Inaugurele rede Universiteit van Amsterdam. / Uitg. onder auspiciën van de Universiteit van Amsterdam. Description based on print version record. Met lit. opg. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1932. / Typescript. With this is bound: N-methyl-N-phenylalkyl-amino-alkyl benzoates and para-aminobenzoates / By Arthur C. Cope and S.M. McElvain. Reprinted from Journal of the American Chemical Society, vol. 53 (1931), p. 1587-1594. Includes bibliographical references.

No description available.

No description available.

Thesis (Ph. D.)--Columbia University, 1942. / Reproduced from type-written copy. Vita. Bibliography: p. [19].

The most widely accepted hypotheses suggest that general anaesthetics interrupt conscious processes in the brain by decreasing synaptic excitation or by potentiating synaptic inhibition, especially in the neocortex. The putative transmitters in the neurological systems that generate neocortical arousal include acetylcholine, glutamate and γ-aminobutyrate (GABA). The primary objective here was to determine the neuronal mechanisms by which anaesthetics may obtund this arousal. The majority of the investigations were carried out on pyramidal neurons in layers IV and V of guinea pig neocortex (in vitro slices), using intracellular recording and pharmacological, including microiontophoretic, techniques. Bath applications of structurally dissimilar anaesthetics, isoflurane - a halogenated ether, and Althesin - a steroidal preparation, in concentrations of 0.5-2.5 minimum alveolar concentration (MAC) and 10-1300 μM, respectively, produced a small hyperpolarization (3-5 mV) which was associated with an increase in input conductance (10-30%). The lower concentrations (0.5-1.5 MAC and 10-200 μM) of these agents which are most relevant to the production of unconsciousness did not significantly affect the passive membrane properties. However, they produced striking decreases in spontaneous activities and the repetitive spike firing evoked by orthodromic (electrical) stimulation or intracellular current injections. Because the observed changes in membrane properties could not explain the reduction in neuronal excitability, the effects of anaesthetics were investigated extensively on excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). The application of isoflurane or Althesin induced a dose-dependent, reversible depression in the amplitude of EPSPs, with EC₅₀s of 1 MAC and ~50 μM, respectively. The IPSPs also were reduced in a dose-dependent manner. In order to eliminate possible shunting of the EPSPs by the GABA-activated Cl-conductance that produces the IPSP in the observed EPSP-IPSP sequence, a GABA[symbol omitted]-antagonist, bicuculline, was additionally applied. Despite this IPSP-blockade, the anaesthetics strongly depressed the EPSPs as well as epileptiform activities evoked by subpial electrical stimulation. In cognizance of the possibility that a postsynaptic attenuation of responsiveness to transmitter substances may be involved in the EPSP depression, the neuronal sensitivities to acetylcholine, glutamate. and GABA were determined. Anaesthetic administration markedly reduced the depolarizations and associated conductance changes evoked by dendritic applications of acetylcholine, glutamate and N-methyl-D-aspartate (NMDA). The hyperpolarizing responses to somatic applications of GABA were not affected significantly whereas the depolarizing effects observed with its dendritic application were slightly depressed. Same degree of selectivity also was evident from the lower EC₅₀s for the isoflurane- and Althesin-induced depressions of responses to acetylcholine compared with glutamate. Under in vitro conditions of hypomagnesia the responses to acetylcholine were totally blocked and the order of depression in the responses to GABA and glutamate was reversed; this may be of importance in the mechanism for the known increase in anaesthetic requirements in clinical syndromes associated with hypomagnesaemia. Because the genesis of synaptic transients is affected by Ca²⁺ influx or disposition, the interactions of anaesthetics were investigated on spike afterhyperpolarizations (AHPs). The AHPs which are produced specifically by a Ca²⁺ -activated K⁺ -conductance were suppressed by the anaesthetics in a dose-dependent manner under conditions where contaminating IPSPs had been blocked by bicuculline. Since the passive membrane properties were unaffected, an interference with a transmembrane Ca⁺ -influx may be involved in the anaesthetic actions. The effects of anaesthetics on glutamate-induced and voltage-dependent increases in intraneuronal Ca²⁺ ([Ca²⁺]i) were determined in cultured hippocampal neurons with a Ca-sensitive probe (Fura-2) and microspectro- fluorometric techniques. Isoflurane application depressed the increases in [Ca²⁺]i. produced by application of glutamate under conditions where its actions would be favoured at NMDA- and quisqualate-subtypes of receptors. K⁺ -induced increases in [Ca²⁺]i also were reduced by application of isoflurane, probably due to actions on voltage-dependent Ca-channels in the membrane. These investigations have provided evidence for the first time that excitatory transmitter actions in neocortex are selectively depressed by anaesthesia. A plausible mechanism would include suppression of the postsynaptic Ca-conductances associated with the AHPs and glutamatergic, as well as cholinergic interactions at pre- and post-synaptic sites on neurons involved in neocortical arousal. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Thesis (doctoral)--Georg-August-Universität zu Göttingen, 1932.

Thesis (doctoral)--Georg-August-Universität zu Göttingen, 1932.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2004. / Bibliography: leaves 96-101.

Alcohol is abundantly consumed by society and general anesthetics are used everyday in operating suites throughout the world, yet the sites and mechanisms of action for these drugs are not completely understood. Glycine receptors (GlyRs) are pentameric ion channels expressed throughout the brain and spinal cord and have become increasingly popular targets in the study of alcohol action. Each GlyR subunit is composed of four alpha helical transmembrane segments (TM1-4), and although amino acids involved with alcohol action have been previously identified in TM1-4, the orientation of each of these residues with respect to a putative alcohol/anesthetic binding cavity remains controversial. In order to better characterize this binding cavity within the GlyR, we conducted a series of experiments using cysteine mutagenesis and biochemical cross-linking. In Aim 1, the participation of TM1 with TM3 in a common alcohol/anesthetic binding cavity was further investigated. We used two-electrode voltage clamp electrophysiology in Xenopus oocytes to demonstrate the ability of A288 in TM3 to form cross-links with I229 in TM1, which reduced the ability of both alcohol and anesthetics to modulate GlyR function. Aim 2 investigated whether TM3 could also participate in a binding cavity with TM4. We have shown that residues in TM4 are able to form cross-links with A288 in TM3, and found that cross-linking between TM3 and those residues in TM4 also reduced the ability of alcohol and anesthetics to enhance GlyR function. Aim 3 determined whether these cross-links are formed between residues within the same subunit (intra-subunit) or between subunits (inter-subunit), and ultimately whether these residues participate in a common alcohol/anesthetic binding cavity within or between GlyR subunits. GlyR protein, which measures about 50 kDa, was extracted from oocytes injected with the cysteine mutants, and immunoblotting was used with a GlyR-specific antibody to subsequently help quantify band ratios between cross-linked and uncross-linked conditions. We found an increase in the 100:50 kDa band ratio for the TM1-3 mutant only, but not TM3-4 mutant or the wild-type, which suggests TM1-3 may participate in an alcohol binding cavity between GlyR subunits while TM3-4 may contribute to a binding cavity within a subunit. / text