Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reinstatement of drug-seeking behaviour in animals is relevant to relapse to drug taking in humans. We used the conditioned place preference version of the reinstatement model to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.), a cannabinoid receptor agonist WIN55,212-2 (0.5 mg/kg, i.p.), ethanol (0.5 g/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). The priming injections of nicotine, WIN55,212-2 and ethanol, but not of d-amphetamine renewed a preference for the compartment previously paired with nicotine. Finally, we examined the influence of the calcium channel antagonists, nimodipine (5 and 10 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine place conditioning induced by WIN55,212-2 and ethanol. It was shown that the calcium channel blockers attenuated the reinstatement of nicotine-conditioned response induced by both drugs. As reinstatement of drug-seeking is a factor for the development of dependence, the L-type calcium channel antagonists may be useful in the relapse-prevention phase of addiction treatment, including cannabinoid, ethanol, and/or nicotine dependence.
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PMID:Calcium-dependent mechanisms of the reinstatement of nicotine-conditioned place preference by drug priming in rats. 1817 44

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.
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PMID:Cannabinoids in health and disease. 1828 1

Recent studies have implicated the endocannabinoid (eCB) system in the neuronal mechanisms underlying substance dependence. Here, we review results of studies using cannabinoid receptor subtype 1 (CB1) knockout mice as well as CB1 antagonists to elucidate the role of this neurotransmitter system in psychostimulant addiction. The overall picture is that CB1 receptors appear not to be involved in psychostimulant reward, nor in the development of dependence to such substances. In contrast, the eCB system appears to play a role in the persistence of psychostimulant addiction. In particular, CB1 receptors have been found to play a cardinal role in mediating reinstatement of previously extinguished drug-seeking behavior upon re-exposure to the drug or drug-associated cues. The anatomical loci as well as the neuronal mechanisms of the relapse-preventing effects of CB1 antagonists are still poorly understood, although interactions of the eCB system with afferent glutamatergic and possibly dopaminergic projections to the nucleus accumbens are most likely involved. In addition, CB1 receptors seem to modulate drug-related memories, in line with the hypothesized role of the eCB system in memory-related plasticity. Together, these findings suggest that modulators of the eCB system represent a promising novel type of therapy to treat drug addiction.
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PMID:The role of CB1 receptors in psychostimulant addiction. 1848 32

A large number of psychoactive derivatives have been identified in Cannabis sativa preparations,but their potential ability to produce dependence in humans is still a controversial issue. Cannabinoids were considered different from other addictive drugs in terms of addictive potential and neurobiological targets of action. Experimental evidence indicates that the mesolimbic dopaminergic system is the common neuronal substrate for the motivational and rewarding properties of different drugs of abuse. Many studies have indeed revealed that an increase in extracellular dopamine concentration in the nucleus accumbens was observed after acute and chronic administration of cannabinoid receptor agonists. Many behavioral studies have used different animal models to clarify the consequences of chronic exposure to cannabinoid receptor agonists and the abuse liability of these compounds. This paper reviews research from animal models of cannabinoid addiction in which both motivational and physical aspects of dependence can be measured in order to clarify still unresolved issues of cannabinoid addiction.
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PMID:[Cannabinoid dependence in animal models]. 1854 46

The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.
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PMID:Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. 1880 86

The involvement of the endogenous cannabinoid system has been implicated in the rewarding actions of several drugs of abuse. Recent evidence indicates that the transcription factor CREB (cAMP response element-binding protein) may be an important biochemical substrate for behavioral plasticity that has been associated with the chronic administration of drugs of abuse and addiction. Increased CREB activity was reported as a chronic effect of drugs of abuse in the neurons of the nucleus accumbens, a brain reward region that expresses high-density levels in the CB1 cannabinoid receptors. However, little is known whether a similar change occurs in the hippocampus, a region of the brain that also expresses high-density levels of the CB1 cannabinoid receptors and has intimate synaptic connections with the brain's reward regions. The present study revealed that CREB activities were present in the hippocampal neurons of cultured slice preparations in response to acute and chronic applications of endogenous cannabinoid, anandamide and R(+)-methanandamide (a non-hydrolyzing form of anandamide). When administered acutely at a dose effective for inducing self-administration in vivo, anandamide and R(+)-methanandamide stimulated the expression of pCREB in our hippocampal slice culture. Interestingly, a sub-threshold dose of R(+)-methanandamide, which was not effective in producing acute changes in the CREB activity, was also found to effectively increase pCREB when administered chronically for 10 days. These increases were blocked by the antagonist of the CB1 cannabinoid receptor. Present findings demonstrate: (1) the hippocampus is vulnerable to the direct chemical effect of anandamide and R(+)-methanandamide in isolation of synaptic influences from the midbrain reward neurons, and (2) the effect of R(+)-methanandamide is cumulative as evidenced by the sustained elevation of CREB activities in response to a chronic dosage that is too low and thus fails to exert any acute effect. The ability of hippocampal neurons to integrate a time-dependent effect on the endogenous cannabinoid signaling may be a key function of plasticity as related to the induction and maintenance of maladaptive learning and memory that underlies both cue-induced cravings as well as relapses in drug-seeking.
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PMID:Time-dependent induction of CREB phosphorylation in the hippocampus by the endogenous cannabinoid. 1942 61

