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Systemic blockade of LPA1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior Sánchez-Marín, Laura Ladrón de Guevara-Miranda, David Mañas-Padilla, María del Carmen Alén, Francisco Moreno-Fernández, Román D. Díaz-Navarro, Caridad Pérez-del Palacio, José García-Fernández, María Inmaculada Pedraza-Benítez, María del Carmen Pavón, Francisco Javier Rodriguez-de-Fonseca, Fernando Santín-Núñez, Luis Javier Serrano, Antonia Castilla-Ortega, María Estela Neurorreceptores Alcohol - Efectos fisiológicos https://openpolicyfinder.jisc.ac.uk/id/publication/4662 The systemic administration of lysophosphatidic acid (LPA) LPA1/3 receptor antagonists is a promising clinical tool for cancer, sclerosis and fibrosis-related diseases. Since LPA1 receptor-null mice engage in increased ethanol consumption, we evaluated the effects of systemic administration of an LPA1/3 receptor antagonist (intraperitoneal ki16425, 20 mg/kg) on ethanol-related behaviors as well as on brain and plasma correlates. Acute administration of ki16425 reduced motivation for ethanol but not for saccharine in ethanol self-administering Wistar rats. Mouse experiments were conducted in two different strains. In Swiss mice, ki16425 treatment reduced both ethanol-induced sedation (loss of righting reflex, LORR) and ethanol reward (escalation in ethanol consumption and ethanol-induced conditioned place preference, CPP). Furthermore, in the CPP-trained Swiss mice, ki16425 prevented the effects of ethanol on basal c-Fos expression in the medial prefrontal cortex and on adult neurogenesis in the hippocampus. In the c57BL6/J mouse strain, however, no effects of ki16425 on LORR or voluntary drinking were observed. The c57BL6/J mouse strain was then evaluated for ethanol withdrawal symptoms, which were attenuated when ethanol was preceded by ki16425 administration. In these animals, ki16425 modulated the expression of glutamate-related genes in brain limbic regions after ethanol exposure; and peripheral LPA signaling was dysregulated by either ki16425 or ethanol. Overall, these results suggest that LPA1/3 receptor antagonists might be a potential new class of drugs that are suitable for treating or preventing alcohol use disorders. A pharmacokinetic study revealed that systemic ki16425 showed poor brain penetration, suggesting the involvement of peripheral events to explain its effects. 2025-01-26T18:55:41Z 2025-01-26T18:55:41Z 2018-05-01 journal article Sánchez-Marín, L., Ladrón de Guevara-Miranda, D., Mañas-Padilla, M. C., Alén, F., Moreno-Fernández, R. D., Díaz-Navarro, C., Pérez-Del Palacio, J., García-Fernández, M., Pedraza, C., Pavón, F. J., Rodríguez de Fonseca, F., Santín, L. J., Serrano, A., & Castilla-Ortega, E. (2018). Systemic blockade of LPA1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior. Neuropharmacology, 133, 189–201. https://doi.org/10.1016/j.neuropharm.2018.01.033 https://hdl.handle.net/10630/36990 10.1016/j.neuropharm.2018.01.033 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier