Effects of the endogenous PPAR‐α agonist, oleoylethanolamide on MDMA‐induced cognitive deficits in mice

Abstract

MDMA (3,4-Methylenedioxymethamphetamine) is an amphetamine derivative widely used for recreational purposes. We have recently shown that repeated treatment with high doses of MDMA-induced impairments in the acquisition and recall of an active avoidance task in mice. In this study, we examined whether the endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, oleoylethanolamide (OEA) protects against these MDMA-induced deficits. Mice were pretreated twice a day with OEA (0, 5, and 25 mg/kg) 30 min before an injection of MDMA (30 mg/kg) or saline during four consecutive days. Twenty-four hours after the last treatment, animals were trained in an active avoidance task for two consecutive weeks. After a 5-day resting period, a recall session was performed. Mice treated with MDMA showed reduced learning and recall of the task when compared with saline-treated controls. OEA at 5 mg/kg ameliorated and at 25 mg/kg worsened this deficit. Dopamine transporter (DAT)-binding sites significantly decreased 4 days after the last MDMA administration and pretreatment with both doses of OEA prevented this effect. In immunohistochemical studies, coexpression of tyrosine-hydroxylase and PPAR-alpha receptors was observed in the striatum and substantia nigra pars compacta of mice. These results suggest that OEA administration can modulate the cognitive deficits induced by MDMA in a DAT-independent manner.

In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence

“…Importantly, PPARαs, which are located in brain regions associated with reward (Moreno et al, 2004; Plaza-Zabala et al, 2010; Smaga et al, 2014), have been shown to modulate the rewarding properties of abused substances such as alcohol and nicotine (Bilbao et al, 2015; Melis et al, 2008). Acute administration of PPARα agonists attenuates nicotine (Mascia et al, 2011; Muldoon et al, 2013; Panlilio et al, 2012) and alcohol reinforcement (Bilbao et al, 2015), alcohol intake (Blednov et al, 2016a, 2016b) and nicotine-induced dopamine firing in rodents (Melis et al, 2008).…”

The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats

“…Indeed, PPARα’s are found within limbic structures and expressed on tyrosine-hydroxylase positive neurons (tyrosine-hydroxylase positive) (Moreno et al, 2004; Plaza-Zabala et al, 2010). Administration of the endogenous PPARα ligand, OEA, decreases food consumption and reinforcement that is mediated by central DA neurotransmission (Fu et al, 2003; Plaza-Zabala et al, 2010; Rodriguez de Fonseca et al, 2001; Tellez et al, 2013).…”

“…Indeed, PPARα’s are found within limbic structures and expressed on tyrosine-hydroxylase positive neurons (tyrosine-hydroxylase positive) (Moreno et al, 2004; Plaza-Zabala et al, 2010). Administration of the endogenous PPARα ligand, OEA, decreases food consumption and reinforcement that is mediated by central DA neurotransmission (Fu et al, 2003; Plaza-Zabala et al, 2010; Rodriguez de Fonseca et al, 2001; Tellez et al, 2013). Further, increasing endogenous levels of ligands for PPARα or administration of agonists decrease activation of the mesolimbic DA system and attenuate the behavioral effects of nicotine and morphine (Fernandez-Espejo et al, 2009; Luchicchi et al, 2010; Mascia et al, 2011; Melis et al, 2010; Melis et al, 2008; Melis et al, 2013b; Panlilio et al, 2012).…”

Identification of Lipid Mediators in Peripheral Human Tissues Using an Integrative In Vivo Microdialysis Approach

“…MD sampling of ECs and NAEs have mainly been performed in the brain tissue of rodents [19][20][21][22], although AEA, OEA and PEA have been measured in MD samples from human brain immediately after an ischemic stroke [23]. There are a limited number of MD studies investigating the peripheral levels of ECs in humans.…”