Tag Archives: antagonists

ROLE OF THE ENDOCANNABINOID SYSTEM IN THE DEVELOPMENT OF TOLERANCE TO ALCOHOL

Posted on by
Reply

“Alcohol dependence is a leading cause of morbidity and various medical and socio-economic problems. It is defined by compulsive, excessive use of alcohol despite negative consequences. Alcohol dependence is usually accompanied by tolerance to the intoxicating effects of alcohol and by withdrawal symptoms including tremors and confusion when consumption of alcohol ceases. Although important advances have been made in recent years in understanding the mechanisms underlying the development of tolerance to and dependence on alcohol, the exact mechanisms are still elusive. The present article reviews the role played by the endocannabinoid system in the molecular mechanism involved in the development of alcohol tolerance, which possibly influences alcohol-drinking behaviour.”

“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 (CB1 receptor), which was activated by Δ9-tetrahydrocannabinol (Δ9-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 Δ9-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 CB1 receptors and its signal transduction. The observed downregulation of CB1 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 CB1 receptor function in the brain, consistent with other studies in which the CB1 receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 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.”

“CONCLUSION

Over the past seven years, remarkable advances have been made towards our understanding of the role played by the endocannabinoid system in the development of alcohol tolerance and alcohol-drinking behaviour. These studies have provided strong evidence that CB1 receptors and the endocannabinoid system serve as an attractive therapeutic target for the treatment of alcohol tolerance and alcohol-related disorders. The data reviewed here provide convincing evidence that alcohol tolerance involves the downregulation of the CB1 receptor and its function. The observed neuro-adaptation may be due to increased accumulation of the endocannabinoids AEA and 2-AG. Treatment with the CB1 receptor antagonist SR 141716A led to reduced consumption of alcohol in rodents and activation of the same endogenous cannabinoid systems by the CB1 receptor agonist promoted alcohol craving, which may be related to the change in the levels of dopamine in the NAc. Further, reduced alcohol intake by the CB1 receptor knockout mice is consistent with our previous observation that significantly lower levels of functional CB1 receptors are found in the alcohol-avoiding DBA/2 mouse strain compared with the alcohol-preferring C57BL/6 mouse strain. These observations suggest the involvement of the CB1 receptors in controlling voluntary alcohol consumption and the involvement of the endocannabinoid system in the development of alcohol tolerance. However, further studies are necessary to unfold the exact mechanism by which alcohol exerts its pharmacological and behavioural effects through the endocannabinoid system. The investigation of the detailed signalling cascade for the actions of both endocannabinoids and CB1 receptors will be of great value in understanding their physiological and functional role in several neurological disorders, voluntary alcohol intake and alcohol craving, including the behavioural neuroadaptation to alcohol. Such studies may also lead to the development of endocannabinoid signalling-targeted drugs, which may help to reduce both alcohol intake and alcohol craving. These results suggest that the cannabinoid antagonist, SR 141716A, may be useful as a potential therapeutic agent in alcohol dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/15550443

http://alcalc.oxfordjournals.org/content/40/1/15.long

The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism

Posted on by
Reply

“Alcoholism is a complex disorder affecting modern society in many ways, yet there are few effective treatment strategies currently available.”

“Research into the endocannabinoid signaling system has grown exponentially in recent years following the discovery of cannabinoid receptors (CB) and their endogenous ligands, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism, including alcohol-seeking behavior. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity. Mice treated with the CB1 receptor antagonist SR141716A (rimonabant) or homozygous for a deletion of the CB1 receptor gene exhibit reduced voluntary alcohol intake. CB1 knockout mice also show increased alcohol sensitivity, withdrawal, and reduced conditioned place preference. Conversely, activation of CB1 receptor promotes alcohol intake. Recent studies also suggest that elevated endocannabinoid tone due to impaired degradation contributes to high alcohol preference and self-administration. These effects are reversed by local administration of rimonabant, suggesting the participation of the endocannabinoid signaling system in high alcohol preference and self-administration. These recent advances will be reviewed with an emphasis on the endocannabinoid signaling system for possible therapeutic interventions of alcoholism.”

