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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular biology has a strong impact on current research into drug and alcohol dependence. Spectacular recent results include the cloning of a cannabinoid receptor, nicotine receptors in the CNS and the targets of amphetamine and cocaine action, catecholamine transporters. Alcohol has been found to interact with the GABAA and NMDA (glutamate) receptors at concentrations reached with social alcohol use. The interactions of opiates and other drugs of abuse with the endogenous opioid peptides have been studied at several levels; it is a general finding that precursor gene transcription is suppressed. Although much less is known about the molecular consequences of chronic addictive drug usage, a functional deficit in opioid systems has been described. A general addiction mechanism may have similarities with memory storage mechanisms which are currently being studied with molecular probes.
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PMID:[Molecular neurobiological research in the fight against drug abuse]. 165 Aug 71

This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. The chairpersons were Appa Hungund and George Koob. The presentations were (1) Role of endocannabinoids in ethanol tolerance, by Appa Hungund; (2) Modulation of cannabinoid receptor and its signal transduction in chronic alcoholism, by B. S. Basavarajappa; (3) Endocannabinoid involvement in the control of appetitive behavior, by George Kunos; (4) Regulation of voluntary ethanol intake by cannabinoid receptor agonists and antagonists in alcohol-preferring sP rats, by Giancarlo Colombo; (5) Role of endogenous cannabinoid system in alcoholism, by Fernado Rodriguez de Fonseca; and (6) Endocannabinoids and dopamine interactions in vivo, by Loren Parsons and George Koob.
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PMID:Ethanol, endocannabinoids, and the cannabinoidergic signaling system. 1198 Nov 34

The current review evaluates the evidence that some of the pharmacological and behavioral effects of ethanol (EtOH), including EtOH-preferring behavior, may be mediated through the endocannabinoid signaling system. The recent advances in the understanding of the neurobiological basis of alcoholism suggest that the pharmacological and behavioral effects of EtOH are mediated through its action on neuronal signal transduction pathways and ligand-gated ion channels, receptor systems, and receptors that are coupled to G-proteins. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor) that was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. To date, two fatty acid derivatives identified to be arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta(9)-THC. The involvement of the endocannabinoid signaling system in the development of tolerance to the drugs of abuse including EtOH has not been known until recently. Recent studies from our laboratory have demonstrated for the first time the down-regulation of CB1 receptor function and its signal transduction by chronic EtOH. The observed down-regulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of the receptors by the endogenous CB1 receptor agonists, AEA and 2-AG, the synthesis of which has been found to be increased by chronic EtOH treatment. This enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid EtOH intake, have significantly reduced brain-CB1-receptor function consistent with other studies, where the CB1 receptor antagonist SR141716A has been shown to block voluntary EtOH intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive EtOH drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic strategies for the treatment of alcoholism.
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PMID:Neuromodulatory role of the endocannabinoid signaling system in alcoholism: an overview. 1205 43

Current pharmacotherapies for alcohol dependence in humans (e.g., naltrexone, acamprosate) are meeting with only limited therapeutic success. The development of novel pharmacotherapies is urgently needed but is reliant upon the screening of large numbers of candidate "anticraving" drugs using appropriate animal models. The development of animal models is complex because (1) laboratory animals are often reluctant to consume large quantities of alcohol, (2) inducing a state of alcohol dependence, analogous to the human condition, may require many months of alcohol exposure, (3) concluding that a given drug selectively reduces alcohol craving requires very carefully controlled experiments, and (4) false positives and false negatives may result from the sometimes distinct physiology and psychology of the alcohol-addicted human and rat. To address some of these problems, our laboratory has recently developed the "beer model" of alcohol dependence and craving. Rats, like humans, have a prodigious appetite for beer and will drink much more beer than equivalent ethanol solutions in water. Beer consumption in rats leads to clear signs of intoxication, anxiety reduction, and signs of withdrawal when beer access is suddenly denied. We have found that beer craving in rats is selectively reduced by the cannabinoid receptor antagonist SR 141716 and the opioid receptor antagonist naltrexone. Combining these two drugs appears to have a synergistic anticraving effect. Other promising pharmacotherapies for the future are discussed.
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PMID:Rats on the grog: novel pharmacotherapies for alcohol craving. 1534 69

