The Novel Neuropeptide Y Y₅ Receptor Antagonist Lu AA33810 [N-[[trans-4-[(4,5-Dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide] Exerts Anxiolytic- and Antidepressant-Like Effects in Rat Models of Stress Sensitivity

Abstract

Neuropeptide Y (NPY) regulates physiological processes via receptor subtypes (Y 1 , Y 2 , Y 4 , Y 5 , and y 6 ). The Y 5 receptor is well known for its role in appetite. Based on expression in the limbic system, we hypothesized that the Y 5 receptor might also modulate stress sensitivity. We identified a novel Y 5 receptorselective antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro ]-hPancreatic Polypeptide. In Sprague-Dawley rats subjected to the social interaction test, Lu AA33810 (3-30 mg/kg p.o.) produced anxiolyticlike effects after acute or chronic treatment. In Flinders sensitive line rats, chronic dosing of Lu AA33810 (10 mg/kg/day i.p.) produced anxiolytic-like effects in the social interaction test, plus antidepressant-like effects in the forced swim test. In Wistar rats exposed to chronic mild stress, chronic dosing of Lu AA33810 (3 and 10 mg/kg/day i.p.) produced antidepressant-like activity, i.e., normalization of stress-induced decrease in sucrose consumption. We propose that Y 5 receptors may function as part of an endogenous stress-sensing system to mediate social anxiety and reward or motivational deficits in selected rodent models.Neuropeptide Y (NPY) is a 36-amino acid transmitter belonging to the pancreatic polypeptide family, along with peptide YY (PYY) and pancreatic polypeptide (PP). NPY has widespread distribution throughout the central nervous system and periphery and has been demonstrated to modulate numerous physiological processes (e.g., appetite, metabolism, mood, and reproduction) via G protein-coupled receptors (primarily G i/o type). Receptor subtypes for NPY and relatedThe authors are affiliated with Lundbeck Research USA as either employees or paid collaborators. Lundbeck has a research program to study the therapeutic potential of the Y 5 receptor as a drug target.

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

“…Other authors studying antidepressant-like effect of Lu AA33810 focused rather on chronic treatment (Walker et al 2009; Packiarajan et al 2011). Antidepressant-like effect of Lu AA33819 in rats subjected to chronic mild stress, measured by a normalization of stress-induced decrease in sucrose consumption, was found in response to 10 mg/kg i.p.…”

“…twice a day in the second week of treatment (Packiarajan et al 2011) or in response to 3 mg/kg/day i.p. in the third week (Walker et al 2009). The discrepancies between our and other studies could be explained by the fact that various models of depression (acute glial ablation model of depression vs. chronic mild stress), different strains of rats (Spraque-Dawley vs. Wistar), and different tests for evaluation of potential antidepressant-like effect (FST vs. sucrose consumption test) were used.…”

“…Test FST was performed 1 h after the single administration of Lu AA33810. The doses of the used drugs were selected on the basis of literature data for in vivo treatments (for Lu AA33810 from Walker et al (2009) and Packiarajan et al (2011); for U0126 and LY294002 from Zeni et al (2012) and Manosso et al (2015)). The same protocol of the administration of the above-mentioned drugs was used to evaluate their influence on the locomotor activity.…”

“…All these receptor subtypes mediate the NPY’s biological responses via the G αi signaling pathway (Michel 1991; Dumont et al 1992). There are a number of data indicating that NPY and its receptor ligands produced antidepressant-like effects in animal models of depression (Stogner and Holmes 2000; Redrobe et al 2002; Ishida et al 2007; Walker et al 2009; Packiarajan et al 2011; Morales-Medina et al 2012b; Desai et al 2014). Furthermore, significant changes in NPY-like immunoreactivity (NPY-ir) were observed not only in animal models of depressive disorders (Jiménez-Vasquez et al, 2000a,2000b; Wu et al 2011) but also in depressed patients who presented reduced levels of NPY in the cerebrospinal fluid and plasma in several studies (Widerlöv et al 1988; Westrin et al 1999; Heilig et al 2004; Soleimani et al 2014).…”

“…Recently, it has been found that a highly selective and potent Y5R antagonist, [ N -[[trans-4-[(4,5-dihydro[1] benzothiepino [5,4-d]thiazol-2-yl) amino] cyclohexyl] methyl]-methanesulfonamide] Lu AA33810, produced antidepressant-like effects in the rat chronic mild stress model and anxiolytic-like effects in the social interaction test (Walker et al 2009; Packiarajan et al 2011). This compound could easily cross the blood-brain barrier and was effective after oral and peripheral administration which may be important from the point of view of its possible future clinical applications.…”