title: Hypocretin-1 (orexin-A) facilitates inhibitory and diminishes excitatory synaptic pathways to cardiac vagal neurons in the nucleus ambiguus.
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 central nervous system, 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 was examined using whole-cell patch-clamp recordings in an in vitro brain slice preparation. Hypocretin-1 (1 microM) 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 microM) 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.
authors.affiliation: Department of Pharmacology, George Washington University, Washington, DC 20037, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Dergacheva
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Zheng-Gui
authors.initials: ZG
authors.lastname: Huang
authors.forename: Evguenia
authors.initials: E
authors.lastname: Bouairi
authors.forename: Christopher
authors.initials: C
authors.lastname: Stephens
authors.forename: Chistopher
authors.initials: C
authors.lastname: Gorini
authors.forename: David
authors.initials: D
authors.lastname: Mendelowitz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D006321:Heart / Q000294:innervation*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008526:Medulla Oblongata / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects*; D009479:Neuropeptides / Q000494:pharmacology*; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D005680:gamma-Aminobutyric Acid