Tag Archives: endocannabinoid system

Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors.

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Abstract

“Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.”

http://www.ncbi.nlm.nih.gov/pubmed/20196742cannabinoid op

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

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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

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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/

CB1 receptor antagonists for the treatment of nicotine addiction.

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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.

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“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.

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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 endocannabinoid system: a new molecular target for the treatment of tobacco addiction.

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Abstract

“Tobacco addiction is one of the leading preventable causes of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Several lines of evidence suggest that the rewarding effects of nicotine, which underlie its abuse potential, can be modulated by manipulating the endocannabinoid system. For example, pharmacological blockade or genetic deletion of cannabinoid CB(1) receptors reduces or eliminates many behavioral and neurochemical effects of nicotine that are related to its addictive potential. This review will focus on the recently published literature about the role of the endocannabinoid system in nicotine addiction and on the endocannabinoid system as a novel molecular target for the discovery of medications for tobacco dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/19128204

Involvement of cannabinoid CB1 receptors in drug addiction: effects of rimonabant on behavioral responses induced by cocaine.

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Abstract

“A lot of evidence indicate that endocannabinoids and cannabinoid CB(1) receptors are implicated in drug addiction. In the present study, we investigated the effect of the cannabinoid CB(1) receptor antagonist/partial agonist rimonabant on the cocaine-maintained reinforcement and relapse to cocaine seeking as well as on the cocaine challenge-induced hyperactivity in sensitized rats and on discriminative stimulus effects of cocaine in rats. We found that endocannabinoids were not involved in maintenance of cocaine reinforcement and its subjective effects since pharmacological blockade of cannabinoid CB(1) receptors altered neither self-administration nor discriminative stimulus effects of cocaine. On the other hand, withdrawal from repeated access or exposure to cocaine and then a reinstatement of cocaine-seeking behavior or a sensitized locomotor response to a single cocaine challenge, respectively, was potently reduced by pretreatment with rimonabant. The latter observations may show that repeated cocaine treatment and the drug withdrawal produce–apart from behavioral effects–also different neural consequences in the endocannabinoid systems in rats.”

http://www.ncbi.nlm.nih.gov/pubmed/17220538

A Role for the Endocannabinoid System in the Increased Motivation for Cocaine in Extended Access Conditions

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 “Extended access to cocaine produces an increase in cocaine self-administration in rats that mimics aspects of compulsive drug intake in human addicts. While emerging evidence implicates the endogenous cannabinoid system in aspects of opioid and ethanol addiction, a role of the endocannabinoid system in cocaine addiction remains largely inconclusive. Here, we investigate the effects of systemic and intra-accumbal administration of the CB1 antagonist SR141716A (Rimonabant) on cocaine self-administration (0.5 mg/kg/infusion) under a progressive ratio (PR) schedule in rats with extended (long access, LgA; 6 h/day) or limited (short access, ShA; 1 h/day) access to cocaine. LgA rats, but not ShA rats showed an increase in cocaine intake as previously reported, and responding for cocaine by LgA rats was higher than in ShA rats under a PR schedule. Systemic SR141716A induced a dramatic dose-dependent decrease in the break-point for cocaine by LgA rats, whereas only the highest dose of the antagonist had a significant effect in the ShA group. Anandamide levels in the nucleus accumbens (NAc) shell were decreased in ShA rats but unchanged in LgA rats during cocaine self-administration. Both phosphorylated and total CB1 receptor protein expression were upregulated in LgA rats in the NAc and the amygdala compared to ShA and drug-naïve rats, 24 h after last cocaine session. Finally, intra-NAc infusions of SR141716A reduced cocaine break-points selectively in LgA animals. These results suggest that neuroadaptations in the endogenous cannabinoid system may be part of the neuroplasticity associated with the development of cocaine addiction.”

“Taken together, our results suggest that eCB system neuroplasticity in the NAc may contribute to the motivational drive for cocaine associated with uncontrolled psychostimulant use and, therefore, may be a target for cocaine addiction pharmacotherapies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688678/

Antagonism of cannabinoid 1 receptors reverses the anxiety-like behavior induced by central injections of corticotropin-releasing factor and cocaine withdrawal.

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Abstract

“The endocannabinoid (eCB) system is an important regulator of the stress response and mediates several stress-related behaviors, including anxiety. Despite anatomical evidence that eCBs interact with the principle stress peptide, corticotropin-releasing factor (CRF), few data exist that address functional interactions between these systems. Accordingly, we examined the effects of the CB1 receptor antagonist, AM251, on behavioral anxiety induced by (1) exogenous CRF, and (2) withdrawal from chronic cocaine exposure (mediated by CRF). After behavioral testing, we collected blood and assessed plasma corticosterone levels. In Experiment 1, male Long-Evans rats were pretreated with AM251 (0, 10, 100, or 200 μg, i.c.v.), followed by CRF (0 or 0.5 μg, i.c.v.), before testing for anxiety-like behavior in the elevated plus maze (EPM). In Experiment 2, rats were exposed to cocaine (20 mg/kg, i.p.) or saline for 14 consecutive days. Forty-eight hours following cocaine exposure, rats were pretreated with AM251 (0, 10, or 100 μg, i.c.v.) and tested in the EPM. AM251 produced an anxiogenic response at the highest dose, but reversed the behavioral anxiety induced by CRF and withdrawal from chronic cocaine in a dose-dependent manner. AM251 also increased plasma corticosterone levels, but did so irrespective of CRF treatment or cocaine preexposure. Our findings suggest that the anxiogenic effects of CRF and cocaine withdrawal are mediated, at least in part, by CB1 receptor transmission, and provide evidence in support of eCB-CRF interactions that are independent of the hypothalamic-pituitary-adrenal axis.”

http://www.ncbi.nlm.nih.gov/pubmed/21784132