title: Fear extinction and acute stress reactivity reveal a role of LPA(1) receptor in regulating emotional-like behaviors.
abstract: LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intercellular signaling molecule. It has been proposed that this receptor has a role in controlling anxiety-like behaviors and in the detrimental consequences of stress. Here, we sought to establish the involvement of the LPA1 receptor in emotional regulation. To this end, we examined fear extinction in LPA1-null mice, wild-type and LPA1 antagonist-treated animals. In LPA1-null mice we also characterized the morphology and GABAergic properties of the amygdala and the medial prefrontal cortex. Furthermore, the expression of c-Fos protein in the amygdala and the medial prefrontal cortex, and the corticosterone response following acute stress were examined in both genotypes. Our data indicated that the absence of the LPA1 receptor significantly inhibited fear extinction. Treatment of wild-type mice with the LPA1 antagonist Ki16425 mimicked the behavioral phenotype of LPA1-null mice, revealing that the LPA1 receptor was involved in extinction. Immunohistochemistry studies revealed a reduction in the number of neurons, GABA+ cells, calcium-binding proteins and the volume of the amygdala in LPA1-null mice. Following acute stress, LPA1-null mice showed increased corticosterone and c-Fos expression in the amygdala. In conclusion, LPA1 receptor is involved in emotional behaviors and in the anatomical integrity of the corticolimbic circuit, the deregulation of which may be a susceptibility factor for anxiety disorders and a potential therapeutic target for the treatment of these diseases.
authors.affiliation: Departamento de Psicobiología y Metodología de las CC, Universidad de Málaga and Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, 29071, Spain, mdpedraza@uma.es.
authors.forename: C
authors.initials: C
authors.lastname: Pedraza
authors.forename: J
authors.initials: J
authors.lastname: Sánchez-López
authors.forename: E
authors.initials: E
authors.lastname: Castilla-Ortega
authors.forename: C
authors.initials: C
authors.lastname: Rosell-Valle
authors.forename: E
authors.initials: E
authors.lastname: Zambrana-Infantes
authors.forename: M
authors.initials: M
authors.lastname: García-Fernández
authors.forename: F
authors.initials: F
authors.lastname: Rodriguez de Fonseca
authors.forename: J
authors.initials: J
authors.lastname: Chun
authors.forename: L J
authors.initials: LJ
authors.lastname: Santín
authors.forename: G
authors.initials: G
authors.lastname: Estivill-Torrús
mesh_terms: D000679:Amygdala / Q000166:cytology; D000818:Animals; D003214:Conditioning, Classical; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D003463:Cues; D004195:Disease Models, Animal; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*; D013997:Time Factors
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D010751:Phosphopyruvate Hydratase; C032881:lysophosphatidic acid; D003345:Corticosterone