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Pre- and postsynaptic actions of pentobarbital on corticothalamic transmission Ran, Israeli

Abstract

This thesis examined the pre- and postsynaptic actions of an anesthetic barbiturate, pentobarbital, on neurons of the corticothalamocortical system in vitro. The in vivo system mediates conscious and sleep states. The thesis focuses on pentobarbital actions that induce network oscillations, and modify responses of single thalamocortical neurons to corticothalamic stimulus trains. The thesis addressed the following: (1) does pentobarbital induce oscillations in thalamic slices? (2) what receptors contribute to oscillations? (3) how does pentobarbital interact with modulators of excitability? (4) what are pentobarbital effects on post- and presynaptic parameters of glutamatergic transmission during short-term depression (STD)? (5) how do the effects of pentobarbital on STD compare with selective action potential blockade? (6) given the well-known actions of pentobarbital on metabolism, do its effects on STD mimic glucose deprivation? Pentobarbital at a subanesthetic concentration induced 1-15 Hz oscillations, requiring glutamatergic excitation, but not elevated temperature or low extracellular [Mg²⁺]. Glycine receptors mediated oscillations in ventrobasal nuclei, disconnected from nucleus reticularis thalami (nRT). γ-aminobutyrate (GABA) receptors mediated oscillations in isolated nRT. By acting on N-methyl-D-aspartate (NMDA) receptors, spermine modulated membrane rectification, firing threshold, and decay of excitatory postsynaptic potentials (EPSPs). These interactions occurred at the polyamine site on NMDA receptors. Pentobarbital enhanced STD of excitatory postsynaptic currents (EPSCs) by decreasing quantal size. These use-dependent effects persisted during blockade of desensitization and saturation of glutamate receptors and hence, likely were presynaptic. Pentobarbital decreased apparent quantal size and amplitude in the post-stimulus train, evoked miniature EPSCs (minEPSCs) but not ongoing, pre-train minEPSCs, reaffirming a presynaptic action. Pentobarbital eliminated EPSC facilitation early in a train, due to high extracellular [K⁺] ([K⁺][sub e]). Partial blockade of action potentials by tetrodotoxin reduced the apparent quantal size and evoked minEPSC size, without effect on pre-stimulation minEPSC. Like pentobarbital, glucose deprivation reduced quantal size and rundown of quantal contents. Glucose deprivation abolished STD and intra-train, post-gap jump in EPSC amplitude. In summary, this thesis describes several new types of synaptic modulation by pentobarbital that complement known postsynaptic mechanisms of anesthesia. The analysis techniques provide a new approach for examining the pre- and postsynaptic drug effects on transmission in the brain.

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