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PubMed2005

The endocannabinoid signalling system: biochemical aspects.

Knowledge of the endogenous cannabinoid system has expanded greatly during the past years. After the discovery of the cannabinoid receptors, of their endogenous agonists and of the proteins for their synthesis and inactivation, significant progress has been made towards the understanding of the role of the endocannabinoid system in vital functions. Subsequently, an increasing number of papers has been published on the biochemistry and pharmacology of endocannabinoids. This article overviews the endocannabinoid signalling system with focus on its biochemical aspects. In particular we review the mechanisms for the biosynthesis and inactivation of the endocannabinoids, as well as the various molecular targets for some of the endocannabinoids described so far.

Animals↗
PubMed2005

Functional neuroanatomy of the endocannabinoid system.

Several components of the endocannabinoid system have been fully characterized. Among them are two types of cannabinoid receptors (termed CB1 and CB2), endogenous ligands for those receptors (referred to as "endocannabinoids"), and specific enzymes responsible for their degradation and inactivation. The study of the distribution and abundance of these elements in the central nervous system has provided the basis for the well-known effects of exogenous (both natural and synthetic) and endogenous cannabinoids. In addition, recent developments also support the idea that the endocannabinoid system plays a critical neuromodulatory role in the central nervous system. For instance, cannabinoid CB1 receptor activation is known to modify the release of several neurotransmitters, such as glutamate and gamma-aminobutyric acid. However, we still lack knowledge on fundamental aspects of the physiological roles of this system. Interestingly, changes in the distribution and activity of some of these components of the endocannabinoid system have been reported under different pathological conditions, suggesting their possible involvement in the pathogenesis of these diseases. As comprehensive excellent reviews have been recently published, the present review will focus only on the most recent advances in the field, considering a new perspective of the endocannabinoid system as composed of both neuronal and glial divisions.

Amidohydrolases↗
PubMed2006

Endocannabinoids and the control of energy balance.

Two receptors have been cloned to date for the psychotropic compound Delta(9)-tetrahydrocannabinol, and termed cannabinoid CB(1) and CB(2) receptors. Their endogenous ligands, the endocannabinoids, have also been identified. CB(1) receptors and endocannabinoids are present in brain structures controlling energy intake and in peripheral cells (hepatocytes, adipocytes, pancreatic islet cells) regulating energy homeostasis. CB(2) receptors are more abundant in lymphocytes and macrophages, and participate in immune and inflammatory reactions. Metabolic hormones and peptides regulate the levels of the endocannabinoids and, hence, the activity of cannabinoid receptors in several tissues in a seemingly coordinated way. The endocannabinoids, particularly after stress and brief food deprivation, act in turn as local modulators of the expression and action of neurotransmitters, hormones and adipokines involved in metabolic control. Endocannabinoid overactivity seems to accompany metabolic and eating disorders and to contribute to the development of abdominal obesity, dyslipidemia and hyperglycemia. Accordingly, clinical trials have shown that CB(1) receptor antagonists are efficacious at reducing not only food intake, but also abdominal adiposity and its metabolic sequelae.

Animals↗
PubMed2002

A role for endocannabinoids in indomethacin-induced spinal antinociception.

Inhibition of prostaglandins synthesis does not completely explain non-steroidal anti-inflammatory drug-induced spinal antinociception. Among other mediators, endocannabinoids are involved in pain modulation. Indomethacin-induced antinociception, in the formalin test performed in spinally microdialysed mice, was reversed by co-administration of the cannabinoid 1 (CB(1)) antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide (AM-251), but not by co-infusion of prostaglandin E(2). Indomethacin was ineffective in CB(1) knockout mice. AM-251 also reversed the indomethacin-induced antinociception in a test of inflammatory hyperalgesia to heat. Furthermore, during the formalin test, indomethacin lowered the levels of spinal nitric oxide (NO), which activates cellular reuptake and thus breakdown of endocannabinoids. The pronociceptive effect of an NO donor, 3-methyl-N-nitroso-sydnone-5-imine (RE-2047), was abolished by co-administration of the endocannabinoid transporter blocker N-(4-hydroxyphenyl) arachidonoyl amide (AM-404). Moreover, the antinociceptive activity of the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), was reversed by AM-251. Thus we propose that at the spinal level, indomethacin induces a shift of arachidonic acid metabolism towards endocannabinoids synthesis secondary to cyclooxygenase inhibition. In addition, it lowers NO levels with subsequent higher levels of endocannabinoids.

