title: Modulation of inhibitory and excitatory fast neurotransmission in the rat CNS by heavy water (D2O).
abstract: The effects of heavy water (deuterium oxide, D2O) on GABAergic and glutamatergic spontaneous and evoked synaptic transmission were investigated in acute brain slice and isolated "synaptic bouton" preparations of rat hippocampal CA3 neurons. The substitution of D2O for H2O reduced the frequency and amplitude of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration-dependent manner but had no effect on glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, for evoked synaptic responses in isolated neurons, the amplitude of both inhibitory and excitatory postsynaptic currents (eIPSCs and eEPSCs) was decreased in a concentration-dependent manner. This was associated with increases of synaptic failure rate (Rf) and paired-pulse ratio (PPR). The effect was larger for eIPSCs compared with eEPSCs. These results clearly indicate that D2O acts differently on inhibitory and excitatory neurotransmitter release machinery. Furthermore, D2O significantly suppressed GABAA receptor-mediated whole cell current (IGABA) but did not affect glutamate receptor-mediated whole cell current (IGlu). The combined effects of D2O at both the pre- and postsynaptic sites may explain the greater inhibition of eIPSCs compared with eEPSCs. Finally, D2O did not enhance or otherwise affect the actions of the general anesthetics nitrous oxide and propofol on spontaneous or evoked GABAergic and glutamatergic neurotransmissions, or on IGABA and IGlu. Our results suggest that previously reported effects of D2O to mimic and/or modulate anesthesia potency result from mechanisms other than modulation of GABAergic and glutamatergic neurotransmission.
authors.affiliation: Research Division for Clinical Pharmacology, Medical Corporation, Jyuryo Group, Kumamoto Kinoh Hospital, Kitaku, Kumamoto, Japan; Research Division for Life Science, Kumamoto Health Science University, Kitaku, Kumamoto, Japan; and.
authors.forename: Masahito
authors.initials: M
authors.lastname: Wakita
authors.affiliation: Research Division of Neurophysiology, Kitamoto Hospital, Koshigaya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kotani
authors.affiliation: Research Division for Life Science, Kumamoto Health Science University, Kitaku, Kumamoto, Japan; and.
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Shoudai
authors.affiliation: Research Division for Life Science, Kumamoto Health Science University, Kitaku, Kumamoto, Japan; and.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yamaga
authors.affiliation: Research Division for Clinical Pharmacology, Medical Corporation, Jyuryo Group, Kumamoto Kinoh Hospital, Kitaku, Kumamoto, Japan; Research Division for Life Science, Kumamoto Health Science University, Kitaku, Kumamoto, Japan; and Research Division of Neurophysiology, Kitamoto Hospital, Koshigaya, Japan akaike@kumamoto-hsu.ac.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Akaike
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D002491:Central Nervous System Agents / Q000494:pharmacology*; D017666:Deuterium Oxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009609:Nitrous Oxide / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D015742:Propofol / Q000494:pharmacology; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D011963:Receptors, GABA-A; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D017666:Deuterium Oxide; D009609:Nitrous Oxide; D015742:Propofol
keywords: deuterium oxide; intravenous and inhaled anesthetic agents; neurotransmission; rat hippocampal CA3 neurons; “synaptic bouton” preparations