ANESTHETICS' MECHANISMS OF ACTION--PRESYNAPTIC SITES

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The development of safer and more efficacious general anesthetics has been limited by a lack of knowledge about their neuronal sites and mechanisms of action. Synaptic transmission in the central nervous system (CNS) is regarded as a primary target of anesthetic action, however, only a few studies have investigated possible presynaptic actions. Preliminary results from our laboratory have demonstrated that clinically effective concentrations of volatile anesthetics (e.g. halothane at 0.5 to 1.5 vol %) enhance the release of gamma-aminobutyric acid (GABA) from presynaptic terminals, evidenced by an increased frequency of GABA-mediated miniature inhibitory postsynaptic currents (IPSCs). This presynaptic action would add to the well established post synaptic prolongation of IPSCs produced by halothane, resulting in a marked increase in synaptic inhibition. Increased synaptic inhibition is thought to play a significant role in the CNS depression associated with general anesthesia. The long-term goal of the proposed research is to define the synaptic sites of action which contribute to anesthetic-induced CNS depression. The actions of six clinically used anesthetics (halothane, isoflurane, sevoflurane, pentobarbital, propofol and midazolam) will be compared on five independent measures of presynaptic function. Electrophysiological recording in rat hippocampal cortex slices will be combined with the use of selective pharmacological probes to isolate and identify possible presynaptic sites of anesthetic action. The specific aims are to compare anesthetic effects on: 1) the excitability of afferent fibers, 2) the frequency-dependant facilitation at excitatory synapses, 3) the excitability of GABAergic interneurons, 4) the frequency of miniature GABA-mediated IPSCs, 5) the frequency-dependant depression of inhibitory (GABA) synapses. The proposed study will provide detailed information about anesthetic-induced alterations in presynaptic function and will contribute to an understanding of anesthetic mechanisms of action; prerequisite to the development of better and safer therapeutic agents for general anesthesia.