Exploring the Anxiolytic Potential of NPY by a Dipeptidyl Peptidase-IV Inhibitor in an Animal Model of PTSD

• Published in: The international journal of neuropsychopharmacology Vol. 27; no. 12; p. 1
• Main Authors: Dahan, Matan, Zohar, Joseph, Todder, Doron, Mathé, Aleksander A, Cohen, Hagit
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.12.2024
• Subjects: Animals; Anti-Anxiety Agents - administration & dosage; Anti-Anxiety Agents - pharmacology; Anxiety; Anxiety - drug therapy; Behavior; Behavior, Animal - drug effects; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Disease Models, Animal; Drug therapy; Enzyme-linked immunosorbent assay; Health aspects; Male; Methods; Neuropeptide Y; Neuropeptide Y - metabolism; Neuropeptide Y - pharmacology; Peptides; Post traumatic stress disorder; Rats; Rats, Sprague-Dawley; Regular; Sitagliptin; Sitagliptin Phosphate - pharmacology; Stress Disorders, Post-Traumatic - drug therapy; Stress Disorders, Post-Traumatic - metabolism; Testing; Israel; dipeptidyl peptidase-IV; neuropeptide Y; post-traumatic stress disorder (PTSD); vulnerability; animal model; resilience; neuropeptide Y-Y1 receptor
• ISSN: 1461-1457; 1469-5111; 1469-5111
• DOI: 10.1093/ijnp/pyae062

Abstract Background The regulatory neuropeptide Y (NPY) is implicated in anxiety and post-traumatic stress disorder (PTSD)-related behaviors. NPY exerts its effects through 5 receptor subtypes, with Y1 and Y2 receptors being predominantly expressed in the rat brain. Activation of Y1 by full-length NPY1-36 induces anxiolytic effects, whereas Y2 binds truncated peptides, eliciting region-specific anxiogenic responses. Dipeptidyl peptidase-IV (DPP-IV) cleaves NPY, thereby modulating its functionality. Sitagliptin, a DPP-IV inhibitor (DPP-IV-I), inhibits the degradation of various vasoactive peptides, including cerebral NPY. As such, the therapeutic potential of DPP-IV-I following a traumatic event remains inconclusive. We assessed the effects of a highly selective DPP-IV-I, administered either shortly after the stressor or intermittently over 3 days, on behavioral outcomes using the predator scent stress (PSS) model of PTSD. Methods Rats exposed to PSS or sham-PSS received a single dose of sitagliptin (10 or 30 mg/kg) or saline 1 hour post-exposure, or repeated doses over 3 days (20 mg/kg). Behavioral outcomes were evaluated using the elevated plus maze and acoustic startle response at 7 days post-exposure. Additionally, rats exposed to PSS or sham-PSS were treated with sitagliptin (30 mg/kg) or saline, and their brains were prepared for immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Results Sitagliptin did not attenuate anxiety-related behaviors or PTSD-related behavior prevalence compared to saline. Notably, the 30 mg/kg dose increased NPY levels in several brain regions without affecting NPY-Y1 levels. Conclusions The findings suggest that sitagliptin-induced upregulation of NPY levels shortly after PSS is insufficient to prevent the development of post-traumatic responses. The effectiveness of NPY signaling may be influenced by factors beyond peptide concentration alone, potentially limiting its therapeutic efficacy. Activation of NPY-Y1 receptors, rather than merely increasing NPY levels, appears to be crucial for modulating anti-anxiety and post-traumatic responses.