Formyl peptide receptor as a novel therapeutic target for anxiety-related disorders

• Published in: PloS one 2014-12, Vol.9 (12), p.e114626-e114626
• Main Authors: Gallo, Irene, Rattazzi, Lorenza, Piras, Giuseppa, Gobbetti, Thomas, Panza, Elisabetta, Perretti, Mauro, Dalley, Jeffrey W, D'Acquisto, Fulvio
• Format: Article
• Language: English
• Subjects: Abnormalities; Animals; Anxiety; Anxiety - complications; Anxiety - drug therapy; Anxiety - metabolism; Anxiety - pathology; Behavior; Biology and Life Sciences; Brain research; Cognitive ability; Corticosterone - blood; Disorders; Exploratory behavior; Exploratory Behavior - drug effects; Formyl peptide receptors; Gene Deletion; Health aspects; Homeostasis; Immune system; Infections; Inflammation; Kinases; Ligands; Male; Medicine; Medicine and Health Sciences; Mental disorders; Mice; Microbiota; Molecular Targeted Therapy; Nervous System Diseases - complications; Nervous System Diseases - drug therapy; Neutrophils; Object recognition; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Open-field behavior; Pathogens; Pattern recognition; Peptides; Pharmacology; Proteins; Receptors; Receptors, Formyl Peptide - antagonists & inhibitors; Receptors, Formyl Peptide - deficiency; Receptors, Formyl Peptide - genetics; Receptors, Formyl Peptide - metabolism; Recognition (Psychology) - drug effects; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114626

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface.