Biology subjects

Rodriguez de Fonseca, F.

Publications and source records attributed to Rodriguez de Fonseca, F..

3 recordsLinked to original sources

bioRxiv2023

Oleoylethanolamide effects on stress-induced alcohol consumption: a lipid at crossroads between stress, reward and neuroinflammation

The endocannabinoid system is involved in multiple drug-related behavior as well as in the stress response. The transient increase in endogenous cannabinoids as well as endocannabinoid-like molecules contributes to healthy adaptation to stress exposure. In this study, we tested the effect of systemic OEA treatment (10mg/kg) before or after social defeat (SD) on alcohol self-administration (SA). Mice were divided into non-stressed (EXP) and stressed mice (SD) and randomly assigned to a treatment condition (CTRL, OEA or 10OEA). Mice in the EXP/SD-OEA group received four doses before each SD encounter while mice in the EXP/SD-10OEA mice received 10 daily doses after stress exposure. Three weeks after SD, mice were trained to alcohol 20% (vol/vol) SA. Upon extinction, a cue-induced reinstatement test was performed. Our results showed that only multiple-dose chronic OEA treatment (SD-10OEA group) was effective in preventing the stress-induced increase in alcohol consumption observed in defeated mice. We did not observe any effects of OEA on relapse-like behavior. Altogether, these data suggest that exogenously increasing OEA levels counteracts the adverse effects of stress on alcohol drinking.

animal behavior and cognition↗

bioRxiv2023

Region-specific gene expression changes associated to oleoylethanolamide-induced attenuation of alcohol self-administration

Oleoylethanolamide (OEA) is a lipid with anti-inflammatory activity that modulates multiple reward-related behaviors. Previous studies have shown that OEA treatment reduces alcohol self-administration (SA) while inhibiting alcohol-induced inflammatory signaling. Nevertheless, the specific mechanisms that OEA is targeting to achieve these effects have not been widely explored. Here, we tested the effects of OEA treatment during alcohol SA, extinction or previous to cue-induced reinstatement of alcohol seeking. In addition, we measured gene expression changes in the striatum and hippocampus of relevant receptors for alcohol consumption (DrD1, DrD2, CNR1, OPRM1) as well as immune-related proteins (IL-6, IL-1{beta}, TLR4) and the brain-derived neurotrophic factor (BDNF). Our results confirmed that when administered contingently, systemic OEA administration reduced alcohol SA and attenuated cue-induced reinstatement. Interestingly, we also observed that OEA treatment reduced the number of sessions needed for extinction of alcohol seeking. Biochemical analyses showed region-specific OEA dopaminergic and cannabinoid receptor gene expression alterations. Also, OEA treatment modulated the long-term immune response and increased BDNF expression. These results suggest that boosting OEA levels may be an effective strategy for reducing alcohol SA and preventing relapse.

neuroscience↗

bioRxiv2019

Activation of macrophages by lysophosphatidic acid through the lysophosphatidic acid receptor 1 as a novel mechanism in multiple sclerosis pathogenesis.

Multiple sclerosis (MS) is a neuro-inflammatory disease for which the pathogenesis remains largely unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid that is involved in multiple immune cell functions and is dysregulated in MS. Its receptor LPA1 is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the viable Malaga variant of LPA1-null mutation as well as pharmaceutical inhibition of LPA1 in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. LPA1 expression was also analyzed in both wild-type EAE mice and MS patient immune cells. The effect of LPA and LPA1 on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA1 activity induces a milder clinical course in EAE, and that Lpar1 expression in peripheral blood mononuclear cells (PBMCs) correlates with onset of relapses and severity in wild-type EAE mice. We see the same over-expression in PBMCs from MS patients during relapse compared to progressive forms of the disease, and in monocyte-derived macrophages after exposure to pro-inflammatory stimuli. In addition, LPA induced a pro-inflammatory-like response in macrophages through LPA1, providing a plausible way in which LPA and LPA1 dysregulation can lead to the inflammation seen in MS. These data show a new mechanism of LPA signaling in the pathogenesis of MS, prompting further research into its use as a therapeutic target biomarker.

neuroscience↗