Thesis (Ph. D.)--Case Western Reserve University, 2004. / [School of Medicine] Department of Neurosciences. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Oct. 13, 2008). Includes bibliographical references.

Bibliography: leaves 282-354 / 354 leaves : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1986

Changes in spontaneous spike activities recorded from murine frontal cortex networks grown on substrate-integrated microelectrodes were used to determine the dissociation constant (KB) of three GABAA antagonists. Neuronal networks were treated with fixed concentrations of GABAA antagonists and titrated with muscimol, a GABAA receptor agonist. Muscimol decreased spike activity in a concentration dependent manner with full efficacy (100% spike inhibition) and a 50% inhibitory concentration (IC50) of 0.14 ± 0.05 µM (mean ± SD, n=6). At 10, 20, 40 and 80 µM bicuculline, the muscimol IC50 values were shifted to 4.3 ± 1.8 µM (n=6), 6.8 ± 1.7 µM (n=6), 19.3 ± 3.54 µM (n=10) and 43.5 µM (n=2), respectively (mean ± SD). Muscimol titration in the presence of 10, 20, 40 µM of gabazine resulted in IC50s values of 20.1 (n=2), 37.17 (n=4), and 120.45 (n=2), respectively. In the presence of 20, 80, and 160 µM of TMPP (trimethylolpropane phosphate) the IC50s were 0.86 (n=2), 3.07 (n=3), 6.67 (n=2) µM, respectively. Increasing concentrations of GABAA antagonists shifted agonist log concentration-response curves to the right with identical efficacies, indicating direct competition for the GABAA receptor. A Schild plot analysis with linear regression resulted in slopes of 1.18 ± 0.18, 1.29 ± 0.23 and 1.05 ± 0.03 for bicuculline, gabazine and TMPP, respectively. The potency of antagonists was determined in terms of pA2 values. The pA2 values were 6.63 (gabazine), 6.21 (bicuculline), and 5.4 (TMPP). This suggests that gabazine has a higher binding affinity to the GABAA receptor than bicuculline and TMPP. Hence, using spike rate data obtained from population responses of spontaneously active neuronal networks, it is possible to determine key pharmacological properties of drug-receptor interactions.

Resveratrol and catechin have behavioral and neuroprotective effects that may be due to their interaction with neuronal ion channels. It was hypothesized that the grape compounds, resveratrol and catechin modulate GABAAA receptors. To address this hypothesis, the effects of resveratrol and catechin were investigated on human recombinant GABAA receptors expressed in HEK-293 cells using electrophysiological techniques.<.p> HEK-293 cells were cultured and transfected using eDNA encoding human GABAA receptors. GABA-evoked currents were recorded from HEK cells 24-48 hours following transfection. Cells were voltage clamped in the whole cell configuration at -60mV using the patch-clamp technique. Ligand-activated currents were recorded and stored, using Win WCP software, on a desktop computer. Resveratrol (1- 100μM) dose-dependently potentiated GABA-evoked currents recorded from α1β2< /sup>γ2 and α1β2 GABAA receptors. Resveratrol did not modulate a α1β2< /sup>γ2 and α1β2 GABAA receptors. Furthermore, resveratrol did not act through the benzodiazepine binding site. The low efficacy and subunit selectivity of resveratrol is a promising discovery for the development of a highly specific GABAergic modulator. Conversely, catechin (1-100αM) dose-dependently inhibited GABA-evoked currents recorded from α1β2 and α1β1 GABAA receptors. The degree of inhibition was the same for both receptor subtypes. Catechin did not modulate α1β2γ2 or α1β1γ2 GABAA receptors. The selectivity of catechin for receptors lacking the γ subunit is similar to the effects of zinc and did not involve the benzodiazephine site on GABAA receptors. This study has shown that catechin and resveratrol are subunit-selective modulators of human GABAA receptors. These compounds could lead to the development of novel agents to be used in treating neurological disorders. These data support the use and study of natural products for the development of agents that act selectively on the nervous system.

Diss. Linköping : Univ., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 5 uppsatser. Även tryckt utgåva.