title: Age-dependent changes in the susceptibility to thiopental anesthesia in mice: analysis of the relationship to the functional expression of GABA transporter.
abstract: The potency of anesthetics changes during development, probably due not only to pharmacokinetic factors such as differential distribution and/or metabolism, but also to pharmacodynamic factors such as changes to the GABAergic system in the brain. To explore the latter mechanism, we focused on the GABA transporter (GAT), the uptake system for GABA, which participates in the synaptic clearance of GABA. Thiopental-induced anesthesia, as assessed by the onset and duration of loss of the righting reflex, was more pronounced in 3-week-old mice than in 7-week-old mice. Both NO-711 and SKF89976A, selective GAT-1 inhibitors, significantly enhanced the anesthesia in the 7-week-old but not in the 3-week-old mice. In synaptosomes prepared from the cerebral cortex, the kinetics of GABA transport was similar between the two age groups, as assessed by [(3)H]GABA uptake assay. In addition, expression of GAT mRNA was similar between the two age groups, as assessed by quantitative RT-PCR. Thiopental reduced [(3)H]GABA uptake only at high concentrations in a similar manner at both ages. Conversely, the ability of SKF89976A to inhibit [(3)H]GABA uptake was greater in the 7-week-old mice than in the 3-week-old mice. Based on these results, GAT seems unlikely to contribute to the greater susceptibility to thiopental anesthesia in 3-week-old mice, while the increased ability of GABA uptake inhibitors to enhance thiopental-induced anesthesia in 7-week-old mice is at least partly due to higher sensitivity of GAT to the inhibitors.
authors.affiliation: Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Sogawa
authors.forename: Yuri
authors.initials: Y
authors.lastname: Hazehara
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Kunitomo
authors.forename: Yuya
authors.initials: Y
authors.lastname: Morita
authors.forename: Bupsang
authors.initials: B
authors.lastname: Yoo
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ohyama
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sogawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kitayama
mesh_terms: D000375:Aging / Q000502:physiology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D050485:GABA Plasma Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D013874:Thiopental / Q000008:administration & dosage / Q000494:pharmacology*; D014316:Tritium
chemical_list: D018686:Anesthetics, Intravenous; D017931:DNA Primers; D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; D010091:Oximes; D012333:RNA, Messenger; D014316:Tritium; C078793:NNC 711; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D013874:Thiopental