Neuropeptide Y Reduces Social Fear in Male Mice: Involvement of Y1 and Y2 Receptors in the Dorsolateral Septum and Central Amygdala

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We previously showed that intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC) and localized these effects to the dorsolateral septum (DLS) and central amygdala (CeA). In the present study, we aimed to identify the receptor subtypes that mediate these local effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduced the expression of SFC-induced social fear in a brain region- and receptor-specific manner in male mice. In the DLS, NPY reduced the expression of social fear by acting on Y2 receptors but not on Y1 receptors. As such, prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 μL/side) but not the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 μL/side) blocked the effects of NPY in the DLS. In the CeA, however, BIBO3304 trifluoroacetate but not BIIE0246 blocked the effects of NPY, suggesting that NPY reduced the expression of social fear by acting on Y1 receptors but not Y2 receptors within the CeA. This study suggests that at least two distinct receptor subtypes are differentially recruited in the DLS and CeA to mediate the effects of NPY on the expression of social fear.

Download Full-text

Neuropeptide Y reduces expression of social fear via simultaneous activation of Y1 and Y2 receptors

Journal of Psychopharmacology ◽

10.1177/0269881119862529 ◽

2019 ◽

Vol 33 (12) ◽

pp. 1533-1539 ◽

Cited By ~ 3

Author(s):

Johannes Kornhuber ◽

Iulia Zoicas

Keyword(s):

Neuropeptide Y ◽

Receptor Antagonist ◽

Social Experience ◽

Fear Extinction ◽

Dependent Manner ◽

Contextual Fear ◽

Y1 Receptor ◽

Y2 Receptor ◽

Social Fear ◽

Simultaneous Activation

Background: Neuropeptide Y (NPY) has anxiolytic effects and facilitates extinction of cued and contextual fear in rodents, thereby acting as a resilience factor against exaggerated fear responses after adverse events. We investigated whether NPY influences acquisition, expression and extinction of social fear in a mouse model of social fear conditioning (SFC). Methods: NPY was administered intracerebroventricularly before SFC or before social fear extinction with or without prior administration of Y1 and/or Y2 receptor antagonists. Results: We show that NPY affects SFC-induced social fear in a time point–dependent manner. When administered before SFC, NPY did not affect acquisition, expression and extinction of social fear. However, when administered before social fear extinction, NPY reduced expression of social fear via simultaneous activation of Y1 and Y2 receptors. As such, neither the Y1 receptor antagonist BIBO3304 trifluoroacetate nor the Y2 receptor antagonist BIIE0246 was able to block the effects of NPY completely. However, when administered in combination, they completely blocked the effects of NPY on social fear expression. Conclusions: These findings have important clinical implications, as they suggest that although medication strategies aimed at increasing brain NPY activity are unlikely to prevent the formation of aversive memories after a traumatic social experience, they might improve the recovery from a traumatic social experience by reducing the expression of social fear.

Download Full-text

Evidence That the Inhibition of Luteinizing Hormone Secretion Exerted by Central Administration of Neuropeptide Y (NPY) in the Rat Is Predominantly Mediated by the NPY-Y5 Receptor Subtype1

Endocrinology ◽

10.1210/endo.140.9.6985 ◽

1999 ◽

Vol 140 (9) ◽

pp. 4046-4055 ◽

Cited By ~ 51

Author(s):

Paula D. Raposinho ◽

Pierre Broqua ◽

Dominique D. Pierroz ◽

Amanda Hayward ◽

Yvan Dumont ◽

...

