Orexin-A Depolarizes Nucleus Tractus Solitarius Neurons Through Effects on Nonselective Cationic and K+ Conductances

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Abstract
The nucleus tractus solitarius (NTS) plays central roles in a number of autonomic functions including cardiovascular control. Orexin (ORX)-A is a 33-amino-acid peptide implicated in the central regulation of energy metabolism, sleep, and the cardiovascular system. Studies demonstrate the presence of ORX-immunoreactive axons and both OX1R (orexin receptor) and OX2R mRNA within NTS. In this study, whole cell patch-clamp recordings were obtained from NTS neurons in rat medullary slices. Current-clamp studies showed that bath application of various concentrations of ORX-A depolarized 90.7% (78 of 86) of neurons tested while the remaining cells were either unaffected or showed small hyperpolarizations in response to peptide administration. Depolarizing effects were maintained in the presence of 5 μM TTX, and were concentration dependent. Using voltage-clamp techniques, we also identified modulatory actions of ORX-A on specific ion channels. Our results demonstrate that not only does ORX-A inhibit a specific potassium conductance (the sustained K+ current) in NTS neurons, but it also activates a nonselective cationic conductance (NSCC). These data suggest that ORX-A effects on central cardiovascular control may result from direct actions on NTS neurons and also highlight the ability of this peptide to influence neuronal excitability as a consequence of concurrent modulation of multiple ion channels.