Alcohol affects many neurochemical processes, causing long-lasting changes in both the adult and developing brain. The Jak-Stat transcriptional activation pathway plays a role in the control of neuronal proliferation, survival and differentiation, but the effects of ethanol on the system have not been fully elucidated. The goal of this project was to define the effects of acute and subchronic ethanol exposure on the expression of proteins in the Jak-Stat pathway, using cultured NG108-15 cells, and in addition, to test the hypothesis that these effects are mediated through the NMDA receptor. I found that ethanol dose-dependently decreased Jak2 and Stat3 following subchronic exposure of NG108-15 in culture. Acute ethanol exposure caused a dose-dependent decrease in Stat3 protein levels. Incubation with MK-801 or ketamine, two noncompetitive NMDA receptor antagonists, or the receptor agonist NMDA, produced dose-dependent decreases in Stat3 protein as well.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2006. / Härtill 4 uppsatser.

Thesis (M.Sc.). / Written for the Dept. of Neurology and Neurosurgery. Title from title page of PDF (viewed 2009/06/18). Includes bibliographical references.

Thesis (Ph. D.)--Cornell University, August, 2008. / Vita. Includes bibliographical references (leaves 77-82).

Thesis (Ph.D. in Pharmacology) -- University of Colorado, 2005. / Typescript. Includes bibliographical references (leaves 145-170). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

Clinically relevant concentrations of ethanol modulate the function of a number of ion channel proteins. A fundamental question regarding the effects of alcohol is whether the drug modifies ion channels by directly binding to the protein, indirectly by perturbing the surrounding membrane lipid, or some combination of both. This thesis further characterized ethanol's site of action by examining the effects of ethanol on N-methyl-D-aspartate (NMDA) receptor/channels and large conductance Ca2+-activated K+ (BK) channels at a number of levels using direct electrophysiological methods. In Chapter One, the magnitude of ethanol's inhibition of a number of cloned heteromeric NMDA receptor/channels in the absence or presence of a number of modulators was compared. The rank order of ethanol sensitivity for the subunit combinations studied was NR1b/NR2A > NR1b/NR2B > NR1b/NR2C > NR1b/NR2D. Modulation of the receptor with Mg2+, Zn2+, the glycine antagonist 7-Chlorokynurenic Acid, or after reduction or oxidation of the redox regulatory site did not alter the ethanol sensitivity of heteromeric NMDA receptors. Therefore, the ethanol sensitivity of NMDA receptor/channels is dependent upon which NR2 subunit is present, and ethanol's site of action is unrelated to these modulatory sites on the receptor/channel protein. In Chapter Two, ethanol's site of action at cloned BK channels was characterized using of a number of 1-alkanols. Ethanol, butanol, hexanol, and heptanol reversibly and dose-dependently increased the current carried through BK channels. Longer chain 1-alkanols, such as octanol had no effect on channels. In Chapter Three, the action of ethanol on BK channels reconstituted in a number of model planar bilayers was studied. Ethanol increased the activity of BK channels incorporated in bilayers composed of phosphatidylethanolamine (PE) and phosphatidylserine (PS) or PE alone by decreasing the average amount of time channels dwelled in the closed state. There was no significant effect of alcohol on either channel conductance or unitary current. Taken together, these data suggest that ethanol action on BK channels does not require the complex membrane architecture found in native membranes, and does not require freely diffusible cytoplasmic factors or proteins.

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