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N-acylethanolamine acid amidase (NAAA) inhibition decreases the motivation for alcohol in Marchigian Sardinian alcohol-preferring rats

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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 self-administration 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.

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Abbreviations

AUD:

Alcohol use disorder

FAAH:

Fatty acid amide hydrolase

VTA:

Ventral tegmental area

OEA:

Oleoylethanolamide

PEA:

Palmitoylethanolamide

NAAA:

N-acylethanolamine acid amidase

PPARα:

Peroxisome proliferator–activated receptor-alpha

References

  • Ahern GP (2003) Activation of TRPV1 by the satiety factor oleoylethanolamide. J Biol Chem 278:30429–30434

    Article  CAS  PubMed  Google Scholar 

  • Anton M, Rodriguez-Gonzalez A, Rodriguez-Rojo IC, Pastor A, Correas A, Serrano A, Ballesta A, Alen F, Gomez de Heras R, de la Torre R, Rodriguez de Fonseca F, Orio L (2018) Increased plasma oleoylethanolamide and palmitoleoylethanolamide levels correlate with inflammatory changes in alcohol binge drinkers: the case of HMGB1 in women. Addict Biol 23:1242–1250

    Article  CAS  PubMed  Google Scholar 

  • Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447

    Article  CAS  PubMed  Google Scholar 

  • Artukoglu BB, Beyer C, Zuloff-Shani A, Brener E, Bloch MH (2017) Efficacy of Palmitoylethanolamide for pain: a meta-analysis. Pain Physician 20:353–362

    PubMed  Google Scholar 

  • Bandiera T, Ponzano S, Piomelli D (2014) Advances in the discovery of N-acylethanolamine acid amidase inhibitors. Pharmacol Res 86:11–17

    Article  CAS  PubMed  Google Scholar 

  • Best LM, Williams B, Le Foll B, Mansouri E, Bazinet RP, Lin L, De Luca V, Lagzdins D, Rusjan P, Tyndale RF, Wilson AA, Hendershot CS, Heilig M, Houle S, Tong J, Kish SJ, Boileau I (2020) Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with [C-11]CURB. Neuropsychopharmacology 45:1289–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bilbao A, Serrano A, Cippitelli A, Pavon FJ, Giuffrida A, Suarez J, Garcia-Marchena N, Baixeras E, Gomez de Heras R, Orio L, Alen F, Ciccocioppo R, Cravatt BF, Parsons LH, Piomelli D, Rodriguez de Fonseca F (2016) Role of the satiety factor oleoylethanolamide in alcoholism. Addict Biol 21:859–872

    Article  CAS  PubMed  Google Scholar 

  • Bonezzi FT, Sasso O, Pontis S, Realini N, Romeo E, Ponzano S, Nuzzi A, Fiasella A, Bertozzi F, Piomelli D (2016) An important role for N-acylethanolamine acid amidase in the complete Freund’s adjuvant rat model of arthritis. J Pharmacol Exp Ther 356:656–663

    Article  CAS  PubMed  Google Scholar 

  • Borruto AM, Fotio Y, Stopponi S, Brunori G, Petrella M, Caputi FF, Romualdi P, Candeletti S, Narendran R, Rorick-Kehn LM, Ubaldi M, Weiss F, Ciccocioppo R (2020) NOP receptor antagonism reduces alcohol drinking in male and female rats through mechanisms involving the central amygdala and ventral tegmental area. Br J Pharmacol 177:1525–1537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brodie MS, Shefner SA, Dunwiddie TV (1990) Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro. Brain Res 508:65–69

    Article  CAS  PubMed  Google Scholar 

  • Buczynski MW, Polis IY, Parsons LH (2013) The volitional nature of nicotine exposure alters anandamide and oleoylethanolamide levels in the ventral tegmental area. Neuropsychopharmacology 38:574–584

    Article  CAS  PubMed  Google Scholar 

  • Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281

    Article  CAS  PubMed  Google Scholar 

  • Cannella N, Ubaldi M, Masi A, Bramucci M, Roberto M, Bifone A, Ciccocioppo R (2019) Building better strategies to develop new medications in alcohol use disorder: learning from past success and failure to shape a brighter future. Neurosci Biobehav Rev 103:384–398

    Article  PubMed  PubMed Central  Google Scholar 

  • Ciccocioppo R, Economidou D, Cippitelli A, Cucculelli M, Ubaldi M, Soverchia L, Lourdusamy A, Massi M (2006) Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats: an animal model to study the neurobiology of alcoholism. Addict Biol 11:339–355

