RT Journal Article
T1 Systemic blockade of LPA1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior
A1 Sánchez-Marín, Laura
A1 Ladrón de Guevara-Miranda, David
A1 Mañas-Padilla, María del Carmen
A1 Alén, Francisco
A1 Moreno-Fernández, Román D.
A1 Díaz-Navarro, Caridad
A1 Pérez-del Palacio, José
A1 García-Fernández, María Inmaculada
A1 Pedraza-Benítez, María del Carmen
A1 Pavón, Francisco Javier
A1 Rodriguez-de-Fonseca, Fernando
A1 Santín-Núñez, Luis Javier
A1 Serrano, Antonia
A1 Castilla-Ortega, María Estela
K1 Neurorreceptores
K1 Alcohol - Efectos fisiológicos
AB 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 saccharinein 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.
PB Elsevier
YR 2018
FD 2018-05-01
LK https://hdl.handle.net/10630/36990
UL https://hdl.handle.net/10630/36990
LA eng
NO 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
NO https://openpolicyfinder.jisc.ac.uk/id/publication/4662
NO PI-194-2014, RD16/0017/0001, PI16/01953, PI17-02026, PI16/01698, PND2017/043, FPU13/04819, FPU14-01610, CD14/00259, CP14/00212, CP14/00173, PSI2015-73156-JIN
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 26 ene 2026