Analgesics↗
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↗
PubMed2002

Conformational memories and the endocannabinoid binding site at the cannabinoid CB1 receptor.

Endocannabinoid stucture-activity relationships (SAR) indicate that the CB1 receptor recognizes ethanolamides whose fatty acid acyl chains have 20 or 22 carbons, with at least three homoallylic double bonds and saturation in at least the last five carbons of the acyl chain. To probe the molecular basis for these acyl chain requirements, the method of conformational memories (CM) was used to study the conformations available to an n-6 series of ethanolamide fatty acid acyl chain congeners: 22:4, n-6 (K(i) = 34.4 +/- 3.2 nM); 20:4, n-6 (K(i) = 39.2 +/- 5.7 nM); 20:3, n-6 (K(i) = 53.4 +/- 5.5 nM); and 20:2, n-6 (K(i) > 1500 nM). CM studies indicated that each analogue could form both extended and U/J-shaped families of conformers. However, for the low affinity 20:2, n-6 ethanolamide, the higher populated family was the extended conformer family, while for the other analogues in the series, the U/J-shaped family had the higher population. In addition, the 20:2, n-6 ethanolamide U-shaped family was not as tightly curved as were those of the other analogues studied. To quantitate this variation in curvature, the radius of curvature (in the C-3 to C-17 region) of each member of each U/J-shaped family was measured. The average radii of curvature (with their 95% confidence intervals) were found to be 5.8 A (5.3-6.2) for 20:2, n-6; 4.4 A (4.1-4.7) for 20:3, n-6; 4.0 A (3.7-4.2) for 20:4, n-6; and 4.0 A (3.6-4.5) for 22:4, n-6. These results suggest that higher CB1 affinity is associated with endocannabinoids that can form tightly curved structures. Endocannabinoid SAR also indicate that the CB1 receptor does not tolerate large endocannabinoid headgroups; however, it does recognize both polar and nonpolar moieties in the headgroup region. To identify a headgroup orientation that results in high CB1 affinity, a series of dimethyl anandamide analogues (R)-N-(1-methyl-2-hydroxyethyl)-2-(R)-methyl-arachidonamide (K(i) = 7.42 +/- 0.86 nM), (R)-N-(1-methyl-2-hydroxyethyl)-2-(S)-methyl-arachidonamide (K(i) = 185 +/- 12 nM), (S)-N-(1-methyl-2-hydroxyethyl)-2-(S)-methyl-arachidonamide (K(i) = 389 +/- 72 nM), and (S)-N-(1-methyl-2-hydroxyethyl)-2-(R)-methyl-arachidonamide (K(i) = 233 +/- 69 nM) were then studied using CM and computer receptor docking studies in an active state (R) model of CB1. These studies suggested that the high CB1 affinity of the R,R stereoisomer is due to the ability of the headgroup to form an intramolecular hydrogen bond between the carboxamide oxygen and the headgroup hydroxyl that orients the C2 and C1' methyl groups to have hydrophobic interactions with valine 3.32(196), while the carboxamide oxygen forms a hydrogen bond with lysine 3.28(192) at CB1. In this position in the CB1 binding pocket, the acyl chain has hydrophobic and C-H.pi interactions with residues in the transmembrane helix (TMH) 2-3-7 region. Taken together, the studies reported here suggest that anandamide and its congeners adopt tightly curved U/J-shaped conformations at CB1 and suggest that the TMH 2-3-7 region is the endocannabinoid binding region at CB1.

Binding Sites↗
PubMed2004

Changes in endocannabinoid contents in reward-related brain regions of alcohol-exposed rats, and their possible relevance to alcohol relapse.

