Localization and function of NK(3) subtype tachykinin receptors of layer V pyramidal neurons of the guinea-pig medial prefrontal cortex.
The NK(3) subtype of tachykinin receptor has been implicated as a modulator of synaptic transmission in several brain regions, including the cerebral cortex. The localization and expression of NK(3) receptors within the brain vary from species to species. In addition, the pharmacology of NK(3) receptor-specific antagonists shows significant species variability. Among commonly used animal models, the pharmacology of the guinea-pig NK(3) receptor most closely resembles that of the human NK(3) receptor. Here, we provide anatomical localization studies, receptor binding studies, and studies of the electrophysiological effects of NK(3) receptor ligands of guinea-pig cortex using two commercially available ligands, the NK(3) receptor peptide analog agonist senktide, and the quinolinecarboxamide NK(3) receptor antagonist SB-222,200. Saturation binding studies with membranes isolated from guinea-pig cerebral cortex showed saturable binding consistent with a single high affinity site. Autoradiographic studies revealed dense specific binding in layers II/III and layer V of the cerebral cortex. For electrophysiological studies, brain slices were prepared from prefrontal cortex of 3- to 14-day-old guinea pigs. Whole cell recordings were made from layer V pyramidal neurons. In current clamp mode with a K(+)-containing pipette solution, senktide depolarized the pyramidal neurons and led to repetitive firing of action potentials. In voltage clamp mode with a Cs(+)-containing pipette solution, senktide application produced an inward current and a concentration-dependent enhancement of the amplitude and the frequency of spontaneous excitatory postsynaptic potentials. The glutamatergic nature of these events was demonstrated by block by glutamate receptor antagonists. The effects of senktide were blocked by SB-222,200, an NK(3) receptor antagonist. Taken together, these results are consistent with a functional role for NK(3) receptors located on neurons in the cerebral cortex. In layer V pyramidal neurons of the medial prefrontal cortex, activation of the NK(3) receptor system plays an excitatory role in modulating synaptic transmission.
Simmons
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Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA. simmons@neoucom.edu
Sobotka-Briner
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Medd
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D000818:Animals; D001345:Autoradiography / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000528:radiation effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology*; D011485:Protein Binding / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D007456:Iodine Isotopes; D010446:Peptide Fragments; D011804:Quinolines; D011810:Quinoxalines; D018042:Receptors, Neurokinin-3; C109112:SB 222200; C080394:neurokinin B, MePhe(7)-; C054724:senktide; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D013373:Substance P; C056639:2-amino-5-phosphopentanoic acid; D015287:Neurokinin B; D014633:Valine