The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB(1) receptor), which was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol ether (noladin ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of Delta(9)-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB(1) receptors and its signal transduction. The observed downregulation of CB(1) receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB(1) receptor function in the brain, consistent with other studies in which the CB(1) receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB(1) receptor system promoted alcohol craving, suggesting a role for the CB(1) receptor gene in excessive alcohol drinking behaviour and development of alcoholism. Ongoing investigations may lead to a better understanding of the mechanisms underlying the development of tolerance to alcohol and to develop therapeutic strategies to treat alcoholism.
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PMID:Role of the endocannabinoid system in the development of tolerance to alcohol. 1555 Apr 43

The endogenous cannabinoid system is an ubiquitous lipid signalling system that appeared early in evolution and which has important regulatory functions throughout the body in all vertebrates. The main endocannabinoids (endogenous cannabis-like substances) are small molecules derived from arachidonic acid, anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol. They bind to a family of G-protein-coupled receptors, of which the cannabinoid CB(1) receptor is densely distributed in areas of the brain related to motor control, cognition, emotional responses, motivated behaviour and homeostasis. Outside the brain, the endocannabinoid system is one of the crucial modulators of the autonomic nervous system, the immune system and microcirculation. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and serve as retrograde signalling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters, including dopamine. Endocannabinoids are transported into cells by a specific uptake system and degraded by two well-characterized enzymes, the fatty acid amide hydrolase and the monoacylglycerol lipase. Recent pharmacological advances have led to the synthesis of cannabinoid receptor agonists and antagonists, anandamide uptake blockers and potent, selective inhibitors of endocannabinoid degradation. These new tools have enabled the study of the physiological roles played by the endocannabinoids and have opened up new strategies in the treatment of pain, obesity, neurological diseases including multiple sclerosis, emotional disturbances such as anxiety and other psychiatric disorders including drug addiction. Recent advances have specifically linked the endogenous cannabinoid system to alcoholism, and cannabinoid receptor antagonism now emerges as a promising therapeutic alternative for alcohol dependence and relapse.
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PMID:The endocannabinoid system: physiology and pharmacology. 1555 Apr 44

Over the past few years, advances in the investigation of the neurochemical circuits involved in the development and treatment of alcohol dependence have identified peptides and receptors as potential key targets in the treatment of problems related to alcohol consumption. The endogenous opioid system is modified by alcohol intake in areas of the brain related to reward systems, and differential basal levels of opioid gene expression are found in rodents with a high preference for ethanol. This suggests a greater vulnerability to alcohol consumption in relation to differences in genetic background. Further evidence of the involvement of opioid peptides in alcohol dependence is the ability of the opioid antagonist naltrexone to reduce alcohol intake in animal models of dependence and in alcohol-dependent patients. Abundant evidence indicates that the activation of cannabinoid receptors stimulates the release of opioid peptides, therefore the cannabinoid receptor antagonists may presumably alter opioid peptide release, thus facilitating the reduction of ethanol consumption. However, little is known about the effects of ethanol on the endogenous cannabinoid system, the vulnerability of cannabinoid receptors to alcohol intake or their neurochemical implications in reducing consumption of alcohol. In this paper, we review the role of opioid and cannabinoid receptor systems, their vulnerability to alcohol intake and the development of dependence, and the targeting of these systems in the treatment of alcoholism.
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PMID:Interactions between cannabinoid and opioid receptor systems in the mediation of ethanol effects. 1555 Apr 51