1. Chronic alcohol exposure modifies endocannabinoid levels in different brain regions, while pharmacological targeting of the endocannabinoid system has been reported to influence ethanol intake in laboratory animals. 2. The present study was aimed at evaluating the pattern of changes of endocannabinoids and their receptors, with emphasis on reward-related brain areas, in Wistar rats subjected to consecutive phases of alcoholization, alcohol deprivation (abstinence), and voluntary consumption of alcohol (relapse). 3. We observed that, in the limbic forebrain, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) contents increased after 7 days of alcoholization, then to dramatically decrease after 48 h of alcohol deprivation and, in the case of 2-AG, to further decrease when rats were allowed to relapse to alcohol consumption. By contrast, in the midbrain, there was a marked reduction in AEA, but not 2-AG, content, after alcoholization. This decrease was not affected during alcohol abstinence, but both AEA and 2-AG contents were then significantly reduced when rats were allowed to relapse to alcohol consumption. 4. Based on these data, we examined whether pharmacological activation/blockade of endocannabinoid transmission might influence ethanol intake in rats allowed to relapse to alcohol consumption after subsequent periods of alcoholization and alcohol deprivation. 5. Treatment with either Delta(9)-tetrahydrocannabinol or CP55,940, two cannabinoid agonists, reduced both total liquid and ethanol intake but did not affect ethanol preference. Treatment with SR141716, a selective cannabinoid CB(1) receptor antagonist, also produced a significant reduction in both total liquid and ethanol intake without affecting ethanol preference. Accordingly, none of these effects on ethanol intake were accompanied by changes in dopamine and GABA in limbic structures. 6. In summary, the levels of endocannabinoids underwent significant changes in reward-related areas during alcoholization, alcohol deprivation, and relapse, showing the lowest values in this latter phase. Treatment with cannabinoid agonists or a selective CB(1) receptor antagonist resulted in a reduction of ethanol intake by rats allowed to relapse to alcohol consumption after periods of alcoholization and alcohol deprivation, but these effects did not appear to be due to changes in neurobiological substrates currently involved in alcohol reinforcement/relapse.

Alcoholism↗
PubMed2006

The role of the endocannabinoid system in the control of energy homeostasis.

The endocannabinoid system has recently emerged as an important regulator of energy homeostasis, involved in the control of both appetite and peripheral fat metabolism. We briefly review current understanding of the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in our laboratory, using leptin-deficient obese rodents and CB1 cannabinoid receptor (CB1)-deficient mice, have indicated that endocannabinoids acting via CB1 are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain and amygdala. CB1-/- mice are lean and are resistant to diet-induced obesity (DIO) despite similar energy intake to wild-type mice with DIO, suggesting that CB1 regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB1 expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB1 are present in the liver and are upregulated in DIO. CB1 stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids.

Animals↗
PubMed2006

Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference.

Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoid-related genes in key brain regions of reward and dependence, and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines. A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats, and was accompanied by decreased enzyme activity in this region. Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand (3)[H]SR141716A, and [35S]GTPgammaS incorporation stimulated by the CB1 agonist WIN 55,212-2 were downregulated in the same area. Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals, and a compensatory downregulation of CB1 signaling. The functional role of impaired FAAH function for alcohol self-administration was validated in two independent ways. The CB1 antagonist SR141716A potently and dose-dependently suppressed self-administration in AA rats when given systemically, or locally into the PFC, but not in the striatum. Conversely, intra-PFC injections of the competitive FAAH inhibitor URB597 increased ethanol self-administration in nonselected Wistar rats. These results show for the first time that impaired FAAH function may confer a phenotype of high voluntary alcohol intake, and point to a FAAH both as a potential susceptibility factor and a therapeutic target.

Alcohol Drinking↗
PubMed2006

Endocannabinoids in chronic migraine: CSF findings suggest a system failure.

Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM+PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM+PAOH than in nonmigraineur controls (p<0.01 and p<0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM+PAOH patients (r=0.59, p<0.01 and r=-0.65, p<0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM+PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.

Adult↗
PubMed2002

Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation.

Endocannabinoids are retrograde messengers that are released from central neurons by depolarization-induced elevation of intracellular Ca2+ concentration [Ca2+]I or by activation of a group I metabotropic glutamate receptor (mGluR). We studied the interaction between these two pathways for endocannabinoid production in rat hippocampal neurons. We made a paired whole-cell recording from cultured hippocampal neurons with inhibitory synaptic connections. Activation of group I mGluRs, mainly mGluR5, by the specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), suppressed inhibitory postsynaptic currents (IPSCs) in about half of the neuron pairs. A cannabinoid agonist, WIN55,212-2, suppressed IPSCs in all DHPG-sensitive pairs but not in most of DHPG-insensitive pairs. The effects of both DHPG and WIN55,212-2 were abolished by the cannabinoid antagonists, AM281 and SR141716A, indicating that activation of group I mGluR releases endocannabinoids and suppress inhibitory neurotransmitter release through activation of presynaptic cannabinoid receptors. Depolarization of the postsynaptic neurons caused a transient suppression of IPSCs, a phemomenon termed depolarization-induced suppression of inhibition (DSI) that was also abolished by cannabinoid antagonists. Importantly, DSI was enhanced significantly when group I mGluRs were activated simultaneously by DHPG. This enhancement was much more prominent than expected from the simple summation of depolarization-induced and group I mGluR-induced endocannabinoid release. DHPG caused no change in depolarization-induced Ca2+ transients, indicating that the enhanced DSI by DHPG was not due to the augmentation of Ca2+ influx. Enhancement of DSI by DHPG was also observed in hippocampal slices. These results suggest that two pathways work in a cooperative manner to release endocannabinoids via a common intracellular cascade.

