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Multiple Types of GABA_A Receptors Mediate Inhibition in Brain Stem Parasympathetic Cardiac Neurons In the Nucleus Ambiguus

Department of Pharmacology and Physiology, The George Washington University, Washington, DC

Submitted 6 June 2006; accepted in final form 8 August 2006

Recent work suggests neurons can have different types of -aminobutyric acid type A (GABA_A) receptors that mediate phasic inhibitory postsynaptic currents (IPSCs) and tonic currents. This study examines the diversity of GABAergic synaptic currents in parasympathetic cardioinhibitory neurons that receive rhythmic bursts of GABAergic neurotransmission. Focal application of gabazine (25 µM) to cardiac vagal neurons in vitro did not change the frequency of firing in spontaneously active neurons or the resting membrane potential; however, picrotoxin (100 µM) significantly depolarized cardiac vagal neurons and increased their firing. Similarly, gabazine (25 µM) selectively blocked GABAergic IPSCs but did not change holding current in cardiac vagal neurons, whereas picrotoxin (100 µM) not only blocked GABAergic IPSCs but also rapidly decreased the tonic current. Because the tonic current could be attributable to activation of GABA receptors by ambient GABA or, alternatively, spontaneous opening of constitutively active GABA channels, an antagonist for the GAT-1 GABA transporter NO-711 (10 µM) was applied to distinguish between these possibilities. NO-711 did not significantly alter the holding current in these neurons. The benzodiazepine flunitrazepam (1 µM) significantly increased the tonic current and GABAergic IPSC decay time; surprisingly, however, in the presence of gabazine flunitrazepam failed to elicit any change. These results suggest cardiac vagal neurons possess gabazine-sensitive GABA_A receptors that mediate phasic synaptic currents, a gabazine-insensitive but picrotoxin-sensitive extrasynaptic tonic current that when blocked depolarizes and increases the firing rate of cardiac vagal neurons, and benzodiazepines recruit a third type of GABA_A receptor that is sensitive to gabazine and augments the extrasynaptic tonic current.

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