Behavioral and molecular methods were used to study and determine whether there is a link between depression that may be a factor in drug/alcohol addiction, and the endocannabinoid hypothesis of substance abuse. Depression is a lack of interest in the pleasurable things of life (termed anhedonia) and depressed mood. It is unknown whether CB2 cannabinoid receptors are expressed in the brain and whether they are involved in depression and substance abuse. Therefore, mice were subjected daily for 4 wk to chronic mild stress (CMS), and anhedonia was measured by the consumption of 2% sucrose solution. Behavioral and rewarding effects of abused substances were determined in the CMS and control animals. The expression of CB2 receptors and their gene transcripts was compared in the brains of CMS and control animals by Western blotting using CB2 receptor antibody and reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, the expression and immunocytochemical identification of CB2 cannabinoid receptor in the rat brain were determined. CMS induced gender-specific aversions, which were blocked by WIN55,212-2, a nonspecific CB1 and CB2 cannabinoid receptor agonist. Direct CB2 antisense oligonucleotide microinjection into the mouse brain induced anxiolysis, indicating that CB2 or CB2-like receptors are present in the brain and may influence behavior. The major finding from these studies was the expression of CB2 receptor and its gene transcript in the mouse brain, which was enhanced by CMS. These preliminary results, if confirmed, suggest that the CB2 receptors are expressed in the mammalian brain and may be involved in depression and substance abuse.
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PMID:Methods to study the behavioral effects and expression of CB2 cannabinoid receptor and its gene transcripts in the chronic mild stress model of depression. 1650 15

An alternative promoter producing a novel 5'-untranslated region of cannabinoid receptor mRNA has recently been described in CNR1, the gene encoding the cannabinoid receptor protein. Single nucleotide polymorphisms (SNPs) adjacent to this site were reported to be associated with polysubstance abuse [Zhang et al., 2004]. We examined the association of 4 SNPs (rs6928499, rs806379, rs1535255, rs2023239) in the distal region of intron 2 of CNR1 both with individual substance dependence diagnoses (i.e., alcohol, cocaine, and opioids), as well as with polysubstance dependence. The study samples consisted of European-American (EA) and African-American (AA) subjects with drug and or alcohol dependence (n = 895), and controls (n = 472). Subjects were grouped as polysubstance dependent, opioid dependent, cocaine dependent, cannabis dependent, and alcohol dependent. There was a modest association of marker rs1535255 with alcohol dependence (P = 0.04), though with correction for multiple phenotype comparisons, this effect was not considered statistically significant. These findings fail to replicate the original report of an association between SNPs adjacent to an alternative CNR1 exon 3 transcription start site and polysubstance abuse.
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PMID:Association study of the CNR1 gene exon 3 alternative promoter region polymorphisms and substance dependence. 1674 37

The endocannabinoid system mediates in the pharmacological actions of ethanol and genetic studies link endocannabinoid signaling to alcoholism. Drugs activating cannabinoid CB1 receptors have been found to promote alcohol consumption but their effects on self-administration of alcohol are less clear because of the interference with motor performance. To avoid this problem, a novel pharmacological approach to the study of the contribution of the cannabinoid system in alcoholism may be to use drugs that locally amplify the effects of alcohol on endogenous cannabinoids. In the present study we addressed this model by studying the effects of the anandamide transport inhibitor N-(4-hydroxyphenyl) arachidonoyl-ethanolamide (AM404) on both ethanol self-administration and reinstatement of alcohol-seeking behavior in rats. The results show that AM404 significantly reduced ethanol self-administration in a dose-dependent manner but failed to modify reinstatement for lever pressing induced by the stimulus associated with alcohol. This effect was not due to a motor depressant effect and was not related to a decrease in general motivational state, as it was not effective in other reward paradigms such as lever pressing for a saccharin solution. The mechanism of action of AM404 does not involve cannabinoid CB1 receptors as the CB1-selective antagonist SR141716A did not block the reduction of ethanol self-administration induced by the anandamide uptake blocker. Moreover, 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol (HU-210), a classical cannabinoid receptor agonist, did not affect ethanol self-administration. The effects of AM404 are not mediated by either vanilloid VR1 receptors or cannabinoid CB2 receptors because it is not antagonized by either the VR1 receptor antagonist capsazepine or the CB2 antagonist AM630. These results indicate that AM404 may be considered as an innovative approach to reduce alcohol consumption.
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PMID:The anandamide transport inhibitor AM404 reduces ethanol self-administration. 1765 Jan 18


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