Neurokinin-1 receptors in the rat nucleus tractus solitarius: pre- and postsynaptic modulation of glutamate and GABA release

Abstract

Neurokinins such as substance P and neurokinin A have long been thought to act as neurotransmitters or modulators in the nucleus tractus solitarius. However, the role and location of the receptors for these peptides have remained unclear. We examined the consequences of activation of the neurokinin-1 (NK 1) receptor subtype in the rat nucleus tractus solitarius using whole-cell patch clamp recordings in brain slices. Application of δ-Ala-Phe-Phe-Pro-MeLeu- d-Pro[spiro-γ-lactam]-Leu-Trp-NH 2 (a specific NK 1 agonist) or neurokinin A resulted in depolarization, evident as a slow inward current, mediated by direct postsynaptic NK 1 receptor activation. The effect was conserved in the presence of tetrodotoxin, and protein kinase C-dependent since it was blocked by 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide, a specific protein kinase C inhibitor. In addition, an increase in the frequency and amplitude of spontaneous excitatory postsynaptic currents was observed, reflecting increased glutamate release induced by NK 1 receptor activation. This effect was abolished by tetrodotoxin, suggesting that it resulted from increased firing in afferent neurons, subsequent to somatodendritic excitation via NK 1 receptors. Furthermore, spontaneous inhibitory postsynaptic currents were increased in frequency and amplitude showing that GABA release was promoted by NK 1 receptor activation. However, amplitude of miniature inhibitory postsynaptic currents was unaltered by NK 1 receptor activation, but the increase in frequency persisted. These findings suggest that NK 1 receptors are located on presynaptic terminals as well as at somatodendritic sites of GABAergic neurons. The increase in GABA release was also shown to be protein kinase C-dependent. The data presented here show NK 1 receptors in the rat nucleus tractus solitarius are present both excitatory and inhibitory neurons. Activation of these receptors can result in increases in release of both GABA and glutamate, suggesting a crucial modulatory role for NK 1 receptors in the rat nucleus tractus solitarius.