N-acylethanolamine acid amidase (NAAA) inhibition decreases the motivation for alcohol in Marchigian Sardinian alcohol-p
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ORIGINAL INVESTIGATION
N-acylethanolamine acid amidase (NAAA) inhibition decreases the motivation for alcohol in Marchigian Sardinian alcohol-preferring rats Yannick Fotio 1,2
&
Roberto Ciccocioppo 2 & Daniele Piomelli 1,3
Received: 24 July 2020 / Accepted: 5 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale N-acylethanolamine acid amidase (NAAA) is an intracellular cysteine hydrolase that terminates the biological actions of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), two endogenous lipid-derived agonists of the nuclear receptor, and peroxisome proliferator–activated receptor-α. OEA and PEA are important regulators of energy balance, pain, and inflammation, but recent evidence suggests that they might also contribute to the control of reward-related behaviors. Objectives and methods In the present study, we investigated the effects of systemic and intracerebral NAAA inhibition in the two-bottle choice model of voluntary alcohol drinking and on operant alcohol self-administration. Results Intraperitoneal injections of the systemically active NAAA inhibitor ARN19702 (3 and 10 mg/kg) lowered voluntary alcohol intake in a dose-dependent manner, achieving ≈ 47% reduction at the 10 mg/kg dose (p < 0.001). Water, food, or saccharin consumption was not affected by the inhibitor. Similarly, ARN19702 dose-dependently attenuated alcohol selfadministration under both fixed ratio 1 (FR-1) and progressive ratio schedules of reinforcement. Furthermore, microinjection of ARN19702 (1, 3 and 10 μg/μl) or of two chemically different NAAA inhibitors, ARN077 and ARN726 (both at 3 and 10 μg/ μl), into the midbrain ventral tegmental area produced dose-dependent decreases in alcohol self-administration under FR-1 schedule. Microinjection of ARN19702 into the nucleus accumbens had no such effect. Conclusion Collectively, the results point to NAAA as a possible molecular target for the treatment of alcohol use disorder. Keywords N-acylethanolamine acid amidase (NAAA) . Fatty acid ethanolamides . PEA . OEA . Alcohol use disorder . Ventral tegmental area . ARN19702 . ARN077 . ARN726 . Alcohol-preferring msP rats
List of non-conventional abbreviations AUD Alcohol use disorder FAAH Fatty acid amide hydrolase VTA Ventral tegmental area OEA Oleoylethanolamide PEA Palmitoylethanolamide
* Daniele Piomelli [email protected] 1
Department of Anatomy and Neurobiology, University of California, 837 Health Sciences Rd. Room 3101, 3216, Irvine, CA 92697-4625, USA
2
School of Pharmacy, Pharmacology Unit, University of Camerino, 62032 Camerino, Italy
3
Department of Biological Chemistry, University of California, Irvine, CA 92697-4625, USA
NAAA PPARα
N-acylethanolamine acid amidase Peroxisome proliferator–activated receptor-alpha
Introduction The amides of long-chain fatty acids with ethanolamine (fatty acid ethanolamides, FAEs) are a family of lipid-derived signaling molecules that participate in the control of various physiological and pathological processes, including energy balan
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