    Article  PubMed  PubMed Central  Google Scholar 

  • Cippitelli A, Cannella N, Braconi S, Duranti A, Tontini A, Bilbao A, Defonseca FR, Piomelli D, Ciccocioppo R (2008) Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. Psychopharmacology 198:449–460

    Article  CAS  PubMed  Google Scholar 

  • Coppola M, Mondola R (2013) Palmitoylethanolamide: from endogenous cannabimimetic substance to innovative medicine for the treatment of cannabis dependence. Med Hypotheses 81:619–622

    Article  CAS  PubMed  Google Scholar 

  • Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87

    Article  CAS  PubMed  Google Scholar 

  • Desarnaud F, Cadas H, Piomelli D (1995) Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J Biol Chem 270:6030–6035

    Article  CAS  PubMed  Google Scholar 

  • Devgun MS, Dunbar JA (1990) Alcohol consumption, blood alcohol level and the relevance of body weight in experimental design and analysis. J Stud Alcohol 51:24–28

    Article  CAS  PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1985) Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats. Eur J Pharmacol 115:131–132

    Article  PubMed  Google Scholar 

  • Domi A, Stopponi S, Domi E, Ciccocioppo R, Cannella N (2019) Sub-dimensions of alcohol use disorder in alcohol preferring and non-preferring rats, a comparative study. Front Behav Neurosci 13:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Economidou D, Fedeli A, Fardon RM, Weiss F, Massi M, Ciccocioppo R (2006a) Effect of novel nociceptin/orphanin FQ-NOP receptor ligands on ethanol drinking in alcohol-preferring msP rats. Peptides 27:3299–3306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Economidou D, Mattioli L, Cifani C, Perfumi M, Massi M, Cuomo V, Trabace L, Ciccocioppo R (2006b) Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats. Psychopharmacology 183:394–403

    Article  CAS  PubMed  Google Scholar 

  • Fotio Y, Aboufares El Alaoui A, Borruto AM, Acciarini S, Giordano A, Ciccocioppo R (2019) Efficacy of a combination of N-palmitoylethanolamide, beta-caryophyllene, carnosic acid, and myrrh extract on chronic neuropathic pain: a preclinical study. Front Pharmacol 10:711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fotio Y, Borruto AM, Benvenuti F, Demopulos G, Gaitanaris G, Roberto M, Ciccocioppo R (2020) Activation of peroxisome proliferator-activated receptor gamma reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats. Neuropsychopharmacology

  • Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodriguez De Fonseca F, Rosengarth A, Luecke H, Di Giacomo B, Tarzia G, Piomelli D (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425:90–93

    Article  CAS  PubMed  Google Scholar 

  • Gabrielsson L, Mattsson S, Fowler CJ (2016) Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol 82:932–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Marchena N, Pavon FJ, Pastor A, Araos P, Pedraz M, Romero-Sanchiz P, Calado M, Suarez J, Castilla-Ortega E, Orio L, Boronat A, Torrens M, Rubio G, de la Torre R, Rodriguez de Fonseca F, Serrano A (2017) Plasma concentrations of oleoylethanolamide and other acylethanolamides are altered in alcohol-dependent patients: effect of length of abstinence. Addict Biol 22:1366–1377

    Article  CAS  PubMed  Google Scholar 

  • Gardner EL (2011) Addiction and brain reward and antireward pathways. Adv Psychosom Med 30:22–60

    Article  PubMed  PubMed Central  Google Scholar 

  • Gilpin NW, Koob GF (2008) Neurobiology of alcohol dependence: focus on motivational mechanisms. Alcohol Res Health 31:185–195

    PubMed  PubMed Central  Google Scholar 

  • Godlewski G, Offertaler L, Wagner JA, Kunos G (2009) Receptors for acylethanolamides-GPR55 and GPR119. Prostaglandins Other Lipid Mediat 89:105–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grosshans M, Schwarz E, Bumb JM, Schaefer C, Rohleder C, Vollmert C, Vollstadt-Klein S, Tost H, Meyer-Lindenberg A, Kiefer F, Leweke FM (2014) Oleoylethanolamide and human neural responses to food stimuli in obesity. JAMA Psychiatry 71:1254–1261

    Article  PubMed  Google Scholar 

  • Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F, Freund TF (2004) Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20:441–458