“Overwhelmingly, recent studies suggest that cannabinoids and alcohol activate similar reward pathways. The CB1 receptors also seem to regulate the reinforcing properties of alcohol. The discovery of cannabinoid receptors and their endogenous ligands set a landmark in cannabinoid research. These discoveries impacted significantly on alcohol research, too, since there is now considerable evidence that endocannabinoid signaling plays a key role in alcohol addiction, and this has promising clinical consequences. The purpose of this article is to analyze the interaction between alcohol and endocannabinoid signaling, paying particular attention to the reward mechanism. Therapeutic aspects driving from these new insights are also discussed.”

“THERAPEUTIC OPPORTUNITY”

“Although the detailed physiology, biochemistry and pathophysiology of the endocannabinoid signaling system have not been fully investigated, there is already overwhelming evidence to indicate that pharmacological modulation of the endocannabinoid signaling system could provide new treatments for a number of disease states, including alcohol addiction. Recently it was reported that rimonabant holds an important therapeutic role in treating liver fibrosis and alcohol abuse accounts for more than half of the prevalence of liver fibrosis and cirrhosis in the western world. Therefore, it is important to examine whether alcohol-induced liver fibrosis and cirrhosis results in increased endocannabinoid levels and rimonabant reverses alcohol-induced liver fibrosis/cirrhosis. In terms of drug development, the CB1 receptor antagonist rimonabant has progressed furthest and is in late phase III trials for the treatment of obesity and as an aid for smoking cessation. An NIAAA clinical study of the effectiveness of rimonabant to reduce voluntary alcohol drinking has progressed to phase I trials. Pending results of the clinical trials, rimonabant could become an important addition to the limited arsenal of effective treatments for alcoholism. During drug abuse there are changes in endocannabinoid levels in various brain regions. Therefore, drugs which regulate the level of endocannabinoids by inhibiting their metabolism (FAAH inhibitors such as URB597) or uptake (AM404) could locally target sites while limiting effects in uninvolved cognitive areas to produce a higher therapeutic value. Cannabinoid interactions with the dopamine system have been offered as a possible mechanism for some of the therapeutic potential of cannabinoid-based drugs in alcoholism. A recent study provides evidence of the ability of CB1 receptor antagonist to mitigate alcohol-withdrawal symptoms, and block the formation of physical dependency by inhibiting alcohol intake. Recent data on the role of CB1 receptors in alcohol drinking behavior, including alcohol tolerance as discussed in the earlier sections, clearly suggest that agents such as CB1 receptor antagonists, including rimonabant, will be promising therapeutic agents for the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1975858/

Endogenous cannabinoid and opioid systems and their role in nicotine addiction.

Posted on by
Reply

Abstract

“Nicotine addiction is a complex behavioural alteration, in which many neuronal pathways and neurotransmitters are involved. For a long time, dopamine has been considered one of the most important neurotransmitters in mediating the rewarding effects of nicotine. In addition, a great amount of research suggests that the endogenous cannabinoid and opioid systems play an overall modulatory effect on the reward circuitry and participate in the addictive properties of most of the prototypical drugs of abuse. This review focuses on recent behavioural and biochemical data involving these systems in the different processes that contribute to tobacco addiction. A possible role for the endogenous cannabinoid and opioid systems in the rewarding properties of nicotine as well as in the development of nicotine physical dependence and relapse to nicotine-seeking behaviour will be examined. According to preclinical studies, clinical trials suggest that the manipulation of these systems with cannabinoid or opioid antagonists could be a potential therapeutical strategy for treating nicotine addiction.”

http://www.ncbi.nlm.nih.gov/pubmed/20017727

The Endogenous Cannabinoid System Modulates Nicotine Reward and Dependence

Posted on by
Reply

Abstract

“A growing body of evidence suggests that the endogenous cannabinoid system modulates the addictive properties of nicotine, the main component of tobacco that produces rewarding effects. In our study, complementary transgenic and pharmacological approaches were used to test the hypothesis that the endocannabinoid system modulates nicotine reward and dependence. An acute injection of nicotine elicited normal analgesic and hypothermic effects in cannabinoid receptor (CB)(1) knockout (KO) mice and mice treated with the CB(1) antagonist rimonabant. However, disruption of CB(1) receptor signaling blocked nicotine reward, as assessed in the conditioned place preference (CPP) paradigm. In contrast, genetic deletion, or pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for catabolism of the endocannabinoid anandamide, enhanced the expression of nicotine CPP. Although the expression of spontaneous nicotine withdrawal (14 days, 24 mg/kg/day nicotine) was unaffected in CB(1) KO mice, acute administration of rimonabant (3 mg/kg) ameliorated somatic withdrawal signs in wild-type mice. Increasing endogenous levels of anandamide through genetic or pharmacological approaches exacerbated the physical somatic signs of spontaneous nicotine withdrawal in a milder withdrawal model (7 days, 24 mg/kg/day nicotine). Moreover, FAAH-compromised mice displayed increased conditioned place aversion in a mecamylamine-precipitated model of nicotine withdrawal. These findings indicate that endocannabinoids play a role in the rewarding properties of nicotine as well as nicotine dependence liability. Specifically, increasing endogenous cannabinoid levels magnifies, although disrupting CB(1) receptor signaling, attenuates nicotine reward and withdrawal. Taken together, these results support the hypothesis that cannabinoid receptor antagonists may offer therapeutic advantages to treat tobacco dependence.”

