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

摘要

Hypocretin-1 is a neuropeptide recently shown to be involved in autonomic regulation. Hypocretin-1 is expressed by hypotha-lamic neurons, which project to many regions of the central nervous system, including the nucleus ambiguus. One possible site of action of hypocretin-1 could be cardioinhibitory para-sympathetic 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 glutamater-gic activity to cardiac vagal neurons was examined using whole-cell patch-clamp recordings in an in vitro brain slice preparation. Hypocretin-1 (1 muM) produced a significant in-crease 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 muM) blocked all of the responses to hypocretin-1, indicating the changes in neurotransmission with hypocretin-1 do not occur at presyn-aptic 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.