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

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, 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.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1

Restriction of dietary protein in rats increases progressive-ratio motivation for protein

“…Thus, at a group level, increased lever pressing during FR sessions was associated with increased lever pressing during progressive ratio sessions. Although FR1 and FR2 are low effort schedules of reinforcement and are typically considered a measure of consummatory behavior rather than motivation (Arnold & Roberts, 1997), our data are consistent with other studies reporting a consistency between fixed ratio and progressive ratio measures of reward's motivational properties (Fotio et al, 2021;Velázquez-Sánchez et al, 2014). As regards FR5, it has been proposed as a moderate-effort schedule measuring both intake and motivation (Vendruscolo et al, 2010), therefore the consistency found here between FR5 and PR3 is in support of this idea.…”

Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway

“…One potential limitation of the study is that we used a strain of rats that has a genetically determined preference for alcohol. Although widely used in alcohol research (Economidou et al, 2006;Stopponi et al, 2013Stopponi et al, , 2018Kirson et al, 2018;Logrip et al, 2018;Domi et al, 2019a;Borruto et al, 2020;Fotio et al, 2020aFotio et al, , 2020b, this strain is characterized by the inherent limitation of being a genetic model that likely mimics a specific form of AUD. However, in a recent study we also reported that activation of PPARγ reduces alcohol drinking in nonselected rats and mice suggesting a more general role of this receptor system in AUD (Domi et al, 2020).…”

“…Self-administration experiments were conducted according to our recent reports (Stopponi et al, 2018;Fotio et al, 2020aFotio et al, , 2020b using standard operant chambers (Med Associate, St Albans, VT) located in sound-attenuating, ventilated cubicles. Each chamber was equipped with a drinking reservoir (volume capacity: 0.30 ml) positioned 4 cm above the grid floor in the center of the front panel of the chamber.…”

Genetic Blockade of NAAA Cell-specifically Regulates Fatty Acid Ethanolamides (FAEs) Metabolism and Inflammatory Responses

“…NAAA is believed to primarily control PEA levels and has been proposed as an alternative target for activation of PEA/ PPARα signaling (Tsuboi et al, 2005;Tai et al, 2012;Bottemanne et al, 2018). To date, many potent NAAA inhibitors have been developed, some of them were observed to elevate PEA levels and exhibit potent anti-inflammatory and analgesic effects in a range of rodent models of human disease (Alhouayek et al, 2015;Bonezzi et al, 2016;Alhouayek et al, 2017;Bottemanne et al, 2018;Sagheddu et al, 2019;Fotio et al, 2020;Piomelli et al, 2020;Sgroi et al, 2021). However, the impact of NAAA on AEA and OEA degradation has been poorly investigated.…”