Y2 Receptor Antagonist BIIE0246 Research Articles

Neuropeptide Y Y2 Receptors in Sensory Neurons Tonically Suppress Nociception and Itch but Facilitate Postsurgical and Neuropathic Pain Hypersensitivity.

Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status. The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays. The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.

Valence-dependent effects of neuropeptide Y on the expression of conditioned fear and anxiety-like behavior: Involvement of the bed nucleus of the stria terminalis

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We have previously shown that intracerebroventricular administration of NPY reduces the expression of social fear via simultaneous activation of Y1 and Y2 receptors in a mouse model of social fear conditioning (SFC). In the present study, we investigated whether the anteroventral bed nucleus of the stria terminalis (BNSTav) mediates these effects of NPY, given the important role of BNSTav in regulating anxiety- and fear-related behaviors. We show that while NPY (0.1 nmol/0.2 μl/side) did not reduce the expression of SFC-induced social fear in male CD1 mice, it reduced the expression of both cued and contextual fear by acting on Y2 but not on Y1 receptors within the BNSTav. Prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 μl/side) but not of the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 μl/side) blocked the effects of NPY on the expression of cued and contextual fear. Similarly, NPY exerted non-social anxiolytic-like effects in the elevated plus maze test but not social anxiolytic-like effects in the social approach avoidance test by acting on Y2 receptors and not on Y1 receptors within the BNSTav. These results suggest that administration of NPY within the BNSTav exerts robust Y2 receptor-mediated fear-reducing and anxiolytic-like effects specifically in non-social contexts and add a novel piece of evidence regarding the neural underpinnings underlying the effects of NPY on conditioned fear and anxiety-like behavior.

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.

Neuropeptide Y prolongs non-social memory in a brain region- and receptor-specific way in male mice

Neuropeptide Y (NPY) and its receptors are highly expressed in brain regions involved in learning and memory processes. We have previously shown that intracerebroventricular administration of NPY prolongs the retention of non-social memory in the object discrimination test. Here, we aimed to identify the brain regions which mediate these memory-enhancing effects of NPY. We show that NPY (0.1 nmol/0.2 μl/side) prolongs retention of non-social memory when administered into the dorsolateral septum (DLS) and medial amygdala (MeA), but not when administered into the dorsal hippocampus, central amygdala and basolateral amygdala. In the DLS, the effects of NPY were blocked by the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 μl/side), but not by the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 μl/side). In the MeA, on the other hand, BIIE0246, but not BIBO3304 trifluoroacetate blocked the effects of NPY. This study demonstrates that NPY exerts Y1 receptor-mediated memory-enhancing effects in the DLS and Y2 receptor-mediated memory-enhancing effects in the MeA, and suggests that distinct brain regions and receptor subtypes are recruited to mediate the effects of NPY on non-social memory.

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

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.

Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice.

Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y2-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y2-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y2-receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPYDβH) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y2-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPYDβH and WT mice feeding on chow or Western diet. Treatment with Y2-receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y2-receptors induced obesity in WT mice, whereas OE-NPYDβH mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y2-receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y2-receptor antagonism has beneficial effects on metabolic status.

Peptide YY (3–36) modulates intracellular calcium through activation of the phosphatidylinositol pathway in hippocampal neurons

Peptide YY (PYY) belongs to the neuropeptide Y (NPY) family, which also includes the pancreatic polypeptide (PP) and NPY. PYY is secreted by the intestinal L cells, being present in the blood stream in two active forms capable of crossing the blood brain barrier, PYY (1–36) and its cleavage product, PYY (3–36). PYY is a selective agonist for the Y2 receptor (Y2R) and these receptors are abundant in the hippocampus. Here we investigated the mechanisms by which PYY (3–36) regulates intracellular Ca2+ concentrations ([Ca2+]i) in hippocampal neurons by employing a calcium imaging technique in hippocampal cultures. Alterations in [Ca2+]i were detected by changes in the Fluo-4 AM reagent emission. PYY (3–36) significantly increased [Ca2+] from the concentration of 10−11M as compared to the controls (infusion of HEPES-buffered solution (HBS) solution alone). The PYY (3–36)-increase in [Ca2+]i remained unchanged even in Ca2+-free extracellular solutions. Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase pump (SERCA pump) inhibition partially prevent the PYY (3–36)-increase of [Ca2+]i and inositol 1,4,5-triphosphate receptor (IP3R) inhibition also decreased the PYY (3–36)-increase of [Ca2+]i. Taken together, our data strongly suggest that PYY (3–36) mobilizes calcium from the neuronal endoplasmic reticulum (ER) stores towards the cytoplasm. Next, we showed that PYY (3–36) inhibited high K+-induced increases of [Ca2+]i, suggesting that PYY (3–36) could also act by activating G-protein coupled inwardly rectifying potassium K+ channels. Finally, the co-infusion of the Y2 receptor (Y2R) antagonist BIIE0246 with PYY (3–36) abolished the [Ca2+]i increase induced by the peptide, suggesting that PYY (3–36)-induced [Ca2+]i increase in hippocampal neurons occurs via Y2Rs.

