PubMed · 4735330
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P Kurtz, T Palfai. 1973. State-dependent learning produced by Metrazol.. https://doi.org/10.1016/0031-9384(73)90092-9
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Two experienced drivers who developed severe amnesia due to bilateral hippocampal lesions participated in a series of standardized challenges of driving performance and knowledge of driving rules. During drives in a high fidelity simulator and on the road in an instrumented vehicle, they demonstrated vehicle control similar to that of normal drivers on measures of steering, speed control, safety errors, and driving with distraction. Their knowledge of driving rules, safety procedures, and road sign meaning also was normal. However, both participants were impaired at following route directions, and both had unsafe responses in a difficult crash avoidance scenario on the simulator. These findings suggest that memory impairment acquired by experienced drivers does not impair most aspects of driving performance, but may increase safety risk under some challenging circumstances.
BACKGROUND: Etomidate is a widely used general anesthetic that has become a useful tool to investigate mechanisms of anesthetic action in vivo and in brain slices. However, the free aqueous concentration of etomidate that corresponds to amnesia in vivo and the diffusion profile of etomidate in brain slices are not known. METHODS: The authors assessed the effect of intraperitoneally injected etomidate on contextual fear conditioning in mice. Etomidate concentrations in brain tissue were obtained by high-performance liquid chromatography. Uptake studies in 400-microm-thick brain slices were used to calculate the diffusion and partition coefficients of etomidate. A diffusion model was used to calculate the expected concentration profile within a brain slice as a function of time and depth. The predicted rate of drug equilibration was compared with the onset of electrophysiologic effects on inhibitory circuit function in recordings from hippocampal brain slices. RESULTS: Etomidate impaired contextual fear conditioning with an ED50 dose of 11.0+/-0.1 mg after intraperitoneal injection, which corresponded to an EC50 brain concentration of 208+/-9 ng/g. The brain:artificial cerebrospinal fluid partition coefficient was 3.35, yielding an EC50,amnesia aqueous concentration of 0.25 microm. The diffusion coefficient was approximately 0.2x10 cm/s. The development of etomidate action in hippocampal brain slices was compatible with the concentration profile predicted by this diffusion coefficient. CONCLUSIONS: The free aqueous concentration of etomidate corresponding to amnesia, as defined by impaired contextual fear conditioning in mice, is 0.25 microM. Diffusion of etomidate into brain slices requires approximately an hour to reach 80% equilibration at a typical recording depth of 100 microm. This information will be useful in designing and interpreting in vitro studies using etomidate.