ABSTRACT
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.
Subject(s)
Prefrontal Cortex/cytology , Pyramidal Cells/metabolism , Receptors, Neurokinin-3/metabolism , Animals , Autoradiography/methods , Dose-Response Relationship, Drug , Drug Interactions , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/radiation effects , Guinea Pigs , In Vitro Techniques , Iodine Isotopes/pharmacokinetics , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Neurokinin B/analogs & derivatives , Neurokinin B/pharmacokinetics , Patch-Clamp Techniques , Peptide Fragments/pharmacology , Protein Binding/drug effects , Pyramidal Cells/drug effects , Quinolines/pharmacology , Quinoxalines/pharmacology , Receptors, Neurokinin-3/agonists , Receptors, Neurokinin-3/antagonists & inhibitors , Substance P/analogs & derivatives , Substance P/pharmacology , Valine/analogs & derivatives , Valine/pharmacologyABSTRACT
Degeneration of cochlear neurons is the most commonly observed cellular change in the aging human and gerbil cochlea. Although it is unclear what leads to this neuronal loss, changes in the production of target-derived trophic factors may be the ultimate cause of cochlear neuron degeneration. The present study used an enzyme-linked immunosorbent assay to investigate whether BDNF is produced by the organ of Corti or cochlear ganglia of young, middle aged, or aged gerbils. The results revealed an age-related increase in BDNF in the organ of Corti, but not in the cochlear ganglia.