Neuropeptide Y prolongs non-social memory and differentially affects acquisition, consolidation, and retrieval of non-social and social memory in male mice

Neuropeptide Y (NPY) and its receptors (especially Y1, Y2, and Y5) are highly expressed in brain regions involved in learning and memory processes. Accordingly, NPY was shown to modulate cognitive functions in rodents. Here, we investigated possible memory-enhancing effects of NPY and determined the role of the NPY system in the acquisition, consolidation, and retrieval of non-social and social memory in mice, using the object and social discrimination tests, respectively. Intracerebroventricular (icv) infusion of NPY (1 nmol/2 µl) prolonged retention of non-social (object) memory, but not of social memory. This effect was blocked by the Y1 receptor antagonist BIBO3304 trifluoroacetate (2 nmol/2 µl), but not by the Y2 receptor antagonist BIIE0246 (2 nmol/2 µl). While icv infusion of NPY did not affect the acquisition, consolidation, and retrieval of non-social and social memory, icv infusion of BIBO3304 trifluoroacetate and BIIE0246 blocked the consolidation of non-social memory and the retrieval of both non-social and social memory. This study suggests that NPY has memory-enhancing effects in a non-social context by specifically acting on Y1 receptors. It further suggests that the central NPY system exerts differential effects on the sequential phases of non-social and social memory.

Investigation of 5-HT3 receptor-triggered serotonin release from guinea-pig isolated colonic mucosa: a role of PYY-containing endocrine cell

The effect of a 5-HT3 receptor-selective agonist SR57227A was investigated on the outflow of 5-hydroxytryptamine (5-HT) from isolated muscle layer-free mucosal preparations of guinea-pig colon. The mucosal preparations were incubated in vitro and the outflow of 5-HT from these preparations was determined by high-performance liquid chromatography with electrochemical detection. SR57227A (100μM) produced a tetrodotoxin-resistant and sustained increase in the outflow of 5-HT from the mucosal preparations. The SR57227A-evoked sustained 5-HT outflow was completely inhibited by the 5-HT3 receptor antagonist ramosetron (1μM). The neuropeptide Y1 receptor antagonist BIBO3304 (100nM) partially inhibited the SR57227A-evoked sustained 5-HT outflow, but the Y2 receptor antagonist BIIE0246 (1μM) or the glucagon-like peptide-1 (GLP-1) receptor antagonist exendin-(9−39) (1μM), showed a minimal effect on the SR57227A-evoked sustained 5-HT outflow. In the presence of BIBO3304 (100nM) and exendin-(9−39) (1μM), SR57227A (100μM) failed to produce a sustained increase in the outflow of 5-HT. The Y1 receptor agonist [Leu31, Pro34]-neuropeptide Y (10nM), but not GLP-1-(7−36) amide (100nM), produced a sustained increase in the outflow of 5-HT. We found that 5-HT3 receptor-triggered 5-HT release from guinea-pig colonic mucosa is mediated by the activation of 5-HT3 receptors located at endocrine cells (enterochromaffin cells and peptide YY (PYY)-containing endocrine cells). The activation of both Y1 and GLP-1 receptors appears to be required for the maintenance of 5-HT3 receptor-triggered 5-HT release. It is therefore considered that 5-HT3 receptors located at colonic mucosa play a crucial role in paracrine signaling between enterochromaffin cells and PYY-containing endocrine cells.

