Cell type‐specific postsynaptic effects of neuropeptide Y in substantia gelatinosa neurons of the rat spinal cord

Melnick, Igor V.

doi:10.1002/syn.21550

Cited by 14 publications

(33 citation statements)

References 52 publications

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“…Neur opeptide Y (NPY) exerts its functions via a family of Gprotein-coupled receptor subtypes (1)(2)(3). Of particular interest are the NPY type 2 (NPY2) receptors, found primarily in corticolimbic regions, with particular high densities in the hippocampus of several species including human (4).…”

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confidence: 99%

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs

et al. 2014

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Neuropeptide Y2 (NPY2) receptors are implicated in diverse brain disorders, but no suitable PET radiotracers are currently available for studying NPY2 receptors in the living brain. We developed a novel positron-emitting radioligand based on the NPY2 receptor antagonist JNJ-31020028 (N-(4-(4-[2-(diethylamino)-2-oxo-1-phenylethyl] piperazin-1-yl)-3-fluorophenyl)-2-pyridin-3-ylbenzamide) and used the radiotracer for PET brain imaging in pigs. Methods: In vitro receptor autoradiography studies were performed to establish the anatomic distribution of NPY2 receptors in the pig brain. In vivo, baseline 90-min PET recordings of N-11 C-methyl-JNJ-31020028 were conducted in anesthetized Yorkshire x Landrace pigs, concurrent with arterial blood sampling. Postchallenge scans were conducted after injection of unlabeled JNJ-31020028 as a pharmacologic intervention. Cyclosporine A was used to enhance levels of the PET radiotracer in the brain. The PET images were manually coregistered to a MR imaging atlas of the pig brain. Maps of the N-11 C-methyl-JNJ-31020028 volume of distribution in the brain were prepared, and regional binding potentials of NPY2 receptors toward the radio-ligand were calculated using the simplified reference tissue method. Results: In autoradiography studies, N-11 C-methyl-JNJ-31020028 receptor binding sites were observed primarily in the hippocampus and were inhibited by unlabeled JNJ-31020028. In PET studies, N-11 C-methyl-JNJ-31020028 was metabolized slowly in the bloodstream , with 25% of the 11 C-labeled parent compound remaining 30 min after injection. PET imaging showed baseline binding potentials of 0.64 ± 0.07 in the thalamus, 0.55 ± 0.02 in the caudate, and 0.49 ± 0.03 in the hippocampus. Graphical reference region analyses demonstrated that N-11 C-methyl-JNJ-31020028 binding was reversible; infusion of unlabeled JNJ-31020028 markedly displaced the PET radioligand from binding sites in the hippocampus, thalamus, caudate nucleus, and cerebellum but not in the corpus callosum, which served as reference region for nonspecific binding. Conclusion: N-11 C-methyl-JNJ-31020028 has several suitable properties for PET neuroimaging of NPY2 receptors. First, it is metabolized slowly in the bloodstream of pigs. Second, using cyclosporine, the target-to-background ratio of N-11 C-methyl-JNJ-31020028 is sufficient for estimating pharmacokinetic parameters. Third, N-11 C-methyl-JNJ-31020028 binds reversibly and competitively to cerebral sites known to contain relatively high numbers of NPY2 receptors, such as the hippocampus, thalamus, caudate nucleus, and cerebellum. Fourth, white matter such as corpus callosum, known to contain negligible numbers of NPY2 receptors, can serve as a reference region for estimating binding potentials in brain regions. To our knowledge, there is no other radioligand with these favorable properties and with this specificity for NPY2 receptors, which makes N-11 C-methyl-JNJ-31020028 the first candidate radioligand for PET investigations of NPY2 receptors in the living brain.

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confidence: 99%

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs

et al. 2014

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“…3, A, D, and E). Barium is a known blocker of inwardly rectifying potassium channels, including GIRK channels (Lesage et al 1995;Yamada et al 1998), and it has been shown to block NPY-induced GIRK currents in many different central nervous system neurons (Acuna-Goycolea et al 2005;Fu et al 2004;Melnick 2012;Roseberry et al 2004;Sosulina et al 2008;Sun et al 2001). Extracellular barium reversed and blocked the NPY current along with a basal leak current in VTA dopamine neurons (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Previous studies have reported that the postsynaptic effects of NPY are mediated by NPY acting on Y1 and Y2 receptors (Acuna-Goycolea et al 2005;Fu et al 2004;Melnick 2012;Roseberry et al 2004;Sosulina et al 2008;Sun et al 2001). We initially tested whether Y1 receptors (Y1R) mediated this effect using the Y1R antagonist BIBP3226 (Acuna-Goycolea et al 2005;Fu et al 2004;Melnick 2012;Roseberry et al 2004;Sosulina et al 2008;Sun et al 2001). BIBP3226 (1 M) reversed the NPY-induced current when it was applied at the peak of the NPY current (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to directly inhibiting VTA dopamine neurons, it is possible that NPY could regulate the activity of dopamine neurons indirectly through modulation of their afferent inputs. Glutamatergic and GABAergic afferent inputs are important regulators of dopamine neuron activity (Grace et al 2007;Morikawa and Paladini 2011;Paladini and Roeper 2014), and NPY has been shown to affect glutamatergic and GABAergic transmission in other areas of the CNS (Acuna-Goycolea et al 2005;Fu et al 2004;Melnick 2012;Molosh et al 2013). Thus we next examined whether NPY altered glutamatergic inputs to dopamine neurons.…”

Section: Resultsmentioning

confidence: 99%

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Neuropeptide-Y alters VTA dopamine neuron activity through both pre- and postsynaptic mechanisms

