Here, we investigated the effects of modulation of the GABAergic system using a targeted neuropharmacological, 1H/13C NMR spectroscopy and metabolomic approach in Guinea pig cortical brain slices. The effects of exogenous GABA, agonists, antagonists and allosteric modulators at GABAA receptors were described and classified on the basis of metabolic activity; this corresponded to receptor location rather than pharmacology. The effects of agonists and antagonists at the GABAB receptor were described and classified into inhibitory and excitatory components, consistent with context dependent outcomes of receptor activity. Metabolic evidence for GABAC mediated activity in the cerebral cortex was identified for the first time indicating a strong role for this receptor in the control of neuronal activity. Inhibition of GABA uptake was examined using inhibitors of these transporters. The major effect of individual transporter subtype blockade was increased synaptic inhibition. The paradoxical activity of the GABA-transaminase inhibitor vigabatrin was resolved, with a direct demonstration of a single inhibitory mechanism mediated via this drug, via a mechanism also induced by antagonists at the GABAC receptor. These data were then integrated using multivariate statistics to identify 5 subclasses of activity which corresponded to receptor location (e.g. synaptic or extrasynaptic) rather than receptor pharmacology. This represents a novel and powerful new approach to the study of brain metabolism and the GABAergic system.

Here, we investigated the effects of modulation of the GABAergic system using a targeted neuropharmacological, 1H/13C NMR spectroscopy and metabolomic approach in Guinea pig cortical brain slices. The effects of exogenous GABA, agonists, antagonists and allosteric modulators at GABAA receptors were described and classified on the basis of metabolic activity; this corresponded to receptor location rather than pharmacology. The effects of agonists and antagonists at the GABAB receptor were described and classified into inhibitory and excitatory components, consistent with context dependent outcomes of receptor activity. Metabolic evidence for GABAC mediated activity in the cerebral cortex was identified for the first time indicating a strong role for this receptor in the control of neuronal activity. Inhibition of GABA uptake was examined using inhibitors of these transporters. The major effect of individual transporter subtype blockade was increased synaptic inhibition. The paradoxical activity of the GABA-transaminase inhibitor vigabatrin was resolved, with a direct demonstration of a single inhibitory mechanism mediated via this drug, via a mechanism also induced by antagonists at the GABAC receptor. These data were then integrated using multivariate statistics to identify 5 subclasses of activity which corresponded to receptor location (e.g. synaptic or extrasynaptic) rather than receptor pharmacology. This represents a novel and powerful new approach to the study of brain metabolism and the GABAergic system.

Thesis (M.S.)--Youngstown State University, 1997. / Includes bibliographical references (leaf 94).

Thesis (M.S.)--Rochester Institute of Technology, 1980. / Typescript. Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references. Also available in print.

Thesis--University of California, Berkeley, 1959. / Includes bibliographical references (p. 74-76).

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains v, 68 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 68).

Thesis (M.S.)--University of Wisconsin--Madison, 1966. / eContent provider-neutral record in process. Description based on print version record. Bibliography: l. 22.

Thesis (M.A.)--University of Wisconsin--Madison, 1965. / eContent provider-neutral record in process. Description based on print version record. Bibliography: l. 19.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1963. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 115-117).