selective mitochondrial damage of B-type sensory neurons, as has previously been described for capsaicin.

Animals↗
PubMed2006

The endocannabinoid system: body weight and metabolic regulation.

The endocannabinoid system elicits multiple physiologic functions that are not fully understood. Antagonism of cannabinoid type 1 (CB(1)) receptors has been the only successful new pharmacologic treatment approach in Phase III studies in obesity in the last 8 years. Whereas antagonism of (CB(1)) receptors acutely reduces food intake, the long-term effects on weight reduction and metabolic regulation appear to be mediated by stimulation of energy expenditure and by peripheral effects related to liver, skeletal muscle, adipose tissue, and pancreas physiology. For example, in the liver, lipogenic enzymes and fatty acid synthesis are upregulated by endocannabinoids, and in adipose tissue, antagonism of (CB(1)) receptors increases secretion of adiponectin. Some studies suggest that endocannabinoid formation is increased in obesity, perhaps because endocannabinoid degradation is decreased. Although many questions remain unanswered at present, the emerging concept of endocannabinoids as metabolic regulators helps to explain the success of rimonabant (SR141716), an antagonist of (CB(1)) receptors, currently in Phase III studies.

Anti-Obesity Agents↗
PubMed2003

Endocannabinoids and related fatty acid amides, and their regulation, in the salivary glands of the lone star tick.

The salivary glands and saliva from the lone star tick Amblyomma americanum (L.) were analyzed for the presence of the two endogenous agonists of cannabinoid receptors, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as of the anandamide congener, N-palmitoylethanolamine (PEA), an anti-inflammatory and analgesic mediator that is inactive at cannabinoid receptors. Two very sensitive mass-spectrometric techniques were used for this purpose. Both 2-AG and PEA, as well as other N-acylethanolamines (NAEs), were identified in salivary glands, but anandamide was below detection. The levels of 2-AG were considerably higher in the salivary glands of partially fed than replete females. Ex vivo gland stimulation with arachidonic acid increased the levels of 2-AG, but not of PEA or other NAEs, and caused the formation of anandamide and of the potent analgesic compound N-arachidonoylglycine. Instead, the amounts of anandamide, 2-AG and PEA were not influenced by treatment of salivary glands with dopamine, which stimulates saliva secretion. The possible biosynthetic precursors of anandamide, PEA and other NAEs were also detected in salivary glands, whereas only PEA was detected in tick saliva. These data demonstrate for the first time that the salivary glands of an obligate ectoparasite species can make endocannabinoids and/or related congeners with analgesic and anti-inflammatory activity, which possibly participate in the inhibition of the host defense reactions.

Amides↗
PubMed2002

After a decade of intravesical vanilloid therapy: still more questions than answers.

Vanilloid sensitivity is a functional signature of a subset of unmyelinated fibres innervating the urinary bladder. The role that these nerves have in the physiological control of storage and voiding is unclear. However, after the bladder has been disconnected by spinal injury from the pontine micturition centre, vanilloid-sensitive fibres assume a central role in the reflex emptying of the bladder that occurs at low volumes. Intravesical vanilloid (capsaicin or resiniferatoxin) administration is beneficial in this disorder by "desensitising" these nerves. Resiniferatoxin is superior to capsaicin in terms of its tolerability profile. Investigators are moving rapidly to identify the mechanisms by which desensitisation to vanilloids occurs. Vanilloids induce lasting, but fully reversible, changes in gene expression, including downregulation of the vanilloid receptor subtype 1. It is hoped that application of gene chip technologies will address the global profile of vanilloid-induced changes in gene expression and their relative contribution to desensitisation. Drugs that target signalling mechanisms that bring about these changes in gene expression have obvious therapeutic potential.

Administration, Intravesical↗
PubMedDate not supplied

Endocannabinoids in the intact retina: 3 H-anandamide uptake, fatty acid amide hydrolase immunoreactivity and hydrolysis of anandamide.

