Neurokinins Activate Local Glutamatergic Inputs to Serotonergic Neurons of the Dorsal Raphe Nucleus

Abstract

It has been proposed that antidepressant effects of neurokinin NK1 receptor blockade may result from an increase in serotonin (5-HT) transmission. However, the mechanism by which neurokinins influence 5-HT neurons is not known. In this study, local NK1 and NK3 receptor-mediated responses in 5-HT neurons of the dorsal raphe nucleus (DRN) were studied using intracellular recording in rat brain slices. Bath application of the NK1 receptor agonist substance P (SP) or the NK3 receptor agonists senktide and NKB induced a robust increase in “spontaneous” excitatory postsynaptic currents (EPSCs) in 5-HT neurons. The EPSCs were blocked by the AMPA/kainate glutamate receptor antagonist CNQX and the fast Na+ channel blocker tetrodotoxin (TTX), indicating that the increase in EPSCs resulted from an increase in impulse flow in local glutamatergic neuronal afferents. The neurokinins agonists had no direct excitatory effects on 5-HT neurons and no NK1 or NK3 receptor immunolabeling was found in 5-HT–labeled neurones. However, neurokinins, by increasing excitatory postsynaptic potentials (EPSPs), did increase the spiking of 5-HT neurons. The SP- and NKB-induced EPSCs were preferentially blocked by NK1 and NK3 antagonists, and there was minimal cross-desensitization between agonists at the two receptors. We conclude that neurokinins, via distinct NK1 and NK3 receptors, could promote 5-HT transmission, at least in part, by exciting a local population of glutamatergic inputs to 5-HT neurons in the DRN. However, these local excitatory effects, viewed within the context of the global effects of neurokinins on 5-HT neurons, reveal important differences between the functional role of NK1 and NK3 receptors.