The Y2 receptor antagonist BIIE0246 reverses corticosterone-induced anxiogenic-related behavior and neuronal hypertrophy

The Y2 receptor antagonist BIIE0246 reverses corticosterone-induced anxiogenic-related behavior and neuronal hypertrophy

Effects of peripherally acting neuropeptide Y2 receptor antagonist BIIE0246 on obesity in mice

Effects of peripherally acting neuropeptide Y2 receptor antagonist BIIE0246 on obesity in mice

Evidence for tachykinin NK3 receptors-triggered peptide YY release from isolated guinea-pig distal colon

The anorectic gut hormone, peptide YY (PYY), is released from colonic mucosal endocrine cells, but little is known about the role for tachykinin NK3 receptor in the control of PYY release from the colonic mucosa. We investigated the functional role for NK3 receptors in the control of PYY release from isolated guinea-pig distal colon, and the role for NK3 receptors-triggered PYY release in the control of colonic motility. Isolated colonic preparations were mounted in organ baths for measurement of PYY release and mechanical activity. The release of PYY from these preparations was determined by enzyme immunoassays. The NK3 receptor agonist senktide produced a tetrodotoxin/atropine-sensitive sustained increase in the release of PYY from the colonic preparations. Basal PYY release was transiently inhibited by the NK3 receptor antagonist SB222200. The neuropeptide Y1 receptor antagonist BIBO3304 produced a leftward shift of the concentration–response curves for senktide-evoked neurogenic contraction, but neither the neuropeptide Y2 receptor antagonist BIIE0246 nor the neuropeptide Y5 receptor antagonist CGP71683 affected the senktide concentration–response curves. NK3 receptors appear to play an important role in the control of PYY release from colonic mucosa, and NK3 receptor-triggered PYY release can exert Y1 receptor-mediated inhibition of tachykinergic neuromuscular transmission. This indicates a pathophysiological role for the NK3 receptor-triggered PYY release in the control of colonic motility.

Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-β (Aβ1–40) administration in mice

Neuropeptide Y (NPY) is a 36-amino acid peptide widely distributed in the central nervous system (CNS) that has been associated with the modulation of several functions including food intake, learning and memory, mood and neuroprotection. There is great interest in understanding the role of NPY in the deleterious effects induced by the central accumulation of amyloid-β (Aβ) peptides, a pathological hallmark of Alzheimer's disease (AD). Herein, we evaluated the effects of a single intracerebroventricular (i.c.v.) administration of NPY (0.0234μmol/μL) 15min prior to the i.c.v. injection of aggregated Aβ1–40 peptide (400pmol/mouse) in behavioral and neurochemical parameters related to oxidative stress in mice. Pretreatment with NPY prevented Aβ1–40-induced depressive-like responses and spatial memory impairments evaluated in the tail suspension and object location tasks, respectively. The protective effects of NPY on spatial memory of Aβ1–40-treated mice were abolished by the pretreatment with the selective Y2 receptor antagonist BIIE0246. On the other hand, the administration of NPY and Aβ1–40 did not alter the performance of the animals in the elevated plus-maze and open field arena, indicating lack of effects on anxiety state and locomotor function. Although Aβ1–40 infusion did not change hippocampal and cortical glutathione peroxidase (GPx) activity and glutathione (GSH) levels, Aβ1–40-infused animals showed an increased lipid peroxidation in hippocampus and prefrontal cortex that were blunted by NPY administration. These findings indicate that central administration of NPY prevents Aβ1–40-induced depressive-like behavior and spatial memory deficits in mice and that this response is mediated, at least in part, by the activation of Y2 receptors and prevention of oxidative stress.

Effect of pharmacological manipulations of neuropeptide Y and corticotropin-releasing factor neurotransmission on incubation of conditioned fear

We recently developed a procedure to study fear incubation in which rats given 100 tone-shock pairings over 10 days show low fear 2 days after conditioned fear training and high fear after 30 or 60 days. Here, we studied the role of the stress-related peptides, neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), in fear incubation. We gave rats either 10 or 100 30-s tone–0.5-s footshock pairings over 1 day (short training) or 10 days (long training) and then assessed tone-cue-induced conditioned suppression of lever responding 2 days after short training or 2 days and 1 month after long training. Prior to testing, we injected NPY (5–10 μg, i.c.v.), the NPY Y1 receptor antagonist BIBO3304 (20–40 μg, i.c.v.), the NPY Y2 receptor antagonist BIIE0246 (2.5–5 mg/kg s.c.), the non-selective CRF receptor antagonist D-Phe CRF(12–41) (10 μg, i.c.v.), or the CRF1 receptor antagonist MTIP (10–20 mg/kg s.c.). Conditioned suppression after long training was higher after 1 month than after 2 days (fear incubation); conditioned suppression was robustly expressed 2 days after short training (non-incubated fear). Both incubated and non-incubated fear responses were attenuated by NPY. In contrast, D-Phe CRF(12–41), MTIP, BIBO3304, or BIIE0246 had no effect on conditioned fear at the different time points. Results confirm previous work on the potent effect of exogenous NPY administration on conditioned fear, but the negative results with BIBO3304 and BIIE0246 question whether endogenous NPY contributes to incubated (or non-incubated) fear. Results also suggest that CRF receptors are not involved in cue-induced fear in the conditioned suppression procedure.