There is much evidence for an endocannabinoid system in the retina. However, neither the distribution of endocannabinoid uptake, the regulation of endocannabinoid levels, nor the role of endocannabinoid metabolism have been investigated in the retina. Here we focused on one endocannabinoid, anandamide (AEA), and its major hydrolyzing enzyme, fatty acid amide hydrolase (FAAH), in the goldfish retina. Immunoblots of FAAH immunoreactivity (IR) in goldfish retina, brain and rat retina, and brain homogenates showed a single band at 61 kDa that was blocked by preadsorption with peptide antigen. Specific FAAH IR (blocked by preadsorption) was most prominent over Müller cells and cone inner segments. Weaker label was observed over some amacrine cells, rare cell bodies in the ganglion cell layer, and in four lamina in the inner plexiform layer. FAAH activity assays showed that goldfish-retinal and brain homogenates hydrolyzed AEA at rates comparable to rat brain homogenate, and the hydrolysis was inhibited by methyl arachidonyl fluorophosphonate (MAFP) and N-(4 hydroxyphenyl)-arachidonamide (AM404), with IC(50)s of 21 nM and 1.5 microM, respectively. Cellular 3H-AEA uptake in the intact retina was determined by in vitro autoradiography. Silver-grain accumulation at 20 degrees C was most prominent over cone photoreceptors and Müller cells. Uptake was significantly reduced when retinas were incubated at 4 degrees C, or preincubated with 100 nM MAFP or 10 microM AM404. There was no differential effect of blocking conditions on the distribution of silver grains over cones or Müller cells. The codistribution of FAAH IR and 3H-AEA uptake in cones and Müller cells suggests that the bulk clearance of AEA in the retina occurs as a consequence of a concentration gradient created by FAAH activity. We conclude that endocannabinoids are present in the goldfish retina and underlay the electrophysiological effects of cannabinoid ligands previously shown on goldfish cones and bipolar cells.

Amidohydrolases↗
PubMed2006

Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids.

N-Acyl ethanolamines (NAEs) constitute a large and diverse class of signaling lipids that includes the endogenous cannabinoid anandamide. Like other lipid transmitters, NAEs are thought to be biosynthesized and degraded on-demand rather than being stored in vesicles prior to signaling. The identification of enzymes involved in NAE metabolism is therefore imperative to achieve a complete understanding of this lipid signaling system and control it for potential therapeutic gain. Recently, an N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) was identified as a candidate enzyme involved in the biosynthesis of NAEs. Here, we describe the generation and characterization of mice with a targeted disruption in the NAPE-PLD gene [NAPE-PLD(-/-) mice]. Brain tissue from NAPE-PLD(-/-) mice showed more than a 5-fold reduction in the calcium-dependent conversion of NAPEs to NAEs bearing both saturated and polyunsaturated N-acyl chains. However, only the former group of NAEs was decreased in level in NAPE-PLD(-/-) brains, and these reductions were most dramatic for NAEs bearing very long acyl chains (>or=C20). Further studies identified a calcium-independent PLD activity in brains from NAPE-PLD(-/-) mice that accepted multiple NAPEs as substrates, including the anandamide precursor C20:4 NAPE. The illumination of distinct enzymatic pathways for the biosynthesis of long chain saturated and polyunsaturated NAEs suggests a strategy to control the activity of specific subsets of these lipids without globally affecting the function of the NAE family as a whole.

Animals↗
PubMed2006

Endocannabinoid metabolism in the absence of fatty acid amide hydrolase (FAAH): discovery of phosphorylcholine derivatives of N-acyl ethanolamines.

Lipid transmitters are tightly regulated by a balance of biosynthetic and degradative enzymes. Termination of the activity of the N-acyl ethanolamine (NAE) class of lipid-signaling molecules, including the endocannabinoid anandamide (AEA), is principally mediated by the integral membrane enzyme fatty acid amide hydrolase (FAAH) in vivo. FAAH(-/-) mice are highly sensitized to the pharmacological effects of AEA; however, these animals eventually recover from AEA treatment, implying the existence of alternative routes for NAE metabolism. Here, we have pursued the characterization of these pathways by profiling the metabolome of FAAH(-/-) mice treated with AEA. Multiple AEA-induced metabolites were observed in brains from FAAH(-/-) mice, including a major product with a mass shift of +165 Da (m/z 513). The structure of this product was determined to be O-phosphorylcholine (PC)-AEA. Analysis of untreated mice identified PC-NAEs as endogenous constituents of the central nervous system (CNS) that were highly elevated in FAAH(-/-) animals. PC-NAEs were very poor substrates for FAAH; however, a vanadate-sensitive enzymatic activity was detected in brain membranes that converted PC-NAEs back to their parent NAEs. The choline-specific phosphodiesterase NPP6 was identified as a candidate enzyme responsible for this activity. These data indicate the presence of a complete metabolic pathway for the production and degradation of PC-NAEs in the CNS that constitutes an alternative route for endocannabinoid metabolism.

Amidohydrolases↗