“In conclusion, we have shown that the endocannabinoid system modulates various aspects of nicotine dependence in a differential way. Indeed, FAAH inhibition dramatically enhances nicotine reward through a CB1 mechanism that is most likely due to elevated levels of AEA. Moreover, our findings indicate that endogenous cannabinoid tone indirectly modulates the development of nicotine addiction by affecting the balance between the rewarding and aversive properties of nicotine.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746999/

BLOCKING CANNABINOID CB1 RECEPTORS FOR THE TREATMENT OF NICOTINE DEPENDENCE: INSIGHTS FROM PRECLINICAL AND CLINICAL STUDIES

Posted on by
Reply

Abstract

“Tobacco use is one of the leading preventable causes of death in developed countries. Since existing medications are only partially effective in treating tobacco smokers, there is a great need for improved medications for smoking cessation. It has been recently proposed that cannabinoid CB(1) receptor antagonists represent a new class of therapeutic agents for drug dependence, and notably, nicotine dependence. Here, we will review current evidence supporting the use of this class of drugs for smoking cessation treatment. Pre-clinical studies indicate that nicotine exposure produces changes in endocannabinoid content in the brain. In experimental animals, N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant, SR141716) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), two cannabinoid CB(1) receptor antagonists, block nicotine self-administration behavior, an effect that may be related to the blockade of the dopamine-releasing effects of nicotine in the brain. Rimonabant also seems efficacious in decreasing the influence of nicotine-associated stimuli over behavior, suggesting that it may act on two distinct neuronal pathways, those implicated in drug-taking behavior and those involved in relapse phenomena. The utility of rimonabant has been evaluated in several clinical trials. It seems that rimonabant is an efficacious treatment for smoking cessation, although its efficacy does not exceed that of nicotine-replacement therapy and its use may be limited by emotional side effects (nausea, anxiety and depression, mostly). Rimonabant also appears to decrease relapse rates in smokers. These findings indicate significant, but limited, utility of rimonabant for smoking cessation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752688/

CB1 receptor antagonists for the treatment of nicotine addiction.

Posted on by
Reply

Abstract

“Tobacco smoking is the largest cause of avoidable death and disease in developed countries. It is now viewed as a complex bio-psycho-social problem for which effective pharmacological treatments are needed. Nicotine is considered to be the primary compound of tobacco smoke that establishes and maintains tobacco dependence. The addictive effect of nicotine is mediated by activation of the mesolimbic system and the release of dopamine in the nucleus accumbens. Recently, the existence of a specific functional interaction between nicotine and the endocannabinoid system has been reported. Co-administration of sub-threshold doses of a cannabinoid agonist and nicotine produces rewarding effects and chronic nicotine treatment increases endocannabinoid levels in limbic regions. The CB1 receptor plays a key role in this interaction. CB1 knockout mice are less sensitive to the motivational effects of nicotine although this depends on the experimental model. The selective CB1 antagonist, rimonabant (SR141716), reduces nicotine self-administration and nicotine-seeking behavior induced by conditioned cues in rats. Rimonabant appears to reduce nicotine addiction by attenuating the hyperactivation of the endocannabinoid system and the mesolimbic dopaminergic neuronal pathway. Rimonabant may be considered as a potential alternative to the current substitutive treatments of nicotine addiction and may offer a new hope for the treatment of smokers who wish to quit.”

http://www.ncbi.nlm.nih.gov/pubmed/15935455

Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation.

Posted on by
Reply

“BACKGROUND:

Rimonabant is a selective type 1 cannabinoid (CB1) receptor antagonist. It may assist with smoking cessation by restoring the balance of the endocannabinoid system, which can be disrupted by prolonged use of nicotine. Rimonabant also seeks to address many smokers’ reluctance to persist with a quit attempt because of concerns about weight gain.”

