Item – Theses Canada

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OCLC number
46576166
Link(s) to full text
LAC copy
LAC copy
Author
Paslawski, Teresa,1967-
Title
The antipanic drug phenelzine and its effects on GABA and related amino acids.
Degree
Ph. D. -- University of Alberta, 1998
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, [1999]
Description
3 microfiches.
Notes
Includes bibliographical references.
Abstract
Panic disorder (PD) affects approximately 3% of the population. Phenelzine (PLZ) is an antidepressant which also possesses anxiolytic properties, and is particularly useful as an antipanic agent. In this thesis, the mechanism of action of PLZ is explored in relation to the GABAergic system, which has been suggested to play a significant role in PD. Investigations in rat hypothalamus and whole brain included acute time- and dose-response studies and chronic studies. In addition to elevating GABA and inhibiting MAO-A and -B in brain tissue, PLZ also decreased glutamate and glutamine levels in a dose-dependent manner. The effects of PLZ on glutamine, glutamate and GABA were blocked by prior treatment with another MAO inhibitor, suggesting that the effects of PLZ on these aspects of the GABA shunt are produced by a metabolite of PLZ formed by the action of MAO on the parent drug. GABA$\sb{\rm A}$ receptor activity was also measured following chronic PLZ administration. PLZ did not significantly alter $\rm\sp{36}Cl\sp-$ uptake in synaptoneurosomes, a measure believed to reflect GABA$\sb{\rm A}$ receptor activity. The elevated plus-maze was employed to compare the behavioral effects of PLZ and its acetylated metabolite, N$\sp2$AcPLZ. Like PLZ, N$\sp2$AcPLZ elevates brain levels of the biogenic amines and inhibits MAO-A and -B, but unlike PLZ, has no GABA-elevating properties. PLZ had an anxiolytic effect in the elevated plus-maze whereas N$\sp2$AcPLZ did not. These results provide further support for the role of GABA in anxiety disorders. Clinical analyses were conducted using blood samples taken from PD patients undergoing treatment with PLZ over an 8-week period. Plasma samples showed significant differences in GABA but not in alanine levels during treatment, or between treatment and control groups. Studies on a proposed metabolite of PLZ, phenylethylidene hydrazine (PEH), revealed that, like PLZ, PEH elevated brain GABA and alanine levels and inhibited GABA-T and ALA-T. PEH differs from PLZ in that it does not significantly inhibit MAO-A and MAO-B, suggesting that PEH may have the anxiolytic properties of PLZ but lack some of the side effects and interactions of PLZ. Attempts were made to develop an assay for the detection of PEH in tissues.
ISBN
0612290913
9780612290914