Animals↗
PubMed2003

Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias.

The majority of Parkinson's disease patients undergoing levodopa therapy develop disabling motor complications (dyskinesias) within 10 years of treatment. Stimulation of cannabinoid receptors, the pharmacological target of Delta 9-tetrahydrocannabinol, is emerging as a promising therapy to alleviate levodopa-associated dyskinesias. However, the mechanisms underlying this beneficial action remain elusive, as do the effects exerted by levodopa therapy on the endocannabinoid system. Although levodopa is known to cause changes in CB1 receptor expression in animal models of Parkinson's disease, we have no information on whether this drug alters the brain concentrations of the endocannabinoids anandamide and 2-arachidonylglycerol. To address this question, we used an isotope dilution assay to measure endocannabinoid levels in the caudate-putamen, globus pallidus and substantia nigra of intact and unilaterally 6-OHDA-lesioned rats undergoing acute or chronic treatment with levodopa (50 mg/kg). In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D1/D2 receptors. In 6-OHDA-lesioned rats, anandamide levels were significantly reduced in the caudate-putamen ipsilateral to the lesion; however, neither acute nor chronic levodopa treatment affected endocannabinoid levels in these animals. In lesioned rats, chronic levodopa produced increasingly severe oro-lingual involuntary movements which were attenuated by the cannabinoid agonist R(+)-WIN55,212-2 (1 mg/kg). This effect was reversed by the CB1 receptor antagonist rimonabant (SR141716A). These results indicate that a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB1 receptors.

Animals↗
PubMedDate not supplied

Endocannabinoids in the immune system and cancer.

The present review focuses on the role of the endogenous cannabinoid system in the modulation of immune response and control of cancer cell proliferation. The involvement of cannabinoid receptors, endogenous ligands and enzymes for their biosynthesis and degradation, as well as of cannabinoid receptor-independent events is discussed. The picture arising from the recent literature appears very complex, indicating that the effects elicited by the stimulation of the endocannabinoid system are strictly dependent on the specific compounds and cell types considered. Both the endocannabinoid anandamide and its congener palmitoylethanolamide, exert a negative action in the onset of a variety of parameters of the immune response. However, 2-arachidonoylglycerol appears to be the true endogenous ligand for peripheral cannabinoid receptors, although its action as an immunomodulatory molecule requires further characterization. Modulation of the endocannabinoid system interferes with cancer cell proliferation either by inhibiting mitogenic autocrine/paracrine loops or by directly inducing apoptosis; however, the proapoptotic effect of anandamide is not shared by other endocannabinoids and suggests the involvement of non-cannabinoid receptors, namely the VR1 class of vanilloid receptors. In conclusion, further investigations are needed to elucidate the function of endocannabinoids as immunosuppressant and antiproliferative/cytotoxic agents. The experimental evidence reviewed in this article argues in favor of the therapeutic potential of these compounds in immune disorders and cancer.

Animals↗
PubMedDate not supplied

Endocannabinoids in pain modulation.

Five major approaches have been employed to determine the role of endocannabinoids in pain modulation: (1) studies of various markers of endocannabinoid action aimed at determining whether the necessary cannabinoid biochemical machinery is present in those brain areas that control pain sensitivity; (2) administration of exogenous cannabinoids to determine whether endocannabinoid action at appropriate sites would lead to a loss of pain sensitivity; (3) administration of compounds that would affect endocannabinoid action such as antagonists and transport inhibitors to determine whether drug-induced preterbation of cannabinoid action would alter pain sensitivity; (4) studies of genetically altered animals aimed at determining whether pain responses or responses to cannabinergic drugs are altered; and (5) studies that measure the release of endocannabinoids. Converging evidence from each of these research areas indicates that endocannabinods function to control pain in parallel with endogenous opioids but via different mechanisms.