“OBJECTIVES:

To determine whether selective CB1 receptor antagonists increase the numbers of people stopping smoking. To assess their effects on weight change in successful quitters and in those who try to quit but fail.”

“AUTHORS’ CONCLUSIONS:

From the preliminary trial reports available, rimonabant 20 mg may increase the odds of quitting approximately 1(1/2)-fold. Adverse events include nausea and upper respiratory tract infections; the risk of serious adverse events is reported to be low. However, there is current concern (August 2007) over rates of depression and suicidal thoughts in people taking rimonabant for weight control. The evidence for rimonabant in maintaining abstinence is inconclusive. Rimonabant 20 mg may moderate weight gain in the long term.”

http://www.ncbi.nlm.nih.gov/pubmed/17943852

Cannabinoid type 1 receptor antagonists for smoking cessation.

Posted on by
Reply

Abstract

“BACKGROUND:

Selective type 1 cannabinoid (CB1) receptor antagonists may assist with smoking cessation by restoring the balance of the endocannabinoid system, which can be disrupted by prolonged use of nicotine. They also seeks to address many smokers’ reluctance to persist with a quit attempt because of concerns about weight gain.”

“OBJECTIVES:

To determine whether selective CB1 receptor antagonists (currently rimonabant and taranabant) increase the numbers of people stopping smoking To assess their effects on weight change in successful quitters and in those who try to quit but fail.”

“AUTHORS’ CONCLUSIONS:

From the trial reports available, rimonabant 20 mg may increase the chances of quitting approximately 1½-fold. The evidence for rimonabant in maintaining abstinence is inconclusive. Rimonabant 20 mg may moderate weight gain in the long term. Taranabant 2-8 mg may moderate weight gain, at least in the short term. In 2008, development of both rimonabant and taranabant was discontinued by the manufacturers.”

http://www.ncbi.nlm.nih.gov/pubmed/21412887

The role of endocannabinoid transmission in cocaine addiction.

Posted on by
Reply

Abstract

“Research is beginning to outline a role for the endocannabinoid system in cocaine addiction. Human and animal studies indicate that exogenous cannabinoids modulate the acute rewarding effects of cocaine. These studies, however, cannot directly investigate the necessity of endocannabinoid transmission in cocaine addiction. Studies that do offer a direct assessment show that neither pharmacological antagonism nor deletion of the CB1 receptor alters the acute rewarding effects of cocaine. In contrast, CB1 receptors appear to be involved in the association of cocaine reward with environmental cues and reinstatement of cocaine self-administration. Together, these results point to CB1 receptor antagonists as potential anti-craving compounds in the treatment of cocaine addiction. Given the limitations of human population studies, animal research may be useful in discerning causal inferences between cannabis and cocaine use. While animal research suggests cannabis use may precipitate cocaine relapse, cross-sensitization between cannabinoids and cocaine has not been demonstrated and CB1 receptors do not mediate behavioral sensitization to cocaine. The effect of acute or chronic cocaine on endocannabinoid transmission in reward-related areas of the brain is relatively under-researched. Acute cocaine administration increases anandamide levels in the striatum, an effect that is mediated by dopamine D2-like receptors. Conversely, chronic cocaine exposure has no effect on anandamide, but decreases 2-arachidonylglycerol levels in the limbic forebrain. This review highlights research indicating that the endocannabinoid system may subserve certain aspects of cocaine addiction and suggests avenues for future investigation.”

http://www.ncbi.nlm.nih.gov/pubmed/15925401

Role of endocannabinoids in regulating drug dependence.

Posted on by
Reply

 “This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.”

“In the last 25 years the neurobiological and behavioral mechanisms that lead to drug dependence have been extensively investigated but clinical treatment is still unsatisfactory and ineffective in many subjects.”

“Experimental models are now providing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also to prevent relapse to these various substances of abuse, also including cocaine and metamphetamine. The endocannabinoid system can be manipulated by SR141716A and by all the new compounds that protect AEA and 2-AG from deactivation and prolong the lifespan of these endocannabinoid substances in vivo. Rimonabant reduces the motivational effect of drug-related stimuli and drug re-exposure, probably by altering synaptic plasticity, thus providing an effective means of preventing relapse and a new tool for the treatment of drug abuse.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656312/