Lateral hypothalamic NMDA receptor subunits NR2A and/or  NR2B mediate eating: immunochemical/behavioral evidence

Cells within the lateral hypothalamic area (LHA) are important in eating control. Glutamate or its analogs, kainic acid (KA) and N-methyl-d-aspartate (NMDA), elicit intense eating when microinjected there, and, conversely, LHA-administered NMDA receptor antagonists suppress deprivation- and NMDA-elicited eating. The subunit composition of LHA NMDA receptors (NMDA-Rs) mediating feeding, however, has not yet been determined. Identifying this is important, because distinct second messengers/modulators may be activated by NMDA-Rs with differing compositions. To begin to address this, we detected LHA NR2A and NR2B subunits by immunoblotting and NR2B subunits by immunohistochemistry using subunit-specific antibodies. To help determine whether NMDA-Rs mediating feeding might contain these subunits, we conducted behavioral studies using LHA-administered ifenprodil, an antagonist selective for NR2A- and/or NR2B-containing NMDA-Rs at the doses we used (0.001–100 nmol). Ifenprodil maximally suppressed NMDA- and deprivation-elicited feeding by 63 and 39%, respectively, but failed to suppress KA-elicited eating, suggesting its actions were behaviorally specific. Collectively, these results suggest that LHA NMDA-Rs, some of which contribute to feeding control, are composed of NR2A and/or NR2B subunits, and implicate NR2A- and/or NR2B-linked signal transduction in feeding behavior.

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N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in the Treatment of Experimental Brain Injury: 31P Magnetic Resonance Spectroscopy and Behavioral Studies

Intracranial Pressure VII ◽

10.1007/978-3-642-73987-3_150 ◽

1989 ◽

pp. 581-583 ◽

Cited By ~ 1

Author(s):

T. K. McIntosh ◽

R. Vink ◽

H. Soares ◽

R. Simon

Keyword(s):

Brain Injury ◽

Nmda Receptor ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Resonance Spectroscopy ◽

Nmda Receptor Antagonists ◽

Receptor Antagonists ◽

31P Magnetic Resonance Spectroscopy ◽

Behavioral Studies

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Differences in effects of NMDA receptor antagonists in BARR2-KO mice

10.26226/morressier.5785edc6d462b80296c993e7 ◽

2016 ◽

Author(s):

Ilia Sukhanov

Keyword(s):

Nmda Receptor ◽

Nmda Receptor Antagonists ◽

Receptor Antagonists

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Application of Real-World Data and the REWARD Framework to Detect Unknown Benefits of Memantine and Identify Potential Disease Targets for New NMDA Receptor Antagonists

CNS Drugs ◽

10.1007/s40263-020-00789-3 ◽

2021 ◽

Vol 35 (2) ◽

pp. 243-251

Author(s):

David M. Kern ◽

M. Soledad Cepeda ◽

Christopher M. Flores ◽

Gayle M. Wittenberg

Keyword(s):

Nmda Receptor ◽

Real World ◽

Nmda Receptor Antagonists ◽

Receptor Antagonists ◽

Real World Data ◽

World Data

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Use of Both Fluoro-Jade B and Hematoxylin and Eosin to Detect Cell Death in the Juvenile Rat Brain Exposed to NMDA-Receptor Antagonists or GABA-Receptor Agonists in Safety Assessment

Toxicologic Pathology ◽

10.1177/01926233211007735 ◽

2021 ◽

pp. 019262332110077

Author(s):

Catherine A. Picut ◽

Odete R. Mendes ◽

David S. Weil ◽

Sarah Davis ◽

Cynthia Swanson

Keyword(s):

Cell Death ◽

Nmda Receptor ◽

Rat Brain ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Nmda Receptor Antagonists ◽

Neonatal Rats ◽

Receptor Antagonists ◽

Fluoro Jade B ◽

Hematoxylin And Eosin

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

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Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2011 ◽

2011 ◽

Vol 301 (2) ◽

pp. R448-R455 ◽

Cited By ~ 25

Author(s):

Jason Wright ◽

Carlos Campos ◽

Thiebaut Herzog ◽

Mihai Covasa ◽

Krzysztof Czaja ◽

...

Keyword(s):

Nmda Receptor ◽

Food Intake ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Fourth Ventricle ◽

Nmda Receptor Antagonist ◽

Behavioral Pattern ◽

Vagal Afferents ◽

Nmda Receptor Antagonists ◽

The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

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Neurons in the lateral hypothalamic area and zona incerta with ascending projections to the subfornical organ area in the rat

Brain Research ◽

10.1016/0006-8993(88)90247-8 ◽

1988 ◽

Vol 456 (2) ◽

pp. 397-400 ◽

Cited By ~ 14

Author(s):

Junichi Tanaka ◽

Katsuo Seto

Keyword(s):

Subfornical Organ ◽

Lateral Hypothalamic Area ◽

Zona Incerta ◽

Hypothalamic Area ◽

Lateral Hypothalamic

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Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707752114 ◽

2017 ◽

Vol 114 (33) ◽

pp. E6942-E6951 ◽

Cited By ~ 18

Author(s):

Genevieve E. Lind ◽

Tung-Chung Mou ◽

Lucia Tamborini ◽

Martin G. Pomper ◽

Carlo De Micheli ◽

...

Keyword(s):

Nmda Receptor ◽

Binding Affinity ◽

Binding Mode ◽

Structural Basis ◽

Nmda Receptor Antagonists ◽

Receptor Antagonists ◽

Glutamate Binding ◽

Subunit Interface ◽

The Central Nervous System ◽

Contact Residues

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

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