Sigma 1 receptor‐mediated increase in hippocampal extracellular dopamine contributes to the mechanism of the anticonvulsant action of neuropeptide Y

The potent anticonvulsant properties of neuropeptide Y (NPY) are generally attributed to a Y2 receptor-mediated inhibition of glutamatergic synaptic transmission. Independent studies have shown that NPY increases brain dopamine content, possibly via interaction with sigma 1 receptors. Recently, we showed that increased extracellular hippocampal dopamine attenuates pilocarpine-induced limbic seizures via activation of hippocampal D2 receptors. Our aim in this study was to elucidate the role of increased hippocampal dopamine in the mechanism of the anticonvulsant action of NPY and to investigate the involvement of Y2 and sigma 1 receptors in this process. Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. NPY was administered intracerebroventricularly, intrahippocampally via the microdialysis probe, or coadministered intrahippocampally with the D2 receptor antagonist remoxipride, the Y2 receptor antagonist BIIE0246 or the sigma 1 receptor antagonist BD1047. Changes in hippocampal extracellular dopamine were monitored, and behavioural changes indicative of seizure activity were scored. Intracerebroventricular (10 nmol/3 microL) and intrahippocampal (20-50 microm) NPY administration increased hippocampal dopamine and attenuated pilocarpine-induced seizures. Hippocampal D2 receptor blockade (4 microm remoxipride) reversed the anticonvulsant effect of NPY. Y2 receptor blockade (1 microm BIIE0246) reversed the anticonvulsant effect of NPY but did not prevent NPY-induced increases in hippocampal dopamine. Sigma 1 receptor blockade (10 microm BD1047) abolished NPY-induced increases in hippocampal dopamine and reversed the anticonvulsant effect of NPY. Our results indicate that NPY-induced increases in hippocampal dopamine are mediated via sigma 1 receptors and contribute to the anticonvulsant effect of NPY via increased activation of hippocampal D2 receptors. This novel mechanism of anticonvulsant action of NPY is separate from, and may be complementary to, the well established Y2 receptor-mediated inhibition of hippocampal excitability.

Role of CCK1 and Y2 receptors in activation of hindbrain neurons induced by intragastric administration of bitter taste receptor ligands

G-protein-coupled receptors signaling bitter taste (T2Rs) in the oral gustatory system and the alpha-subunit of the taste-specific G-protein gustducin are expressed in the gastrointestinal (GI) tract. alpha-Subunit of the taste-specific G-protein gustducin colocalizes with markers of enteroendocrine cells in human and mouse GI mucosa, including peptide YY. Activation of T2Rs increases cholecystokinin (CCK) release from the enteroendocrine cell line, STC-1. The aim of this study was to determine whether T2R agonists in the GI tract activate neurons in the nucleus of the solitary tract (NTS) and whether this activation is mediated by CCK and peptide YY acting at CCK(1) and Y(2) receptors. Immunocytochemistry for the protooncogene c-Fos protein, a marker for neuronal activation, was used to determine activation of neurons in the midregion of the NTS, the region where vagal afferents from the GI tract terminate. Intragastric administration of the T2R agonist denatonium benzoate (DB), or phenylthiocarbamide (PTC), or a combination of T2R agonists significantly increased the number of Fos-positive neurons in the mid-NTS; subdiaphragmatic vagotomy abolished the NTS response to the mixture of T2R agonists. Deletion of CCK(1) receptor gene or blockade of CCK(1) receptors with devazepide abolishes the activation of NTS neurons in response to DB, but had no effect on the response to PTC. Administration of the Y(2) receptor antagonist BIIE0246 blocks the activation of NTS neurons to DB, but not PTC. These findings suggest that activation of neurons in the NTS following administration of T2R agonists to the GI tract involves CCK(1) and Y(2) receptors located on vagal afferent terminals in the gut wall. T2Rs may regulate GI function via release of regulatory peptides and activation of the vagal reflex pathway.