Drug addiction is a chronic disorder characterized by a relatively high rate of relapse even after long period of abstinence. In the present study, we used the conditioned place preference (CPP) paradigm to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5mg/kg, i.p., three drug sessions). Once established, nicotine CPP was extinguished by repeated testing. Following this extinction phase, the reinstatement of CPP was investigated. Nicotine-experienced rats were challenged with nicotine (0.5mg/kg, i.p.) or morphine (10mg/kg, i.p.). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Furthermore, the objective of the present study was to evaluate the efficacy of CB1 cannabinoid receptor antagonist rimonabant (0.5, 1 and 2mg/kg, i.p.) in blocking the reinstatement of nicotine-induced CPP provoked by nicotine and morphine. It was shown that rimonabant attenuated the reinstatement of nicotine-conditioned response induced by both drugs. The outcome of our studies may suggest that CB1 receptor antagonists may become a promising target for effective pharmacotherapy of tobacco addiction and polydrug abuse.
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PMID:Effects of rimonabant on the reinstatement of nicotine-conditioned place preference by drug priming in rats. 1946 10

The cannabinoid receptor 1 (CB(1)) and CB(2) cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a beta-arrestin-green fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing beta-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase CbetaII. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of beta-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase CbetaII membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy.
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PMID:Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. 1972 26

Alterations in expression of a cannabinoid receptor (CNR1, CB1), and of fatty acid amide hydrolase (FAAH) that degrades endogenous ligands of CB1, may contribute to the development of addiction. The 385C>A in the FAAH gene and six polymorphisms of CNR1 were genotyped in former heroin addicts and control subjects (247 Caucasians, 161 Hispanics, 179 African Americans and 19 Asians). In Caucasians, long repeats (>or=14) of 18087-18131(TAA)(8-17) were associated with heroin addiction (P=0.0102). Across three ethnicities combined, a highly significant association of long repeats with heroin addiction was found (z=3.322, P=0.0009). Point-wise significant associations of allele 1359A (P=0.006) and genotype 1359AA (P=0.034) with protection from heroin addiction were found in Caucasians. Also in Caucasians, the genotype pattern, 1359G>A and -6274A>T, was significantly associated with heroin addiction experiment wise (P=0.0244). No association of FAAH 385C>A with heroin addiction was found in any group studied.
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PMID:Association of polymorphisms of the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes with heroin addiction: impact of long repeats of CNR1. 2001 Sep 14

Early environmental enrichment (EE) produces several changes in gene expression in the brain and confers protection against the behavioral, neurochemical and molecular effects of repeated administration of drugs of abuse. Because the endogenous cannabinoid system (ECS) is known to play an important role in the rewarding effects of drugs, we investigated whether the positive effects of early exposure to EE are associated with changes in the expression of genes encoding for proteins that belong to the ECS in C57 mice. Using in situ hybridization, we compared the expression of the cannabinoid receptor CB1, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) enzymes in brain regions involved in drug addiction in mice reared in either EE or standard environments (SE) from weaning until adulthood. We found that EE increases CB1 mRNA levels in the hypothalamus and in the basolateral amygdala but decreased them in the basomedial amygdala. Similarly, we found that FAAH mRNA levels are higher in the hypothalamus and the basolateral amygdala of EE mice compared to SE mice, with no change in the basomedial amygdala. In contrast, MGL mRNA levels were not affected by EE in any of the areas analyzed. The regional selectivity of EE-induced changes may indicate that early exposure to EE induces changes in the ECS that could result in reduced responses to stress, as confirmed in EE mice in a novelty-induced suppression of feeding test, and, ultimately, in resistance to addiction.
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PMID:Early exposure to environmental enrichment alters the expression of genes of the endocannabinoid system. 2141 9


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