West

Roseberry

2017

Journal of Neurophysiology

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The mesocorticolimbic dopamine system, the brain's reward system, regulates many different behaviors including food intake, food reward, and feeding-related behaviors, and there is increasing evidence that hypothalamic feeding-related neuropeptides alter dopamine neuron activity to affect feeding. For example, neuropeptide-Y (NPY), a strong orexigenic hypothalamic neuropeptide, increases motivation for food when injected into the ventral tegmental area (VTA). How NPY affects the activity of VTA dopamine neurons to regulate feeding behavior is unknown, however. In these studies we have used whole cell patch-clamp electrophysiology in acute brain slices from mice to examine how NPY affects VTA dopamine neuron activity. NPY activated an outward current that exhibited characteristics of a G protein-coupled inwardly rectifying potassium channel current in ~60% of dopamine neurons tested. In addition to its direct effects on VTA dopamine neurons, NPY also decreased the amplitude and increased paired-pulse ratios of evoked excitatory postsynaptic currents in a subset of dopamine neurons, suggesting that NPY decreases glutamatergic transmission through a presynaptic mechanism. Interestingly, NPY also strongly inhibited evoked inhibitory postsynaptic currents onto dopamine neurons by a presynaptic mechanism. Overall these studies demonstrate that NPY utilizes multiple mechanisms to affect VTA dopamine neuron activity, and they provide an important advancement in our understanding of how NPY acts in the VTA to control feeding behavior. Neuropeptide-Y (NPY) has been shown to act on mesolimbic dopamine circuits to increase motivated behaviors toward food, but it is unclear exactly how NPY causes these responses. Here, we demonstrate that NPY directly inhibited a subset of ventral tegmental area (VTA) dopamine neurons through the activation of G protein-coupled inwardly rectifying potassium currents, and it inhibited both excitatory postsynaptic currents and inhibitory postsynaptic currents onto subsets of dopamine neurons through a presynaptic mechanism. Thus NPY uses multiple mechanisms to dynamically control VTA dopamine neuron activity.

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“…Such a steroid-induced switch has been described for adrenergic signaling in the VMH (Etgen et al, 2001). In the presence of estradiol, GABA B receptor signaling may change NPY-Y1 receptor coupling, which is nominally inhibitory (Klenke et al, 2010; Melnick, 2012). Alternatively, estradiol may directly mediate VGCC (Bray and Mynlieff, 2011; Park et al, 2010; Rhim and Miller, 1994), or induce G-protein activation of PKC (Dewing et al, 2008) and PKA that enhance L-type VGCC currents (Bray and Mynlieff, 2011; Park et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Modulation of the arcuate nucleus–medial preoptic nucleus lordosis regulating circuit: A role for GABAB receptors

Sinchak

Dewing²,

Ponce

et al. 2013

Hormones and Behavior

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Estradiol rapidly activates a microcircuit in the arcuate nucleus of the hypothalamus (ARH) that is needed for maximal female sexual receptivity. Membrane estrogen receptor-α complexes with and signals through the metabotropic glutamate receptor-1a stimulating NPY release within the ARH activating proopiomelanocortin (POMC) neurons. These POMC neurons project to the medial preoptic nucleus (MPN) and release β-endorphin. Estradiol treatment induces activation/ internalization of MPN μ-opioid receptors (MOR) to inhibit lordosis. Estradiol membrane action modulates ARH gamma-aminobutyric acid receptor-B (GABA B ) activity. We tested the hypothesis that ARH GABA B receptors mediate estradiol-induced MOR activation and facilitation of sexual receptivity. Double label immunohistochemistry revealed expression of GABA B receptors in NPY, ERα and POMC expressing ARH neurons. Approximately 70% of POMC neurons expressed GABA B receptors. Because estradiol initially activates an inhibitory circuit and maintains activation of this circuit, the effects of blocking GABA B receptors were evaluated before estradiol benzoate (EB) treatment and after at the time of lordosis testing. Bilateral infusions of the GABA B receptor antagonist, CGP52432, into the ARH prior to EB treatment of ovariectomized rats prevented estradiol-induced activation/internalization of MPN MOR, and the rats remained unreceptive. However, in EB treated rats, bilateral CGP52432 infusions 30 minutes before behavior testing attenuated MOR internalization and facilitated lordosis. These results indicated that GABA B receptors were located within the lordosis-regulating ARH microcircuit and are necessary for activation and maintenance of the estradiol inhibition of lordosis behavior. Although GABA B receptors positively influence estradiol signaling, they negatively regulate lordosis behavior since GABA B activity maintains the estradiol-induced inhibition.

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Cell type‐specific postsynaptic effects of neuropeptide Y in substantia gelatinosa neurons of the rat spinal cord

Cited by 14 publications

References 52 publications

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs

Neuropeptide-Y alters VTA dopamine neuron activity through both pre- and postsynaptic mechanisms

Modulation of the arcuate nucleus–medial preoptic nucleus lordosis regulating circuit: A role for GABAB receptors

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Cell type‐specific postsynaptic effects of neuropeptide Y in substantia gelatinosa neurons of the rat spinal cord

Cited by 14 publications

References 52 publications

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-11C-Methyl-JNJ-31020028 in Pigs

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-11C-Methyl-JNJ-31020028 in Pigs

Neuropeptide-Y alters VTA dopamine neuron activity through both pre- and postsynaptic mechanisms

Modulation of the arcuate nucleus–medial preoptic nucleus lordosis regulating circuit: A role for GABAB receptors

Contact Info

Product

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About

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs

PET Brain Imaging of Neuropeptide Y2 Receptors Using N-¹¹C-Methyl-JNJ-31020028 in Pigs