title: Activation of neurokinin-1 receptors promotes GABA release at synapses in the rat entorhinal cortex.
abstract: We have previously shown that activation of neurokinin-1 receptors reduces acutely provoked epileptiform activity in rat entorhinal cortex in vitro, and suggested that this may result from an increase in GABA release from inhibitory interneurones. In the present study we have made whole cell patch clamp recordings of spontaneous GABA-mediated inhibitory postsynaptic currents as an indicator of GABA release in slices of rat entorhinal cortex, and determined the effects of neurokinin receptor activation on this release. The neurokinin-1 receptor agonists septide and GR73632 provoked a robust increase in the frequency of GABA-mediated currents, and an increase in mean amplitude. The effects were mimicked by substance P, and blocked by a neurokinin-1 receptor antagonist. High concentrations of neurokinin A had similar effects, which were also blocked by the neurokinin-1 receptor antagonist, but agonists at neurokinin-2 or neurokinin-3 receptors were ineffective. The increases in amplitude and frequency of events provoked by septide were prevented by prior blockade of action potential-dependent release with tetrodotoxin. In current clamp recordings from putative interneurones, GR73632 evoked depolarisation and a prolonged discharge of action potentials. Finally, recordings from pyramidal neurones and oriens-alveus interneurones in CA1 of the hippocampus showed that application of GR73632 caused an increase in frequency and amplitude of GABA-mediated inhibitory postsynaptic currents in the former and persistent firing of action potentials in the latter. The results demonstrate that neurokinin-1 receptor activation promotes the release of GABA at synapses on principal neurones in both entorhinal cortex and hippocampus. The abolition of this effect by tetrodotoxin and the excitatory responses seen in interneurones clearly suggest that the neurokinin-1 receptor is localised on the soma-dendritic domain of the inhibitory neurones. Thus, substance P inputs to inhibitory neurones may have a widespread influence on cortical network excitability and could play a role in epileptogenesis and its control.
authors.affiliation: Department of Physiology and MRC Centre for Synaptic Plasticity, School of Medical Sciences, University of Bristol, University Walk, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Stacey
authors.forename: G L
authors.initials: GL
authors.lastname: Woodhall
authors.forename: R S G
authors.initials: RS
authors.lastname: Jones
mesh_terms: D000818:Animals; D018728:Entorhinal Cortex / Q000166:cytology / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007395:Interneurons / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D015288:Neurokinin A / Q000494:pharmacology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D005680:gamma-Aminobutyric Acid; D015288:Neurokinin A