Ventricular Fibrillation Induced by Ischemia-Reperfusion Is Not Prevented by the NPY Y2 Receptor Antagonist BIIE0246

Neuropeptide Y is released together with norepinephrine from sympathetic nerve terminals during conditions of increased sympathetic activity. Neuropeptide Y is known to inhibit vagal activity, and accordingly, it might increase the risk for ventricular fibrillation during myocardial ischemia-reperfusion, with concomitant sympathetic stimulation. Counteracting the inhibiting effect of neuropeptide Y by the specific neuropeptide Y2 antagonist, BIIE0246, we expected occurrence of ventricular fibrillation in association with repeated periods of myocardial ischemia-reperfusion to decrease. The midleft anterior descending coronary artery was repeatedly occluded in 16 open-chest pigs. Eight pigs received BIIE0246, and the controls received the vehicle only. Ventricular fibrillation developed in 2 animals of the control group, but in 4 pigs receiving BIIE0246. Occurrence of ventricular fibrillation and ventricular tachycardia did not differ significantly between the 2 groups, and in association with repeated periods of regional myocardial ischemia, did not decline in pigs treated by the specific neuropeptide Y2-receptor antagonist BIIE0246.

Effect of PYY antagonist and ghrelin agonist on food intake after RYGB

Introduction: Having previously reported low plasma ghrelin and high PYY concentrations to explain loss of appetite and sustained weight loss after Roux-en-Y gastric bypass (RYGB) in a diet induced obese rat model, we tested our hypothesis that infusion of PYY antagonist or ghrelin agonist after RYGB could increased food intake (FI). Method: 20 diet induced obese rats had a RYGB. After 30 days an Aztec(r) infusion pump was implanted intra-peritoneal and randomized to continuously infuse PYY antagonist: Y2-receptor antagonist BIIE0246 (400nmol/rat/d; n=5), or ghrelin (30nmol/rat/d; n=6), or their combination (n=4) for 10 days.

Intravenous Peptide YY3‐36 and Y2 Receptor Antagonism in the Rat: Effects on Feeding Behaviour

Systemic injection of peptide YY3-36 reduces food intake in rodents and humans, although some groups have reported a lack of response. PYY3-36 is thought to act via the Y2 receptor to presynaptically inhibit the release of neuropeptide Y and GABA from hypothalamic arcuate neurones. Due to the controversy surrounding its action in rodents, we tested the peptide intravenously on feeding behaviour in rats and attempted to block its actions with the Y2 receptor antagonist BIIE0246. PYY3-36 significantly decreased food intake during the first hour in male Sprague-Dawley rats fasted overnight and then re-fed. BIIE0246 had no effect alone on re-feeding, but completely blocked the action of PYY3-36. In a second experiment of similar design, the behavioural satiety sequence (BSS) was studied. Normal rats eat, drink, explore and groom before entering rest. PYY3-36 significantly reduced food eaten maintaining the normal BSS, although shifting it to the left as expected for a natural satiety factor. The latency to rest occurred earlier for animals given PYY3-36 alone and PYY3-36 tended to increase the total time in rest compared with controls. These behavioural effects of PYY3-36 were blocked by BIIE0246, and BIIE0246 alone did not have an effect on the BSS. These results support the role of PYY3-36 as a natural satiety factor acting through Y2 receptors.

Suppression of ethanol self-administration by the neuropeptide Y (NPY) Y2 receptor antagonist BIIE0246: evidence for sensitization in rats with a history of dependence

Evidence from genetically modified mice suggests a role for NPY in regulation of ethanol intake, but results of pharmacological studies have been more variable. We have previously shown that potentiation of NPY signaling through antagonism at NPY-Y2 receptors decreases operant responding for ethanol in Wistar rats without a history of dependence. Here, we examined the effects of Y2-antagonism in animals with a history of dependence induced by long-term intermittent exposure to ethanol vapor. The Y2-receptor antagonist BIIE0246 suppressed operant responding for ethanol (approximately 50%, p = 0.01), at a dose (0.5 nmol i.c.v.) which was ineffective in subjects without a history of dependence. Responding for the ethanol-free control solution was unaffected. These data confirm that antagonism at central NPY-Y2 receptors selectively suppresses motivation to self-administer ethanol, and indicate that the NPY system is sensitized in animals with a history of dependence. This may render the NPY system, and Y2 receptors in particular, an attractive target for treatment of alcohol dependence.