Tag Archives: CB1

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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“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

Modulation Of The Endo-Cannabinoid System: Therapeutic Potential Against Cocaine Dependence

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 “Dependence on cocaine is still a main unresolved medical and social concern, and in spite of research efforts, no pharmacological therapy against cocaine dependence is yet available. Recent studies have shown that the endocannabinoid system participates in specific stages and aspects of drug dependence in general, and some of this evidence suggests an involvement of the cannabinoid system in cocaine effects. For example, cocaine administration has been shown to alter brain endocannabinoid levels, and the endocannabinoid system has been involved in long-term modifications of brain processes that might play a role in neuro/behavioral effects of psychostimulant drugs like cocaine. Human studies show that marijuana dependence is frequently associated with cocaine dependence, and that the cannabinoid receptor CNR1 gene polymorphism might be related to cocaine addiction. This article will review the main papers in the field showing how a modulation of different components of the cannabinoid system might interact with some of the neurobiological/behavioral effects of cocaine related to its reinforcing effects, evaluated in preclinical models or in clinical settings. The goal of this review will be to provide insights into the complex picture of cocaine abuse and addiction, and to extrapolate from such endocannabinoid-cocaine interactions useful information to test the therapeutic potential of cannabinoid ligands and endocannabinoid-level enhancers against cocaine dependence for future preclinical/clinical trials.”

“Summary and concluding remarks

Most of the scientific articles reviewed in the present manuscript have described studies of cannabinoid CB1 receptor agonists and antagonists tested against cocaine effects in preclinical models thought to be predictive of cocaine abuse. These studies have provided interesting results, especially for the ability of cannabinoid antagonists, and Rimonabant in particular, to significantly counteract some of the reinforcing actions of cocaine (104, 143). Collectively, the studies suggest that a cannabinoid tone, impaired by cannabinoid antagonist administration, is indeed involved in many of the reinforcing effects of cocaine which are believed to be responsible for cocaine abuse and addiction. On the other hand, there are no studies available showing interactions of drugs acting as cannabinoid levels modulators/enhancers on cocaine-induced behaviors. These drugs affecting directly the endogenous cannabinoid tone could interfere with cocaine effects in these preclinical procedures and could substantially increase our knowledge about the cannabinoid-neurobiology related to cocaine dependence.”

“Suggestions about possible genetic predisposition/vulnerability to cocaine dependence from human studies due to variants of the cannabinoid receptor CNR1 gene have given more strength to the link between endocannabinoids and cocaine. Due to the widespread distribution of cannabinoid receptors in the brain, and their abundance in brain areas playing pivotal roles in drug abuse and addiction, the different expression and regulation of cannabinoid receptors induced by genetic differences might be an important factor in the predisposition or vulnerability to drug dependence. For this reason, the potential to directly interact with endocannabinoid tone in selected brain areas, an effect that can be obtained with endocannabinoid uptake inhibitors or metabolism blockers (as shown also in genetically modified mice, 170), as compared to widespread actions of cannabinoid receptors agonists/antagonists, should be one of the next challenges in the research for medications able to counteract the abuse- and dependence-related behavioral/neurobiological effects of cocaine.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2134985/

The role of endocannabinoid transmission in cocaine addiction.

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“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.

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 “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/

The role of the endogenous cannabinoid system in drug addiction.

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“This review aims to present the more recent knowledge on the role of the endocannabinoid system in drug addiction. For a long time, dopamine has been consistently associated with the reinforcing effects of most drugs of abuse but, recently, pharmacological evidence points to the possibility that pharmacological management of the endocannabinoid system might not only block the direct reinforcing effect of cannabis, opioids, nicotine and ethanol, but also prevent the relapse to various drugs of abuse including opioids, cocaine, nicotine, alcohol and amphetamine. Preclinical and clinical studies suggest that the manipulation of the endocannabinoid system through the CB(1) receptor antagonist SR-141716A (rimonabant) might constitute a new therapeutical strategy for treating addiction across different classes of abused drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/18560613

Cannabinoid CB1 receptor antagonists as potential pharmacotherapies for drug abuse disorders.

