Abstract
A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related 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. 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. 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-, yohimbine- and 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. 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. 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.
Highlights
The endocannabinoid system is considered one of the major pharmacological targets for the development of new therapeutics
Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of fatty acid amide hydrolase (FAAH) does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal
We can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct cannabinoid receptor 1 (CB1) receptor activators
Summary
The endocannabinoid system is considered one of the major pharmacological targets for the development of new therapeutics. 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, 2004) and alcohol drinking motivation (Gallate et al 1999), while Δ9THC significantly reinstates responding previously reinforced with beer (McGregor et al 2005). Blockade of FAAH increases endocannabinoid transmission with a mechanism that does not require direct activation of cannabinoid receptors via synthetic cannabinoid agonists
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