    Article  CAS  PubMed  Google Scholar 

  • Hasin DS, Auriacombe M, Borges G, Bucholz K, Budney A, Crowley T, Grant BF, O'Brien C, Petry NM, Schuckit M, Wall MM (2013) The DSM-5 field trials and reliability of alcohol use disorder. Am J Psychiatry 170:442–443

    Article  PubMed  PubMed Central  Google Scholar 

  • Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944

    Article  CAS  PubMed  Google Scholar 

  • Ikemoto S (2007) Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 56:27–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikemoto S (2010) Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 35:129–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • June HL, Gilpin NW (2010) Operant self-administration models for testing the neuropharmacological basis of ethanol consumption in rats. Curr Protoc Neurosci Chapter 9: Unit 9 12 1-26

  • Kirson D, Oleata CS, Parsons LH, Ciccocioppo R, Roberto M (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676–688

    Article  CAS  PubMed  Google Scholar 

  • Leeman RF, Heilig M, Cunningham CL, Stephens DN, Duka T, O'Malley SS (2010) Ethanol consumption: how should we measure it? Achieving consilience between human and animal phenotypes. Addict Biol 15:109–124

    Article  PubMed  PubMed Central  Google Scholar 

  • Logrip ML, Walker JR, Ayanwuyi LO, Sabino V, Ciccocioppo R, Koob GF, Zorrilla EP (2018) Evaluation of alcohol preference and drinking in msP rats bearing a Crhr1 promoter polymorphism. Front Psychiatry 9:28

    Article  PubMed  PubMed Central  Google Scholar 

  • LoVerme J, La Rana G, Russo R, Calignano A, Piomelli D (2005) The search for the palmitoylethanolamide receptor. Life Sci 77:1685–1698

    Article  CAS  PubMed  Google Scholar 

  • LoVerme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G, Meli R, Hohmann A, Calignano A, Piomelli D (2006) Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J Pharmacol Exp Ther 319:1051–1061

    Article  CAS  PubMed  Google Scholar 

  • McKinney MK, Cravatt BF (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74:411–432

    Article  CAS  PubMed  Google Scholar 

  • Melis M, Pillolla G, Luchicchi A, Muntoni AL, Yasar S, Goldberg SR, Pistis M (2008) Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors. J Neurosci 28:13985–13994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michel MC, Murphy TJ, Motulsky HJ (2020) New author guidelines for displaying data and reporting data analysis and statistical methods in experimental biology. J Pharmacol Exp Ther 372:136–147

    Article  PubMed  Google Scholar 

  • Migliore MD, Pontis SD, Fuentes de Arriba AL, Realini N, Torrente E, Armirotti A, Romeo E, Di Martino S, Russo D, Pizzirani D, Summa M, Lanfranco M, Ottonello G, Busquet P, Jung KM, Garcia-Guzman M, Heim R, Scarpelli R, Piomelli D (2016) Second-generation non-covalent NAAA inhibitors are protective in a model of multiple sclerosis. Angew Chem Int Ed Eng 55:11193–11197

    Article  CAS  Google Scholar 

  • Nadal R, Armario A, Janak PH (2002) Positive relationship between activity in a novel environment and operant ethanol self-administration in rats. Psychopharmacology 162:333–338

    Article  CAS  PubMed  Google Scholar 

  • Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305

    Article  CAS  PubMed  Google Scholar 

  • Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884

    Article  CAS  PubMed  Google Scholar 

  • Piomelli D, Sasso O (2014) Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci 17:164–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piomelli D, Scalvini L, Fotio Y, Lodola A, Spadoni G, Tarzia G, Mor M (2020) N-acylethanolamine acid amidase (NAAA): structure, function, and inhibition. J Med Chem 63:7475–7490

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro A, Pontis S, Mengatto L, Armirotti A, Chiurchiu V, Capurro V, Fiasella A, Nuzzi A, Romeo E, Moreno-Sanz G, Maccarrone M, Reggiani A, Tarzia G, Mor M, Bertozzi F, Bandiera T, Piomelli D (2015) A potent systemically active N-acylethanolamine acid amidase inhibitor that suppresses inflammation and human macrophage activation. ACS Chem Biol 10:1838–1846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez de Fonseca F, Navarro M, Gomez R, Escuredo L, Nava F, Fu J, Murillo-Rodriguez E, Giuffrida A, LoVerme J, Gaetani S, Kathuria S, Gall C, Piomelli D (2001) An anorexic lipid mediator regulated by feeding. Nature 414:209–212

