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

Abstract

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.

Persistent Increase of Alcohol-Seeking Evoked by Neuropeptide S: an Effect Mediated by the Hypothalamic Hypocretin System

“…Because of the effects of NPS on inactive lever responding, which is a potential measure of general (non-directed) activity and response generalization, data were reanalyzed using change-scores (active lever minus inactive lever presses). This changescore analysis replicated that of active lever responding (F (3,6) ¼ 2.35; po0.001) for the treatment, suggesting that inactive lever responding cannot account for the results obtained for active lever responding (Cippitelli et al, 2008;Le et al, 2005). The three subjects with incorrect cannula placement showed increased active lever pressing in the reinstatement test (NPS vehicle;19.66 ± 3.28).…”

CB1Receptors Mediate the Analgesic Effects of Cannabinoids on Colorectal Distension-Induced Visceral Pain in Rodents

“…containing the activation of pain pathways and thus maintaining the overall response to pain within a physiologically manageable range. Supporting this view, tonic release of endocannabinoids has been described in several systems, including the gastrointestinal tract (Izzo et al, 1999;Pinto et al, 2002;Hentges et al, 2005;Narushima et al, 2007), and has also been postulated from results obtained after the pharmacological blockade (Cippitelli et al, 2008;Moreira et al, 2008) or the genetic deletion of the endocannabinoids catabolic system (Cravatt et al, 2001;Moreira et al, 2008). In vitro studies showed that SR141716 behaves as an inverse agonist on the CB 1 R (Landsman et al, 1997;Shire et al, 1999) and that CB 1 Rs are constitutively active (Leterrier et al, 2006;Canals and Milligan, 2008).…”

Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates with the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition

“…These findings are particularly relevant because they allow generalizing to humans the results of the existing literature on the antianxiety effects of reduced FAAH activity in rodents. Both genetic and pharmacological inactivation of FAAH, in fact, exerts anxiolytic and antidepressant actions in rodents (Kathuria et al, 2003;Gobbi et al, 2005;Patel and Hillard, 2006;Bortolato et al, 2007;Hill et al, 2007;Naidu et al, 2007;Cippitelli et al, 2008;Moreira et al, 2008;Rubino et al, 2008;Scherma et al, 2008;Haller et al, 2009;Micale et al, 2009, and does not cause sedation, hypothermia, hyperphagia, or abuse potential Gobbi et al, 2005;Lichtman and Martin, 2005), which are important side effects of the direct CB1R agonist ⌬ 9 -tetrahydrocannabinol.…”

“…Enhancement of AEA signaling through FAAH inhibition has emerged recently as an interesting novel route in the treatment of mood disorders (Kathuria et al, 2003;Gobbi et al, 2005;Patel and Hillard, 2006;Bortolato et al, 2007;Hill et al, 2007;Naidu et al, 2007;Cippitelli et al, 2008;Moreira et al, 2008;Rubino et al, 2008;Scherma et al, 2008;Haller et al, 2009;Micale et al, 2009). The mechanism by which FAAH inhibition results in ameliorated emotional control is largely undetermined, although magnification of AEA signaling at cannabinoid CB1 receptors (CB1Rs) has been implicated based on the fact that blockade of these receptors prevents the anxiolytic properties of both pharmacological and genetic inactivation of FAAH (Moreira et al, 2008;Haller et al, 2009;Micale et al, 2009).…”