Keyword(s):

Food Intake ◽

Neuropeptide Y ◽

Receptor Antagonist ◽

Pancreatic Polypeptide ◽

Inhibitory Action ◽

Receptor Subtypes ◽

Y1 Receptor ◽

Npy Receptor ◽

Gonadotropic Axis ◽

Lh Secretion

Abstract A number of studies have indicated that neuropeptide Y (NPY) is a central regulator of the gonadotropic axis, and the Y1 receptor was initially suggested to be implicated. As at least five different NPY receptor subtypes have now been characterized, the aim of the present study was to reinvestigate the pharmacological profile of the receptor(s) mediating the inhibitory action of NPY on LH secretion by using a panel of NPY analogs with different selectivity toward the five NPY receptor subtypes. When given intracerebroventricularly (icv) to castrated rats, a bolus injection of native NPY (0.7–2.3 nmol) dose-dependently decreased plasma LH. Peptide YY (PYY; 2.3 nmol) was as potent as NPY, suggesting that the Y3 receptor is not implicated. Confirming previous data, the mixed Y1, Y4, and Y5 agonist[ Leu31,Pro34]NPY (0.7–2.3 nmol) inhibited LH release with potency and efficacy equal to those of NPY. Neither the selective Y2 agonist C2-NPY (2.3 nmol) nor the selective Y4 agonist rat pancreatic polypeptide affected plasma LH, excluding Y2 and Y4 subtypes for the action of NPY on LH secretion. The mixed Y4-Y5 agonist human pancreatic polypeptide (0.7–7 nmol) as well as the mixed Y2-Y5 agonist PYY3–36 (0.7–7 nmol) that displayed very low affinity for the Y1 receptor, thus practically representing selective Y5 agonists in this system, decreased plasma LH with potency and efficacy similar to those of NPY, indicating that the Y5 receptor is mainly involved in this inhibitory action of NPY on LH secretion.[ d-Trp32]NPY, a selective, but weak, Y5 agonist, also inhibited plasma LH at a dose of 7 nmol. Furthermore, the inhibitory action of NPY (0.7 nmol) on LH secretion could be fully prevented, in a dose-dependent manner (6–100 μg, icv), by a nonpeptidic Y5 receptor antagonist. This antagonist (60 μg, icv) also inhibited the stimulatory action of NPY (0.7 nmol) on food intake. The selectivity of PYY3–36, human PP,[ d-Trp32]NPY, and the Y5 antagonist for the Y5 receptor subtype was further confirmed by their ability to inhibit the specific[ 125I][Leu31,Pro34]PYY binding to rat brain membrane homogenates in the presence of the Y1 receptor antagonist BIBP3226, a binding assay system that was described as being highly specific for Y5-like receptors. With the exception of[ d-Trp32]NPY, all analogs able to inhibit LH secretion were also able to stimulate food intake. Taken together, these results indicate that the Y5 receptor is involved in the negative control by NPY of the gonadotropic axis.

Download Full-text

Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents

British Journal of Pharmacology ◽

10.1038/sj.bjp.0702084 ◽

1998 ◽

Vol 125 (3) ◽

pp. 549-555 ◽

Cited By ~ 200

Author(s):

H A Wieland ◽

W Engel ◽

W Eberlein ◽

K Rudolf ◽

H N Doods

Keyword(s):

Neuropeptide Y ◽

Receptor Antagonist ◽

The Novel ◽

Y1 Receptor ◽

Subtype Selectivity

Download Full-text

P2.21 Effects of the neuropeptide Y Y1 receptor antagonist BIBP 3226 on food intake

European Journal of Pharmaceutical Sciences ◽

10.1016/s0928-0987(97)84054-7 ◽

1997 ◽

Vol 5 ◽

pp. S38

Keyword(s):

Food Intake ◽

Neuropeptide Y ◽

Receptor Antagonist ◽

Y1 Receptor

Download Full-text

Stimulation of neurons in rat ARC inhibits gastric acid secretion via hypothalamic CRF1/2- and NPY-Y1 receptors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00125.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. G1075-G1083 ◽

Cited By ~ 15

Author(s):

Johannes J. Tebbe ◽

Silke Mronga ◽

Martin K.-H. Schäfer ◽

Jens Rüter ◽

Peter Kobelt ◽

...

