Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors

Woldbye, David P. D.; Nanobashvili, Avtandil; Sørensen, Andreas T.; Husum, Henriette; Bolwig, Tom G.; Sørensen, Gunnar; Ernfors, Patrik; Kokaia, Mérab

doi:10.1016/j.nbd.2005.05.010

Cited by 53 publications

(58 citation statements)

References 64 publications

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“…4 E). Finally, activation of NPY Y 5 receptors may mediate inhibitory effects in the hippocampus as well (Woldbye et al, 2005), although another study did not confirm inhibitory effects of Y 5 receptors in the hippocampus (El Bahh et al, 2005). Also, binding studies show that Y 5 receptor subtype is preferentially expressed in the ventral hippocampus (Dumont et al, 1998).…”

Section: Npy Is Involved In ␤-Estradiol-induced Enhancement Of Pairedmentioning

confidence: 94%

“…Similar cleaning procedures for the tubing and the chamber were used as described above. To determine the role of Y 1 , Y 2 , and Y 5 NPY receptors, the following specific antagonists to individual NPY receptors were bath applied for at least 30 min before recording: 100 (El Bahh et al, 2002;Tu et al, 2005) (Y 2 receptor antagonist; 30 nM, n ϭ 8; 100 nM, n ϭ 6), and 250 nM 5,5-dimethyl-2-(2,3,4,9-tetrahydro-3,3-dimethyl-1 oxo-1H-xanthen-9-yl)-1,3-cyclohexanedione (L-152,804) (Woldbye et al, 2005) (Y 5 receptor antagonist; n ϭ 5). To determine the role of GABA B receptors in the ␤-estradiol-induced enhancement of the late paired-pulse inhibition, 400 M (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) (Velíšek and Velíšková, 2002) was bath applied for at least 30 min before recordings (n ϭ 10).…”

Section: Methodsmentioning

confidence: 99%

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β-Estradiol Increases Dentate Gyrus Inhibition in Female Rats via Augmentation of Hilar Neuropeptide Y

Velı́šková

Velı́šek²

2007

J. Neurosci.

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The dentate gyrus filters incoming activity into the hippocampus proper. It plays a role in learning and memory and in pathological states such as epilepsy. Some of hilar interneurons of the dentate gyrus express neuropeptide Y (NPY), which modulates granule cell activity. A subpopulation of the NPY-expressing inhibitory interneurons is sensitive to seizure-induced damage. Pretreatment with ␤-estradiol in ovariectomized rats protects hilar interneurons against seizure-induced injury, including the NPY-containing damage-sensitive subpopulation. Here, we demonstrate that ␤-estradiol enhances NPY expression within the hilar interneurons. In vitro paired-pulse stimulation of the mixed perforant path revealed ␤-estradiol-induced augmentation of granule cell network inhibition, which at interstimulus intervals between 200 and 300 ms (corresponding to ϳ3-5 Hz) was NPY sensitive and involved Y 1 receptors, whereas it was insensitive to GABA B or metabotropic glutamate receptor antagonists. Additionally, ␤-estradiol pretreatment attenuated propagation of lowfrequency (3.3 or 5 Hz) burst activity through the dentate gyrus. Scavenging endogenous NPY by intracerebroventricular administration of anti-NPY antibody accelerated kainic acid-induced seizure onset and increased seizure-induced neuronal damage in the hilus compared with rats treated with ␤-estradiol alone. Together, we show that ␤-estradiol upregulates hilar NPY and that this leads to enhancement in dentate gyrus inhibition of incoming frequencies between 3 and 5 Hz. Such frequencies are similar to the discharge frequencies recorded during seizure initiation in some patients with epilepsy. Thus, ␤-estradiol-induced NPY-sensitive filtering of 3-5 Hz frequencies may be an important regulator of incoming seizure activity, but it could also serve a physiological purpose in modulating information flow into the hippocampus proper.

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Section: Npy Is Involved In ␤-Estradiol-induced Enhancement Of Pairedmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

β-Estradiol Increases Dentate Gyrus Inhibition in Female Rats via Augmentation of Hilar Neuropeptide Y

Velı́šková

Velı́šek²

2007

J. Neurosci.

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“…induced seizures (21,23,24,36,37). The Y1, Y2, and Y5 receptor are also expressed by macrophages, with different functions for these receptors in the macrophage response to NPY (11).…”

Section: Fig 9 Influence Of Npy Deficiency On Virus Levels In the Cmentioning

confidence: 99%

Neuropeptide Y Has a Protective Role during Murine Retrovirus-Induced Neurological Disease

Butchi

Woods

et al. 2010

J Virol

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Viral infections in the central nervous system (CNS) can lead to neurological disease either directly by infection of neurons or indirectly through activation of glial cells and production of neurotoxic molecules.Understanding the effects of virus-mediated insults on neuronal responses and neurotrophic support is important in elucidating the underlying mechanisms of viral diseases of the CNS. In the current study, we examined the expression of neurotrophin-and neurotransmitter-related genes during infection of mice with neurovirulent polytropic retrovirus. In this model, virus-induced neuropathogenesis is indirect, as the virus predominantly infects macrophages and microglia and does not productively infect neurons or astrocytes. Virus infection is associated with glial cell activation and the production of proinflammatory cytokines in the CNS. In the current study, we identified increased expression of neuropeptide Y (NPY), a pleiotropic growth factor which can regulate both immune cells and neuronal cells, as a correlate with neurovirulent virus infection. Increased levels of Npy mRNA were consistently associated with neurological disease in multiple strains of mice and were induced only by neurovirulent, not avirulent, virus infection. NPY protein expression was primarily detected in neurons near areas of virus-infected cells. Interestingly, mice deficient in NPY developed neurological disease at a faster rate than wild-type mice, indicating a protective role for NPY. Analysis of NPY-deficient mice indicated that NPY may have multiple mechanisms by which it influences virus-induced neurological disease, including regulating the entry of virus-infected cells into the CNS.

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“…Central administration of NPY promotes feeding behavior, reduces cerebrocortical excitability, reduces anxiety and potentiates the sedative and hypnotic effects of certain drugs (166)(167)(168)(169). NPY is overall an inhibitory peptide and regulates neuronal hyperexcitability by suppressing hippocampal glutamatergic transmission (170)(171)(172). Previous studies have revealed that NPY has a major role in the pathophysiology of mood disorders including anxiety and depression and this has been associated with downregulation of NPY in animal models and in human depressed patients (173,174).…”

Section: Neuropeptide Ymentioning

confidence: 99%

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

Aziz¹

2017

Linköping University Medical Dissertations

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Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol-seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced "hangover" anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stressinduced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats. Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for...

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Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors

Cited by 53 publications

References 64 publications

β-Estradiol Increases Dentate Gyrus Inhibition in Female Rats via Augmentation of Hilar Neuropeptide Y

β-Estradiol Increases Dentate Gyrus Inhibition in Female Rats via Augmentation of Hilar Neuropeptide Y

Neuropeptide Y Has a Protective Role during Murine Retrovirus-Induced Neurological Disease

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

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