title: Benzodiazepine inhibits hypothalamic presympathetic neurons by potentiation of GABAergic synaptic input.
abstract: Presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus receive inputs from gamma-aminobutyric acid (GABA)-containing neurons, which regulate sympathetic outflow and cardiovascular function. Benzodiazepines can decrease blood pressure and sympathetic nerve activity when used for induction of anesthesia, but the sites and mechanisms of action are uncertain. In this study, we determined the effect of the benzodiazepine agonist diazepam on GABAergic inhibitory postsynaptic currents (IPSCs) and the firing activity of rostral ventrolateral medulla (RVLM)-projecting PVN neurons. RVLM-projecting PVN neurons were retrogradely labeled by fluorescent microspheres injected into the RVLM in rats. Whole-cell and cell-attached recordings were performed on labeled PVN neurons in the hypothalamic brain slice. Bath application of 1-10 microM diazepam significantly increased the decay time constants of the GABAergic miniature IPSCs and evoked IPSCs in a dose-dependent manner. Also, diazepam significantly increased the amplitude of evoked IPSCs but not of miniature IPSCs. Pretreatment with the benzodiazepine antagonist flumazenil completely blocked the diazepam-induced increases in the amplitude and decay time constants of the evoked IPSCs. Furthermore, diazepam significantly decreased the firing activity of PVN-RVLM neurons that responded with increased firing to the GABA(A) receptor antagonist bicuculline. In contrast, diazepam had no significant effect on the firing activity of bicuculline-unresponsive PVN-RVLM neurons. This study provides new information that the benzodiazepine suppresses the firing activity of PVN presympathetic neurons by potentiation of GABAergic inputs.
authors.affiliation: Department of Anesthesiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Zahner
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Li
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018757:GABA Modulators / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018757:GABA Modulators; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D003975:Diazepam