Keyword(s):

Acid Secretion ◽

Receptor Antagonist ◽

Gastric Acid Secretion ◽

Gastric Acid ◽

Excitatory Amino Acid ◽

Inhibitory Effect ◽

Receptor Subtypes ◽

Npy Receptor ◽

Y1 Receptors ◽

Open Question

Neuropeptide Y (NPY) neuronal projections from the arcuate nucleus (ARC) have been proposed to target corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus (PVN) as part of the ARC-PVN axis. The existence of a positive feedback loop involving CRF receptors in the PVN has been suggested. Exogenous NPY and CRF in the PVN have been shown to inhibit gastric acid secretion. Recently, we have demonstrated that activation of ARC neurons inhibits gastric acid secretion via vagal pathways. To what extent NPY- and CRF-mediated mechanisms in the PVN contribute to the CNS modulation of gastric acid secretion is still an open question. In the present study, we performed consecutive bilateral microinjections of antagonists to NPY receptor subtypes Y1 and Y2 and to CRF1/2 receptors in the PVN and of the excitatory amino acid kainate in the ARC to assess the role of NPY- and CRF-mediated mechanisms in the kainate-induced effects on gastric acid secretion. Gastric acid secretion was measured at the basal condition and during pentagastrin (16 μg/kg body wt) stimulation. Microinjection of vehicle in the PVN and kainate in the ARC decreased gastric acid secretion. Microinjection of the specific NPY-Y1 receptor antagonist BIBP-3226 (200 pmol) and the nonspecific CRF1/2 antagonist astressin (30 pmol) in the PVN abolished the inhibitory effect of neuronal activation in the ARC by kainate on gastric acid secretion. The CRF antagonist astressin was more effective. Pretreatment with the NPY-Y2 receptor antagonist BIIE-0246 (120 pmol) in the PVN had no significant effect. Our results indicate that activation of neurons in the ARC inhibits gastric acid secretion via CRF1/2 and NPY-Y1 receptor-mediated pathways in the PVN.

Download Full-text

Involvement of Neuropeptide Y Y1 Receptors in the Regulation of Neuroendocrine Corticotropin-Releasing Hormone Neuronal Activity

Endocrinology ◽

10.1210/en.2006-1730 ◽

2007 ◽

Vol 148 (8) ◽

pp. 3666-3673 ◽

Cited By ~ 48

Author(s):

Eugene L. Dimitrov ◽

M. Regina DeJoseph ◽

Mark S. Brownfield ◽

Janice H. Urban

Keyword(s):

Neuropeptide Y ◽

Hpa Axis ◽

Binding Protein ◽

Plasma Corticosterone ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Y1 Receptor ◽

Element Binding Protein ◽

Y1 Receptors

The neuroendocrine parvocellular CRH neurons in the paraventricular nucleus (PVN) of the hypothalamus are the main integrators of neural inputs that initiate hypothalamic-pituitary-adrenal (HPA) axis activation. Neuropeptide Y (NPY) expression is prominent within the PVN, and previous reports indicated that NPY stimulates CRH mRNA levels. The purpose of these studies was to examine the participation of NPY receptors in HPA axis activation and determine whether neuroendocrine CRH neurons express NPY receptor immunoreactivity. Infusion of 0.5 nmol NPY into the third ventricle increased plasma corticosterone levels in conscious rats, with the peak of hormone levels occurring 30 min after injection. This increase was prevented by pretreatment with the Y1 receptor antagonist BIBP3226. Immunohistochemistry showed that CRH-immunoreactive neurons coexpressed Y1 receptor immunoreactivity (Y1r-ir) in the PVN, and a majority of these neurons (88.8%) were neuroendocrine as determined by ip injections of FluoroGold. Bilateral infusion of the Y1/Y5 agonist, [leu31pro34]NPY (110 pmol), into the PVN increased c-Fos and phosphorylated cAMP response element-binding protein expression and elevated plasma corticosterone levels. Increased expression of c-Fos and phosphorylated cAMP response element-binding protein was observed in populations of CRH/Y1r-ir cells. The current findings present a comprehensive study of NPY Y1 receptor distribution and activation with respect to CRH neurons in the PVN. The expression of NPY Y1r-ir by neuroendocrine CRH cells suggests that alterations in NPY release and subsequent activation of NPY Y1 receptors plays an important role in the regulation of the HPA.

Download Full-text