Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats

Colombo, Giancarlo; Serra, Salvatore; Brunetti, Giuliana; Gómez, R.; Melis, Samuele; Vacca, Giovanni; Carai, Mauro A.M.; Gessa, Gian Luigi

doi:10.1007/s002130100887

Cited by 161 publications

(123 citation statements)

References 18 publications

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“…This is in line with the very well characterised stimulatory effects on food intake following CB1 receptor activation (Williams et al 1998;Gomez et al 2002). Previous reports showed that administration of direct cannabinoid receptor agonists like CP 55,940 and WIN 55,212-2 increases alcohol intake and alcohol reinforcement in both nonselected and genetically selected alcoholpreferring rats (Colombo et al 2002;Gallate et al 1999). These effects are mediated by activation of CB1 receptors because they are abolished by pre-treatment with the selective CB1 receptor antagonist rimonabant.…”

Section: Discussionsupporting

confidence: 85%

“…We speculate that drugs like URB597 or other endocannabinoid modulators may offer important advantages over drugs that activate CB1 receptors directly. For instance, CB1 receptor direct agonists show intrinsic abuse potential and increase consumption of other drugs of abuse (Colombo et al 2002;Gallate et al 1999;McGregor et al 2005). Conversely, as shown here, modulation of endogenous anandamide levels did not increase alcohol abuse-related behaviours.…”

Section: Discussionsupporting

confidence: 51%

“…One of the major concerns with the use of CB1 receptor agonists comes from results showing that these compounds may have abuse potential and increase intake of other drugs of abuse, especially alcohol. It is known, for example, that in rodents, direct activation of CB1 receptors by CP 55,940 and WIN 55,212-2 dose dependently increase voluntary alcohol consumption (Colombo et al 2002(Colombo et al , 2004 and alcohol drinking motivation (Gallate et al 1999), while Δ 9 -THC significantly reinstates responding previously reinforced with beer (McGregor et al 2005). Administration of the CB1 receptor agonist WIN 55,212-2 during abstinence was also shown to increase alcohol consumption when the alcoholic solution was made available again (López-Moreno et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

et al. 2008

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Rationale A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuserelated behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors. Objective Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists.Materials and methods URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbineand cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested. Results Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress-and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration. Conclusions Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

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Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

et al. 2008

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“…Pharmacological blockade or genetic ablation of CB1 receptors decrease operant self-administration of ethanol (148,149) and decrease voluntary consumption of ethanol in rats (150)(151)(152)(153)(154) and in mice (155)(156)(157)(158)(159). Conversely, cannabinoid CB1 receptor agonists increase voluntary consumption of ethanol in rats (160,161). A caveat for the results obtained with oral self-administration or voluntary consumption of ethanol is that cannabinoid CB1 agonists have facilitating effects and cannabinoid CB1 antagonists have inhibitory effects on food and fluid intake, on the motivation to respond to obtain food, and on ingestive behaviour and palatability (162)(163)(164)(165), and these actions may contribute to the behavioral effects of CB1 receptor blockade or deletion on ethanol selfadministration and voluntary ethanol consumption.…”

Section: Alcoholmentioning

confidence: 99%

Endocannabinoid system involvement in brain reward processes related to drug abuse

Solinas

Yaşar

Goldberg

2007

Pharmacological Research

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Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoids can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of noncannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocannadinoid system as a promising target for the development of medications for the treatment of drug abuse.

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“…Interestingly, the prefrontal cortex (PFC) appears to play a critical role in regulating the alcohol drinking behavior as revealed by a dose dependent suppression of alcohol self-administration in alcohol preferring rats when rimonabant was given locally into the PFC [82]. Conversely, the CB1 receptor stimulation is shown to enhance alcohol drinking behavior in both alcohol preferring and alcohol non-preferring rodents [55,61,84,104]. In addition, an increased motivation to drink more beer in rats following administration of the CB1 receptor agonist (CP-55, 940) and complete abolition of this effect after treatment with rimonabant has also been shown [83].…”

Section: Alcoholism and Endocannabinoid Systemmentioning

confidence: 99%

Role of the Endocannabinoid System in Alcohol-Related Behaviors

Hungund¹

2011

tonj

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Alcoholism is a psychiatric disorder characterized by impaired control over drinking, leading to tolerance, physical dependence, uncontrollable craving and relapse. The mechanism/s underlying this disorder is poorly understood at present. Ethanol (alcohol) effects are mediated through several signal transduction pathways involving many neurotransmitters and ion channels in various brain regions. There is a growing body of evidence now suggesting a critical role for the endocannabinoid (EC) system in alcohol-related behaviors. The EC system is comprised of endogenous cannabimimetic substances (endocannabinoids) and their receptors [cannabinoid (CB)] and the enzymes involved in the synthesis and degradation of the ECs. Recent studies have demonstrated that both the genetic and pharmacological manipulation of the EC system modulate the development of tolerance to and dependence on alcohol. The present article provides a review of the existing literature on the role of the EC system, and possible mechanisms and the therapeutic potential of the drugs targeted against this system in preventing alcohol addiction.

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Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats

Cited by 161 publications

References 18 publications

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

Endocannabinoid system involvement in brain reward processes related to drug abuse

Role of the Endocannabinoid System in Alcohol-Related Behaviors

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