N-Oleoyl-glycine reduces nicotine reward and withdrawal in mice

Abstract

Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction.

Obesity Affects the Microbiota–Gut–Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators

“…One such effector gene family (Cbeg12) encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide), which was also found in culture from Bacteroides vulgatus that harbors a gene highly similar to Cbeg12 [99]. Commendamide resembles long-chain N-acyl-amino acids that function as mammalian signaling molecules through activation of GPCRs or PPARs, such as N-oleoyl-glycine [100], and was found to activate GPCR G2A/GPR132, which has been implicated in autoimmunity and atherosclerosis [99]. More recently, the same authors, by again using bioinformatic approaches, found that some commensal bacteria can produce other N-acyl-amides as well as complex long-chain fatty acids capable of activating the same GPCRs as their host counterparts and, in some cases, GPR119, that belongs to the eCBome [101,102].…”

N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

“…Although the functional activities of NOleGly are still largely unknown, its predominant role in the regulation of behavioral actions, such as body temperature and motor activity, in the control of physiological processes, such as energy homeostasis and food, has been recently reported [52,54,55]. NOleGly ameliorated withdrawal-associated behaviors and prevented nicotine addiction in vivo [56]. The anti-reward effect, assessed in the conditioned place preference (CPP) paradigm, required PPAR-α activation as was reverted by PPAR-α antagonist administration [56].…”

“…NOleGly ameliorated withdrawal-associated behaviors and prevented nicotine addiction in vivo [56]. The anti-reward effect, assessed in the conditioned place preference (CPP) paradigm, required PPAR-α activation as was reverted by PPAR-α antagonist administration [56]. Moreover, the capability of NOleGly to interfere with the aversive properties associated with acute naloxone-precipitated morphine withdrawal (MWD) and the rewarding effects of morphine in Sprague-Dawley rats has been investigated [57].…”

“…Body and motor activities [54] Cancer cell proliferation [58] Energy homeostasis [52] Food intake [55] Nicotine addiction [56] Bone metabolism [65,66]…”

Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction

“…Among NAEs, the cannabinoid agonist AEA binds to CB1 and CB2 receptors and transient receptor potential vanilloid type 1 (TRPV1) at physiologically relevant concentrations, the others display an affinity for peroxisome proliferator-activated receptor-α (PPARα; Lo Verme et al, 2005 ; Hansen, 2010 ; Petrosino et al, 2010 ; Pistis and Muntoni, 2017 ), G protein-coupled receptors such as GPR55 (Baker et al, 2006 ) and GPR119, and TRPV1 (Piomelli, 2013 ). N- acyl amino acids are less characterized; however, evidence suggests a role for GPR18, GPR55, and GPR92, and PPARα in mediating some of the actions of N- oleoylglycine (Burstein, 2018 ; Donvito et al, 2019 ), which is one of the most studied among these molecules.…”