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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 9, 2005; DOI: 10.1124/jpet.105.086421

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Received for publication March 16, 2005.
Revised June 3, 2005.
Accepted for publication June 6, 2005.

Hypocretin 1 (Orexin A) Facilitates Inhibitory and Diminishes Excitatory Synaptic Pathways to Cardiac Vagal Neurons in the Nucleus Ambiguus

Olga Dergacheva 1, Xin Wang 1, Zheng-Gui Huang 1, Evguenia Bouairi 1, Christopher Stephens 1, Christopher Gorini 1, David Mendelowitz 1*

1 George Washington University

* Address correspondence to: E-mail: dmendel{at}gwu.edu

Abstract

Hypocretin-1 is a neuropeptide recently shown to be involved in autonomic regulation. Hypocretin-1 is expressed by hypothalamic neurons which project to many regions of the CNS including the nucleus ambiguus. One possible site of action of hypocretin-1 could be cardioinhibitory parasympathetic vagal neurons within the nucleus ambiguus. This study examines whether hypocretin-1 modulates inhibitory and excitatory postsynaptic currents in cardiac vagal neurons in the rat Nucleus Ambiguus. GABAergic, glycinergic, and glutamatergic activity to cardiac vagal neurons were examined using whole-cell patch-clamp recordings in an in vitro brain slice preparation. Hypocretin-1 (1 µM) produced a significant increase in the frequency and amplitude of both GABAergic and glycinergic inhibitory postsynaptic currents and a significant decrease in the frequency of glutamatergic excitatory postsynaptic currents. Application of tetrodotoxin (0.5 µM) blocked all of the responses to hypocretin-1 indicating the changes in neurotransmission with hypocretin-1 do not occur at presynaptic terminals but rather occur at the preceding GABAergic, glycinergic, and glutamatergic neurons that project to cardiac vagal neurons. The increase in GABAergic and glycinergic inhibitory postsynaptic currents, and the decrease in glutamatergic excitatory postsynaptic currents, could be mechanisms by which hypocretin-1 affects heart rate and cardiac function.


Key words: ambiguus, autonomic, brainstem, cardiac, parasympathetic, vagal


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