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“Since the discovery of the cannabinoid CB1 receptor (CB1R) in 1988, and subsequently of the CB2 receptor (CB2R) in 1993, there has been an exponential growth of research investigating the functions of the endocannabinoid system. The roles of CB1Rs have been of particular interest to psychiatry because of their selective presence within the CNS and because of their association with brain-reward circuits involving mesocorticolimbic dopamine systems. One potential role that has become of considerable focus is the ability of CB1Rs to modulate the effects of the drugs of abuse. Many drugs of abuse elevate dopamine levels, and the ability of CB1R antagonists or inverse agonists to modulate these elevations has suggested their potential application as pharmacotherapies for treating drug abuse disorders. With the identification of the selective CB1R antagonist, rimonabant, in 1994, and subsequently of other CB1R antagonists, there has been a rapid expansion of research investigating their ability to modulate the effects of the drugs of abuse. This review highlights some of the preclinical and clinical studies that have examined the effects of CB1R antagonists under conditions potentially predictive of their therapeutic efficacy as treatments for drug abuse disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/19367507

Current evidence supporting a role of cannabinoid CB1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders.

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“Since the discovery of the cannabinoid CB1 receptor (CB1R) in 1988, and subsequently of the CB2 receptor (CB2R) in 1993, there has been an exponential growth of research investigating the functions of the endocannabinoid system. The roles of CB1Rs have been of particular interest to behavioral pharmacologists because of their selective presence within the central nervous system (CNS) and because of their association with brain-reward circuits involving mesocorticolimbic dopamine systems. One potential role that has become of considerable recent focus is the ability of CB1Rs to modulate the effects of drugs of abuse. Many drugs of abuse elevate dopamine levels, and the ability of CB1R antagonists or inverse agonists to attenuate these elevations has suggested their potential application as pharmacotherapies for treating drug abuse disorders. With the identification of the selective CB1R antagonist, SR141716, in 1994, and its subsequent widespread availability, there has been a rapid expansion of research investigating its ability to modulate the effects of drugs of abuse. The preliminary clinical reports of its success in retarding relapse in tobacco users have accelerated this expansion. This report critically reviews preclinical and clinical studies involving the ability of CB1R antagonists to attenuate the effects of drugs of abuse, while providing an overview of the neuroanatomical and neurochemical points of contact between the endocannabinoid system and systems mediating abuse-related effects.”

http://www.ncbi.nlm.nih.gov/pubmed/16148435

Marijuana withdrawal and craving: influence of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes

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 “While cannabis withdrawal may not include some of the serious medical problems observed with alcohol and opioid withdrawal, it is likely that the symptoms associated with cannabis withdrawal (e.g. negative affect, appetite and sleep disturbance) contribute to the development and intractability of cannabis dependence. In this sense, cannabis withdrawal may be analogous to other, better-understood withdrawal syndromes (e.g. tobacco withdrawal, alcohol withdrawal) that have been the target of intervention efforts. Furthermore, cannabis withdrawal has been described increasingly in terms of the physiological sequelae that coincide with this syndrome, including alterations in dopamine neurotransmission, as well as alterations in other systems.”.

“These findings may have both etiological and treatment implications. For example, individuals with the CNR1 T/C genotype may be more likely to develop dependence and/or more likely to have trouble establishing abstinence or reducing marijuana use. However, longitudinal studies will be needed to clarify whether this genetic variable actually influences the trajectory of marijuana use/dependence. In addition, treatment studies that incorporate this information are needed to determine whether these (or other) genetic variants may influence treatment outcomes and determine whether alternative treatments may be indicated for these individuals.”

“In conclusion, the cannabis dependence endophenotypes, craving and withdrawal, are important factors in the etiology and treatment of cannabis dependence and, given growing recognition of the underlying physiological sequalae that coincide with long-term cannabis use, these phenotypes are likely to lend themselves to the identification of underlying genetic factors that have direct implications for treatment approaches.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873690/