    Article  CAS  PubMed  Google Scholar 

  • Sagheddu C, Scherma M, Congiu M, Fadda P, Carta G, Banni S, Wood JT, Makriyannis A, Malamas MS, Pistis M (2019) Inhibition of N-acylethanolamine acid amidase reduces nicotine-induced dopamine activation and reward. Neuropharmacology 144:327–336

    Article  CAS  PubMed  Google Scholar 

  • Sasso O, Moreno-Sanz G, Martucci C, Realini N, Dionisi M, Mengatto L, Duranti A, Tarozzo G, Tarzia G, Mor M, Bertorelli R, Reggiani A, Piomelli D (2013) Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models. Pain 154:350–360

    Article  CAS  PubMed  Google Scholar 

  • Stopponi S, de Guglielmo G, Somaini L, Cippitelli A, Cannella N, Kallupi M, Ubaldi M, Heilig M, Demopulos G, Gaitanaris G, Ciccocioppo R (2013) Activation of PPARgamma by pioglitazone potentiates the effects of naltrexone on alcohol drinking and relapse in msP rats. Alcohol Clin Exp Res 37:1351–1360

    Article  CAS  PubMed  Google Scholar 

  • Stopponi S, Fotio Y, Domi A, Borruto AM, Natividad L, Roberto M, Ciccocioppo R, Cannella N (2018) Inhibition of fatty acid amide hydrolase in the central amygdala alleviates co-morbid expression of innate anxiety and excessive alcohol intake. Addict Biol 23:1223–1232

    Article  CAS  PubMed  Google Scholar 

  • Suardiaz M, Estivill-Torrus G, Goicoechea C, Bilbao A, Rodriguez de Fonseca F (2007) Analgesic properties of oleoylethanolamide (OEA) in visceral and inflammatory pain. Pain 133:99–110

    Article  CAS  PubMed  Google Scholar 

  • Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N (2005) Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem 280:11082–11092

    Article  CAS  PubMed  Google Scholar 

  • Tsuboi K, Zhao LY, Okamoto Y, Araki N, Ueno M, Sakamoto H, Ueda N (2007) Predominant expression of lysosomal N-acylethanolamine-hydrolyzing acid amidase in macrophages revealed by immunochemical studies. Biochim Biophys Acta 1771:623–632

    Article  CAS  PubMed  Google Scholar 

  • Weiss F, Porrino LJ (2002) Behavioral neurobiology of alcohol addiction: recent advances and challenges. J Neurosci 22:3332–3337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wise RA (2002) Brain reward circuitry: insights from unsensed incentives. Neuron 36:229–240

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Schwartz BI, Giza J, Gross SS, Lee FS, Kreek MJ (2017) Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice. Psychopharmacology 234:2955–2970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was partially supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) grant AA017447 to R. Ciccocioppo (with M. Roberto).

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of California, 837 Health Sciences Rd. Room 3101, 3216, Irvine, CA, 92697-4625, USA

    Yannick Fotio & Daniele Piomelli

  2. School of Pharmacy, Pharmacology Unit, University of Camerino, 62032, Camerino, Italy

    Yannick Fotio & Roberto Ciccocioppo

  3. Department of Biological Chemistry, University of California, Irvine, CA, 92697-4625, USA

    Daniele Piomelli

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  1. Yannick Fotio
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  2. Roberto Ciccocioppo
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  3. Daniele Piomelli
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Contributions

YF, RC, and DP were responsible for the study design. YF performed the experiments and data analysis. YF, RC, and DP wrote the manuscript and approved the final version for publication.

Corresponding author

Correspondence to Daniele Piomelli.

Ethics declarations

Formal approval was obtained from the Italian Ministry of Health and the Internal Ethical Committee for the Laboratory Animal Protection and Use of the University of Camerino. All efforts were made to minimize animals suffering and distress.

Conflict of interest

DP is an inventor in patent applications owned by the University of California, Irvine, which describe NAAA inhibitors. YF and RC have no conflict of interest.

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Fotio, Y., Ciccocioppo, R. & Piomelli, D. N-acylethanolamine acid amidase (NAAA) inhibition decreases the motivation for alcohol in Marchigian Sardinian alcohol-preferring rats. Psychopharmacology 238, 249–258 (2021). https://doi.org/10.1007/s00213-020-05678-7

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