3 years ago

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

Inhibition of fatty acid amide hydrolase in the central amygdala alleviates co-morbid expression of innate anxiety and excessive alcohol intake
Roberto Ciccocioppo, Marisa Roberto, Nazzareno Cannella, Yannick Fotio, Luis Natividad, Anna Maria Borruto, Ana Domi, Serena Stopponi
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. Hyperactive fatty acid amide hydrolase (FAAH) in amygdalar regions is associated with increased stress sensitivity and a hyper-anxious phenotype in genetically selected alcohol-preferring msP rats. Central amygdala administration of the selective FAAH inhibitor URB597 reduces alcohol self-administration and stress-induced anxiety in msP, but not Wistar rats.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/adb.12573

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