title: Both genetic deletion and pharmacological blockade of lysophosphatidic acid LPA1 receptor results in increased alcohol consumption.
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.
authors.affiliation: Unidad de Gestión Clínica de Salud Mental e Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, Málaga 29010, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Castilla-Ortega
authors.affiliation: Unidad de Gestión Clínica de Salud Mental e Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, Málaga 29010, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Unidad de Gestión Clínica de Salud Mental e Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, Málaga 29010, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez-Marín
authors.affiliation: Unidad de Microscopía and Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Estivill-Torrús
authors.affiliation: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pedraza
authors.affiliation: Departament de Pedagogia i Psicología, Facultat d'Educació, Psicologia i Treball Social, Universitat de Lleida, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Unidad de Gestión Clínica de Salud Mental e Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, Málaga 29010, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
authors.affiliation: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Santín
authors.affiliation: 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.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: 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.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology; D002186:Cannabinoids / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D007555:Isoxazoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D057897:Reflex, Righting / Q000187:drug effects; D012890:Sleep / Q000187:drug effects
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D002186:Cannabinoids; D007555:Isoxazoles; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D000431:Ethanol; D018698:Glutamic Acid
keywords: Ethanol intake; Ki16425; LPA(1) receptors; LPA(1)-Null mice; Preference