Alcohol abuse is frequently characterized by a specific pattern of intake in binge drinking episodes, inducing neuroinflammation and brain damage. Here, we characterized the temporal profile of neuroinflammation in rats exposed to intragastric binge ethanol administrations (3 times/day × 4 days) and tested the anti-inflammatory/neuroprotective properties of the satiety factor oleoylethanolamide (OEA). Pre-treatment with OEA (5 mg/kg, i.p.) previous each alcohol gavage blocked the expression of high mobility group box 1 (HMGB1) danger signal and the innate immunity Toll-like receptors 4 (TLR4) in frontal cortex, and inhibited the nuclear factor-kappa B (NF-kB) proinflammatory cascade induced by alcohol binge administration. OEA reduced the levels of interleukin-1beta (IL-1β), the monocyte chemoattractant protein-1 (MCP-1), and the enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in ethanol binged animals. Elevations in plasma tumor necrosis factor alpha (TNF-α) and IL-1β after ethanol were also inhibited by OEA. OEA also prevented ethanol-induced lipid peroxidation, caspase-8 and pro-apoptotic caspase-3 activation in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone levels after ethanol with no alteration in blood ethanol levels and may affect ethanol-induced gut permeability for endotoxin. Finally, OEA, administered as a pre-treatment during the ethanol binge, exerted antidepressant-like effects during acute withdrawal. Altogether, results highlight a beneficial profile of OEA as a potent anti-inflammatory, antioxidant, neuroprotective and antidepressant-like compound to treat alcohol abuse.

The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Tumor necrosis factor-alpha, chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 and chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) were decreased in cocaine users, although all cytokines were identified as predictors of a lifetime pathological use of cocaine. Interleukin-1 beta (IL-1β), chemokine (C-X3-C motif) ligand 1 (CX3CL1)/fractalkine and CXCL12/SDF-1 positively correlated with the cocaine symptom severity when using the DSM-IV-TR criteria for cocaine abuse/dependence. These cytokines allowed the categorization of the outpatients into subgroups according to severity, identifying a subgroup of severe cocaine users (9-11 criteria) with increased prevalence of co-morbid psychiatric disorders [mood (54%), anxiety (32%), psychotic (30%) and personality (60%) disorders]. IL-1β was observed to be increased in users with such psychiatric disorders relative to those users with no diagnosis. In addition to these clinical data, studies in mice demonstrated that plasma IL-1β, CX3CL1 and CXCL12 were also affected after acute and chronic cocaine administration, providing a preclinical model for further research. In conclusion, cocaine exposure modifies the circulating levels of pro-inflammatory mediators. Plasma cytokine/chemokine monitoring could improve the stratification of cocaine consumers seeking treatment and thus facilitate the application of appropriate interventions, including management of heightened risk of psychiatric co-morbidity. Further research is necessary to elucidate the role of the immune system in the etiology of cocaine addiction.

Oleoylethanolamide (OEA) is a satiety factor released by the gut that controls motivational responses for caloric foods. Here, using both, rat and mice models, we determined that the administration of alcohol releases OEA that, by engaging peroxisome proliferator-activated receptor alpha (PPARα), reduces alcohol consumption. Animals lacking FAAH, the enzyme that degrades OEA, accumulates this lipid in response to ethanol and displayed reduced alcohol preference. Pharmacological administration of OEA reduced operant alcohol self-administration via a peripheral mechanism, since this effect was abrogated by chemical deafferentation with capsaicin. Intracerebral injection of PPARα agonists did not affect alcohol self-administration. OEA also abolished both, cue-induced reinstatement of alcohol self-administration and the enhancement of alcohol consumption induced by a period of alcohol deprivation, suggesting a role for OEA on alcohol relapse. In addition, animals fed with a liquid diet containing 10% alcohol displayed elevated plasma levels of OEA that decreases upon removal of alcohol in the diet. This decrease paralleled the onset of alcohol withdrawal (AWD) symptoms and the administration of OEA reduced the severity of AWD. Finally, OEA, by inhibiting the expression of lipogenic enzymes, reduces chronic alcohol-induced liver steatosis, an effect not observed in PPARα-deficient mice. These results link OEA to the homeostatic adaption to alcohol and opens new opportunities for the treatment of alcoholism.