The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test

Abstract

The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY)inNeuropeptide Y (NPY) is a 36-amino acid peptide that is widely distributed in the central nervous system (CNS). Intracerebroventricular (ICV) administration of NPY stimulates food intake (Clark et al. 1985;Levine and Morley 1984;Stanley and Leibowitz 1984), modulates cognition (Flood et al. 1987;Redrobe et al. 1999), inhibits neuronal excitability (Colmers and Bleakman 1994) and has anticonvulsant effects (Vezzani et al. 1999). NPY modulates the secretion of various hypothalamic neuropeptides, stimulates the corticotrophic axis (Krysiak et al. 1999;Small et al. 1997) and has potent inhibitory effects on gonadotrophic and somatotrophic axes (Catzeflis et al. 1993). In addition, NPY is thought to play a role in the pathophysiology of certain mood disorders and in the mechanism of action of antidepressant drugs (Heilig et al. 1988;Caberlotto et al. 1998 (Michel et al. 1998).Clinical studies have demonstrated decreased NPY levels in the cerebrospinal fluid (CSF) (Heilig and Widerlov 1990) and plasma (Nilsson et al. 1996) of depressed patients, when compared with healthy control subjects. In addition, NPY levels have been shown to be negatively correlated to scores of anxiety in clinically depressed patients (Heilig and Widerlov 1990), suggesting a possible link between low levels of NPY and predisposition to anxiety-related or stress-induced depression.Moreover, pre-clinical studies have shown that electroconvulsive shock stimulation increased NPY gene expression (Heilig et al. 1988), as well as the expression of NPY mRNA in distinct brain regions in rats (Caberlotto et al. 1998;Mikkelsen et al. 1994). In addition, chronic antidepressant treatment has been shown to alter NPY and NPY Y 1 -type receptor mRNA levels (Caberlotto et al. 1998), and to reduce NPY Y 2 -type receptor densities in certain brain regions (Widdowson and Halaris 1991). Interestingly, NPY-like immunoreactivity and NPY Y 1 -type receptor binding sites were shown to be decreased or increased, depending on the brain region studied, in the recently developed Flinders Sensitive Line (FSL) rats (Caberlotto et al. 1999), a purported genetic animal model of depression (Overstreet 1993;Overstreet et al. 1995).Additional evidence of a role for NPY in depressive disorders is found in studies using the olfactory bulbectomized (OB) rat model of depression. Sub-chronic ICV administration of NPY attenuated the increase in ambulation, rearing, grooming and defecation scores consistently found when OB animals are tested in the open field (Song et al. 1996). Treatment with NPY also increased noradrenaline (NA) and serotonin (5-HT) levels in the amygdala and hypothalamus (Song et al. 1996). In addition, NPY reversed the supression of lymphocyte proliferation seen following OB (Song et al. 1994). A decrease in lymphocyte proliferation has also been reported in depressed patients (Kronfol and House 1989). Another study demonstrated that OB caused long term...

The Neuropeptide VGF Produces Antidepressant-Like Behavioral Effects and Enhances Proliferation in the Hippocampus

“…NPY itself has been shown to have antidepressant-like activity. Intracerebroventricular injections of NPY or NPY receptor 1 (Y 1 ) agonists significantly reduced immobility time in both the FST (Husum et al, 2000;Stogner and Holmes, 2000;Redrobe et al, 2002a) and LH paradigms (Ishida et al, 2007). However, the role of VGF in depression has not been explored.…”

Effects of NPY and the specific Y1 receptor agonist [d-His26]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats

“…The effect of [D-His 26 ]-NPY on nicotine withdrawal was investigated as this compound, in contrast to NPY, has a low affinity for the Y5 receptor (NPY, Ki of 0.28 nM for Y1, Ki of 1.5 nM for Y5; ]-NPY, Ki of 2.0 nM for Y1, Ki of 34.6 nM for Y5) (Mullins et al, 2001). Activation of the Y5 receptor has been suggested to mediate NPY's sedative effects while NPY's anxiolytic and antidepressant-like effects have been suggested to be mediated via the activation of the Y1 receptor (Ishida et al, 2007;Redrobe et al, 2002a;Sorensen et al, 2004). Experiment 1 and 2 indicated that NPY and [D-His 26 ]-NPY elevated the brain reward thresholds of the saline-treated control rats.…”

“…NPY levels in the cerebrospinal fluid of depressed patients are lower than those in schizophrenics or healthy controls Widerlov et al, 1988). In addition, the central administration of NPY has antidepressant-like effects in animal models such as the rat forced swim test (Redrobe et al, 2002a;Stogner and Holmes, 2000) and clinically effective antidepressant treatments (e.g., repeated electroconvulsive shock stimulation and the selective serotonin reuptake inhibitor fluoxetine) elevate central NPY levels in rats (Baker et al, 1996;Heilig et al, 1988;Stenfors et al, 1989). Taken together, the above-discussed studies suggest that NPY attenuates somatic opioid and alcohol withdrawal signs and low levels of NPY may be implicated in the etiology of negative mood states.…”

Topiramate Normalizes Hippocampal NPY-LI in Flinders Sensitive Line ‘Depressed’ Rats and Upregulates NPY, Galanin, and CRH-LI in the Hypothalamus: Implications for Mood-Stabilizing and Weight Loss-Inducing Effects

“…Most clinical studies have found reduced NPY concentrations in cerebrospinal fluid and plasma from depressed patients and suicide attempters (Westrin et al, 1999;Nilsson et al, 1996;Hashimoto et al, 1996;Gjerris et al, 1992;Widerlöv et al, 1986). Further, in rats as well as mice, NPY induces antidepressant-like behavior following central administration (Redrobe et al, 2002;Stogner and Holmes, 2000;Husum et al, 2000). The rise in hippocampal NPY-LI in FSL animals in the present study may therefore also be of importance to the proposed mood-stabilizing properties of topiramate.…”

“…We have previously shown that levels of neuropeptide Y (NPY), a highly conserved 36 amino-acid neuropeptide that is abundantly distributed in mammalian brain (Tatemoto et al, 1982), are reduced in the hippocampus of FSL rats (Husum et al, 2001;Jiménez Vasquez et al, 2000). Furthermore, in rodents and mice, exogenous NPY exerts antidepressant-like activity and modulates anxiety and stress behavior (Redrobe et al, 2002;Stogner and Holmes, 2000;Thorsell et al, 2000;Husum et al, 2000;Heilig et al, 1989). Most clinical studies have found reduced NPY concentrations in cerebrospinal fluid (CSF) and plasma from depressed patients and suicide attempters (Westrin et al, 1999;Nilsson et al, 1996;Hashimoto et al, 1996;Gjerris et al, 1992;Widerlöv et al, 1986).…”