Inhibition of fatty acid amide hydrolase in the central amygdala alleviates co‐morbid expression of innate anxiety and excessive alcohol intake

Abstract

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.

Brain activity of anandamide: a rewarding bliss?

“…This would be in agreement with other reports showing, for example, that AEA elicits place aversion in rats [169]. However, blockade of FAAH by URB597 has been shown to elicit anti-anxiety effects in rats [170][171][172][173][174][175]. Furthermore, to complicate this picture, AEA has been shown to be intravenously self-administered in squirrel monkeys, suggesting that under some circumstances it works as a behavioral reinforcer.…”

“…Similarly, Hansson and colleagues showed that intra-PFC administration of URB597 increased operant alcohol self-administration in non-selected Wistar rats [216]. More recently, Stopponi et al [175] investigated the blockade of FAAH by URB597 in the central (CeA) and basolateral (BLA) amygdala in Marchigian Sardinian alcoholpreferring (msP) and control rats. They reported, partially in contrast to Hansson and co-workers, that intra-CeA URB597 as well as intra-BLA URB597 (in a less pronounced manner) leads to a reduction of the anxiogenic effects of restraint stress and alcohol self-administration in msP but not in control rats [175].…”

“…More recently, Stopponi et al [175] investigated the blockade of FAAH by URB597 in the central (CeA) and basolateral (BLA) amygdala in Marchigian Sardinian alcoholpreferring (msP) and control rats. They reported, partially in contrast to Hansson and co-workers, that intra-CeA URB597 as well as intra-BLA URB597 (in a less pronounced manner) leads to a reduction of the anxiogenic effects of restraint stress and alcohol self-administration in msP but not in control rats [175]. Recently, URB597 effects were tested in a voluntary alcohol drinking model in mice.…”

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…Consistent with studies on cocaine, nicotine and opioid seeking behaviour [Panlilio et al, 2013;Sloan et al, 2017], our findings show initial, promising data that FAAH inhibitors decrease alcohol excessive drinking, and "relapse" drinking in both male and female mice. Consistently, a new report demonstrates that the CeA of alcohol-preferring rats is involved in the URB597 effect on [Gobbi et al, 2005], have the potential to become useful compounds for treating alcoholism [Zhou et al, 2017c;Stopponi et al, 2018].…”

Modulation of mean arterial pressure and diuresis by renomedullary infusion of a selective inhibitor of fatty acid amide hydrolase

“…Kidneys modulate pressure and diuresis through multiple systems, including the renin angiotensin system (35), the sympathetic nervous system (6), and the endocannabinoid (EC) system (1). The roles of the EC system have been well studied in gastrointestinal tract disorders (36), peripheral neuropathic pain management (25), immunoregulatory role in infectious diseases (15), and the brain (31). However, little is known about specific mechanisms of EC regulation of renal functions and its role in hypertension.…”