Estela Castilla-Ortega1, Francisco Javier Pavón1, Laura Sánchez-Marín1, Guillermo Estivill-Torrús2, Carmen Pedraza3, Eduardo Blanco4, Juan Suárez1, Luis Santín3, Fernando Rodríguez de Fonseca5, Antonia Serrano6. 1. Unidad de Gestión Clínica de Salud Mental e Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, Málaga 29010, Spain. 2. Unidad de Microscopía and Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain. 3. Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, Spain. 4. Departament de Pedagogia i Psicología, Facultat d'Educació, Psicologia i Treball Social, Universitat de Lleida, Spain. 5. Unidad de Gestión Clínica de Salud Mental e Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, Málaga 29010, Spain. Electronic address: antonia.serrano@ibima.eu. 6. Unidad de Gestión Clínica de Salud Mental e Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, Málaga 29010, Spain. Electronic address: fernando.rodriguez@ibima.eu.
Abstract
BACKGROUND: Lysophosphatidic acid species (LPA) are lipid bioactive signaling molecules that have been recently implicated in the modulation of emotional and motivational behaviors. The present study investigates the consequences of either genetic deletion or pharmacological blockade of lysophosphatidic acid receptor-1 (LPA1) in alcohol consumption. METHODS: The experiments were performed in alcohol-drinking animals by using LPA1-null mice and administering the LPA1 receptor antagonist Ki16425 in both mice and rats. RESULTS: In the two-bottle free choice paradigm, the LPA1-null mice preferred the alcohol more than their wild-type counterparts. Whereas the male LPA1-null mice displayed this higher preference at all doses tested, the female LPA1-null mice only consumed more alcohol at 6% concentration. The male LPA1-null mice were then further characterized, showing a notably increased ethanol drinking after a deprivation period and a reduced sleep time after acute ethanol administration. In addition, LPA1-null mice were more anxious than the wild-type mice in the elevated plus maze test. For the pharmacological experiments, the acute administration of the antagonist Ki16425 consistently increased ethanol consumption in both wild-type mice and rats; while it did not modulate alcohol drinking in the LPA1-null mice and lacked intrinsic rewarding properties and locomotor effects in a conditioned place preference paradigm. In addition, LPA1-null mice exhibited a marked reduction on the expression of glutamate-transmission-related genes in the prefrontal cortex similar to those described in alcohol-exposed rodents. CONCLUSIONS: Results suggest a relevant role for the LPA/LPA1 signaling system in alcoholism. In addition, the LPA1-null mice emerge as a new model for genetic vulnerability to excessive alcohol drinking. The pharmacological manipulation of LPA1 receptor arises as a new target for the study and treatment of alcoholism.
BACKGROUND:Lysophosphatidic acid species (LPA) are lipid bioactive signaling molecules that have been recently implicated in the modulation of emotional and motivational behaviors. The present study investigates the consequences of either genetic deletion or pharmacological blockade of lysophosphatidic acid receptor-1 (LPA1) in alcohol consumption. METHODS: The experiments were performed in alcohol-drinking animals by using LPA1-null mice and administering the LPA1 receptor antagonist Ki16425 in both mice and rats. RESULTS: In the two-bottle free choice paradigm, the LPA1-null mice preferred the alcohol more than their wild-type counterparts. Whereas the male LPA1-null mice displayed this higher preference at all doses tested, the female LPA1-null mice only consumed more alcohol at 6% concentration. The male LPA1-null mice were then further characterized, showing a notably increased ethanol drinking after a deprivation period and a reduced sleep time after acute ethanol administration. In addition, LPA1-null mice were more anxious than the wild-type mice in the elevated plus maze test. For the pharmacological experiments, the acute administration of the antagonist Ki16425 consistently increased ethanol consumption in both wild-type mice and rats; while it did not modulate alcohol drinking in the LPA1-null mice and lacked intrinsic rewarding properties and locomotor effects in a conditioned place preference paradigm. In addition, LPA1-null mice exhibited a marked reduction on the expression of glutamate-transmission-related genes in the prefrontal cortex similar to those described in alcohol-exposed rodents. CONCLUSIONS: Results suggest a relevant role for the LPA/LPA1 signaling system in alcoholism. In addition, the LPA1-null mice emerge as a new model for genetic vulnerability to excessive alcohol drinking. The pharmacological manipulation of LPA1 receptor arises as a new target for the study and treatment of alcoholism.
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