urb-597 and Alcoholism

Fatty acid amide hydrolase (FAAH) is an enzyme that prominently degrades the major endocannabinoid N-arachidonoylethanolamine (anandamide). Inhibition of this enzyme leads to increased anandamide levels in brain regions that modulate stress and anxiety. Recently, we found that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats display hyperactive FAAH in amygdalar regions that was associated with increased stress sensitivity and a hyper-anxious phenotype. Our previous work has also demonstrated that msPs display an innate preference for and excessive consumption of alcohol, potentially reflecting a form of self-medication to gain relief from hyper-anxious states. Here, we expand on our previous work by microinjecting the selective FAAH inhibitor URB597 (vehicle, 0.03, 0.1 and 1.0 μg per rat) into the central amygdala (CeA) and basolateral amygdala in msP versus non-selected Wistar rats to evaluate the effects of localized FAAH inhibition on operant alcohol self-administration and restraint-induced anxiety using the elevated plus maze. Intra-CeA URB597 significantly reduced alcohol self-administration in msP but not in Wistar rats. Intra-basolateral amygdala URB597 also attenuated alcohol drinking in msPs, although the effect was less pronounced relative to CeA treatment. In contrast, control experiments administering URB597 into the ventral tegmental area produced no genotypic differences in drinking. We also found that URB597 treatment in the CeA significantly reduced the anxiogenic effects of restraint stress in msPs, although no effects were detected in Wistars. Dysregulation of FAAH regulated systems in the major output region of the amygdala may drive the propensity for co-morbid expression of anxiety and excessive alcohol use.

Topics: Alcoholism; Amidohydrolases; Analysis of Variance; Animals; Anxiety Disorders; Benzamides; Carbamates; Central Amygdaloid Nucleus; Central Nervous System Depressants; Conditioning, Operant; Enzyme Inhibitors; Ethanol; Male; Maze Learning; Microinjections; Rats, Inbred Strains; Rats, Wistar; Restraint, Physical; Self Administration; Stress, Psychological

Anandamide (AEA)-dependent signaling is regulated by the catabolic enzyme fatty acid amide hydrolase (FAAH). Several lines of evidence have demonstrated that FAAH and AEA are involved in the behavioral effects of alcohol. Therefore, we investigated whether a selective FAAH inhibitor, URB597 (cyclohexylcarbamic acid 3'-[aminocarbonyl]-[1,1'-biphenyl]-3-yl ester), altered alcohol intake in mice in a voluntary alcohol drinking model.. Mice, subjected to 3 weeks of chronic intermittent access (IA) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We evaluated the pharmacological effects of URB597 after both acute (1-day) withdrawal from chronic IA and 1-week withdrawal using the alcohol deprivation effect (ADE) model. AEA and N-acyl ethanolamide (NAE) abundances were determined after chronic IA, acute (1-day), or long-term (1 and 2 weeks) withdrawal in four brain regions.. Acute pretreatment with URB597 reduced alcohol intake and preference after acute withdrawal. This effect was blocked by pretreatment with a selective type 1 cannabinoid receptor (CB1) antagonist, suggesting a CB1-mediated mechanism. Both single- and multiple-dosing regimens with an effective dose of URB597 prevented the ADE, with no tolerance development after the multi-dosing regimen. AEA and NAE levels were transiently increased in all brain regions measured after acute withdrawal, indicating that the endocannabinoid system is involved in acute alcohol withdrawal stress response.. FAAH inhibitors reduce alcohol escalation and "relapse" drinking in mice.

Topics: Alcohol Drinking; Alcoholism; Amidohydrolases; Animals; Benzamides; Carbamates; Endocannabinoids; Ethanol; Male; Mice; Mice, Inbred C57BL; Random Allocation; Receptor, Cannabinoid, CB1; Recurrence

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.

Topics: Adrenergic alpha-Antagonists; Alcohol Drinking; Alcoholism; Amidohydrolases; Animals; Anxiety; Arachidonic Acids; Benzamides; Brain Chemistry; Carbamates; Conditioning, Operant; Cues; Electroshock; Endocannabinoids; Enzyme Inhibitors; Extinction, Psychological; Male; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Recurrence; Reinforcement Schedule; Self Administration; Stress, Psychological; Yohimbine