title: Endogenous acetylcholine and nicotine activation enhances GABAergic and glycinergic inputs to cardiac vagal neurons.
abstract: The heart slows during expiration and heart rate increases during inspiration. This cardiorespiratory interaction is thought to occur by increased inhibitory synaptic events to cardiac vagal neurons during inspiration. Since cholinergic receptors have been suggested to be involved in this cardiorespiratory interaction, we tested whether endogenous cholinergic activity modulates GABAergic and glycinergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus, whether nicotine can mimic this facilitation, and we examined the nicotinic receptors involved. Cardiac vagal neurons in the rat were labeled with a retrograde fluorescent tracer and studied in an in vitro slice using patch-clamp techniques. Application of neostigmine (10 microM), an acetylcholinerase inhibitor, significantly increased the frequency of both GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) in cardiac vagal neurons. Exogenous application of nicotine increased the frequency and amplitude of both GABAergic and glycinergic IPSCs. The nicotinic facilitation of both GABAergic and glycinergic IPSCs were insensitive to 100 nM alpha-bungarotoxin but were abolished by dihydro-beta-erythrodine (DHbetaE) at a concentration (3 microM) specific for alpha4beta2 nicotinic receptors. In the presence of TTX, nicotine increased the frequency of GABAergic and glycinergic miniature synaptic events, which were also abolished by DHbetaE (3 microM). This work demonstrates that there is endogenous cholinergic facilitation of GABAergic and glycinergic synaptic inputs to cardiac vagal neurons, and activation of alpha4beta2 nicotinic receptors at presynaptic terminals facilitates GABAergic and glycinergic neurotransmission to cardiac vagal neurons. Nicotinic facilitation of inhibitory neurotransmission to premotor cardiac parasympathetic neurons may be involved in generating respiratory sinus arrhythmia.
authors.affiliation: Department of Pharmacology, George Washington University, Washington, DC 20037, USA.
authors.forename: Jijiang
authors.initials: J
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Mustapha
authors.initials: M
authors.lastname: Irnaten
authors.forename: Priya
authors.initials: P
authors.lastname: Venkatesan
authors.forename: Cory
authors.initials: C
authors.lastname: Evans
authors.forename: Sunit
authors.initials: S
authors.lastname: Baxi
authors.forename: David
authors.initials: D
authors.lastname: Mendelowitz
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005456:Fluorescent Dyes; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000502:physiology*; D018684:Glycine Agents / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D009388:Neostigmine / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D010852:Picrotoxin / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D013331:Strychnine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve / Q000166:cytology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D015763:2-Amino-5-phosphonovalerate; D000109:Acetylcholine; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D018756:GABA Antagonists; D005998:Glycine; D018684:Glycine Agents; D009388:Neostigmine; D009538:Nicotine; D018722:Nicotinic Agonists; D010852:Picrotoxin; D011724:Pyridazines; D013331:Strychnine; D005680:gamma-Aminobutyric Acid; C049853:gabazine