Palmitoylethanolamide attenuates cocaine-induced behavioral sensitization and conditioned place preference in mice

Abstract

Cocaine addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and drug-taking behaviors. Previous studies have demonstrated that cocaine, as well as other drugs of abuse, alters the levels of lipid-based signaling molecules, such as N-acylethanolamines (NAEs). Moreover, brain levels of NAEs have shown sensitivity to cocaine self-administration and extinction training in rodents. Given this background, the aim of this study was to investigate the effects of repeated or acute administration of palmitoylethanolamide (PEA), an endogenous NAE, on psychomotor sensitization and cocaine-induced contextual conditioning. To this end, the potential ability of repeated PEA administration (1 or 10 mg/kg, i.p.) to modulate the acquisition of cocaine-induced behavioral sensitization (BS) and conditioned place preference (CPP) was assessed in male C57BL/6J mice. In addition, the expression of cocaine-induced BS and CPP following acute PEA administration were also studied. Results showed that repeated administration of both doses of PEA were able to block the acquisition of cocaine-induced BS. Furthermore, acute administration of both doses of PEA was able to abolish the expression of BS, while the highest dose also abolished the expression of cocaine-induced CPP. Taken together, these results indicate that exogenous administration of PEA attenuated psychomotor sensitization, while the effect of PEA in cocaine-induced CPP depended on whether PEA was administered repeatedly or acutely. These findings could be relevant to understand the role that NAEs play in processes underlying the development and maintenance of cocaine addiction.

Cocaine-Induced Reinstatement of Cocaine Seeking Provokes Changes in the Endocannabinoid and N-Acylethanolamine Levels in Rat Brain Structures

“…Decreased levels of OEA and PEA in nucleus accumbens after the cocaine challenge only in rats self-administering cocaine suggest an impaired control of the release of neurotransmitters during reinstatement, and correlate with the previously reported the participation of the TRPV1 receptor [13,20,28]. Recently, Zambrana-Infantes et al (2018) demonstrated that repeated administration of PEA can block behavioral cocaine sensitization in the mechanism, probably independent of the PPAR-α receptor, but rather as a result of the anti-inflammatory properties of PEA [29]. The decrease in PEA and OEA in the nucleus accumbens observed in our study may confirm the increased cocaine sensitization as a result of the habit forming, since the same changes have not been observed in cocaine-experienced animals following repeated passive (yoked) treatment.…”

“…They act through the nuclear proliferator-activated receptor alpha (PPARα), the transient receptor potential vanilloid 1 (TRPV1), and the orphan G-protein-coupled receptors GPR55 and GPR119. NAEs participate in the regulation of many physiological processes and they have neuroprotective, antinociceptive, and anti-inflammatory effects [29]. In this paper, we found that a cocaine-induced relapse resulted in a potent increase in OEA levels in the prefrontal cortex and striatum and in PEA in the prefrontal cortex, hippocampus and dorsal striatum.…”

The Potential Benefits of Palmitoylethanolamide in Palliation: A Qualitative Systematic Review

“…83 Palmitoylethanolamide blocks cocaine behaviors in animals as measured by conditioned place preference. 84 GPR55 is highly expressed in the gastrointestinal tract and modulates inflammatory responses. 85 Palmitoylethanolamide has the potential to influence intestinal motility, secretion, inflammation, and cellular proliferation, not only through GPR55 but also by way of PPAR-a and the entourage effect on CB1 and CB2.…”

The presence of a social stimulus reduces cocaine-seeking in a place preference conditioning paradigm

“…More methodological details and results from these groups are shown in the Supplementary Material Information. All the experiments were conducted during the light phase of the light/dark cycle following previous standardised and published protocols from our group (Castilla-Ortega et al, 2016; Ladrón de Guevara-Miranda et al, 2018; Zambrana-Infantes et al, 2018).…”