Animals↗
PubMed2006

Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons.

Endocannabinoids are emerging as potent modulators of neuronal activity throughout the brain, and activation of the type-1 cannabinoid receptor (CB1R) reduces sensory-evoked cortical responses in vivo, presumably by decreasing excitatory transmission. In the neocortex, CB1R is differentially expressed across neocortical laminae, with highest levels of expression in layers 2/3 and 5. Although we have shown that cannabinoid signaling in layer 2/3 of somatosensory cortex targets both gamma-aminobutyric acid (GABA) and glutamate release, the predominant effect is a net increase in pyramidal neuron (PN) activity due to disinhibition. The role of endocannabinoid signaling in layer 5, the main output layer of the neocortex, remains unknown. We found that inducing activity in layer 5 PNs resulted in endocannabinoid-mediated depolarization-induced suppression of excitation (DSE), whereas the majority of inhibitory inputs were cannabinoid insensitive. Furthermore, in contrast to layer 2/3, the net effect of elevations in action potential firing of layer 5 PNs was an endocannabinoid-mediated decrease in PN spike probability. Interestingly, excitatory synaptic currents in layer 5 evoked by intralaminar stimulation were cannabinoid sensitive, whereas inputs evoked from layer 2/3 were insensitive, suggesting specificity of cannabinoid signaling across glutamatergic inputs. Thus, cannabinoids have differential effects on excitation and inhibition across cortical layers, and endocannabinoid signaling in layer 5 may serve to selectively decrease the efficacy of a subset of excitatory inputs.

Animals↗
PubMed2000

Endocannabinoids control spasticity in a multiple sclerosis model.

Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non-spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re-uptake and hydrolysis-probably through the enhancement of endogenous levels of AEA, and, possibly, 2-arachidonoyl glycerol-significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity.

Amides↗
PubMed2005

The endocannabinoid system drives neural progenitor proliferation.

The discovery of multipotent neural progenitor (NP) cells has provided strong support for the existence of neurogenesis in the adult brain. However, the signals controlling NP proliferation remain elusive. Endocannabinoids, the endogenous counterparts of marijuana-derived cannabinoids, act as neuromodulators via presynaptic CB1 receptors and also control neural cell death and survival. Here we show that progenitor cells express a functional endocannabinoid system that actively regulates cell proliferation both in vitro and in vivo. Specifically, NPs produce endocannabinoids and express the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase (FAAH). CB1 receptor activation promotes cell proliferation and neurosphere generation, an action that is abrogated in CB1-deficient NPs. Accordingly, proliferation of hippocampal NPs is increased in FAAH-deficient mice. Our results demonstrate that endocannabinoids constitute a new group of signaling cues that regulate NP proliferation and thus open novel therapeutic avenues for manipulation of NP cell fate in the adult brain.

Amidohydrolases↗
PubMed2006

Endocannabinoids modulate stress-induced suppression of hippocampal cell proliferation and activation of defensive behaviours.

The endocannabinoid system has been shown to regulate both the hypothalamic-pituitary-adrenal (HPA) axis and emotionality. The present experiment was designed to examine whether pharmacological modulation of the endocannabinoid system would affect the suppression of hippocampal cell proliferation and increase in defensive behaviours seen following exposure to predator odour (trimethylthiazoline; TMT) stress. Rats were administered either an endocannabinoid uptake inhibitor (AM404; 2 mg/kg) or a cannabinoid CB1 receptor antagonist (AM251; 5 mg/kg) 30 min prior to exposure to TMT. Exposure to TMT reduced cell proliferation in the dentate gyrus and increased the expression of defensive burying. Administration of AM404 significantly inhibited defensive burying, and attenuated the reduction in cell proliferation in response to TMT exposure. Administration of AM251 alone significantly increased cell proliferation; however, pretreatment with AM251 prevented neither the stress-induced suppression of cell proliferation nor the stress-induced increase in behavioural responses. These results support previous research demonstrating that augmentation of endocannabinoid signalling can suppress stress-responsive systems. They also suggest that endocannabinoids may play a complex role in the regulation of neurogenesis via cell proliferation in the hippocampus.

Aggression↗