| Type of Document |
Dissertation |
| Author |
Chandra, Dev
|
| URN |
etd-04222008-095833 |
| Title |
Extrasynaptic GABA Type A Receptors in the Mechanism of Action of Ethanol |
| Degree |
Doctor of Philosophy |
| Program |
Molecular Pharmacology |
| School |
School of Medicine |
| Advisory Committee |
| Advisor Name |
Title |
| Gregg E. Homanics, Ph.D. |
Committee Chair |
| Joan M. Lakoski, Ph.D. |
Committee Co-Chair |
| A. Paula Monaghan-Nichols, Ph.D. |
Committee Member |
| Michael J. Palladino, Ph.D. |
Committee Member |
| William C. de Groat, Ph.D. |
Committee Member |
|
| Keywords |
- GABA receptors
- tonic inhibition
- GABA
- extrasynaptic
- muscimol
- ethanol
- gaboxadol
|
| Date of Defense |
2008-01-29 |
| Availability |
unrestricted |
Abstract
The gamma-aminobutyric acid (GABA) Type A receptor (GABAA-R) mediates the majority of rapid inhibition in the central nervous system and is the site of action for many clinically used drugs. GABAA-R mediated inhibition can occur via the conventional mechanism - the transient activation of synaptic receptors i.e. phasic inhibition, or via continuous activation of extrasynaptic, high affinity receptors by low concentrations of ambient GABA, leading to “tonic” inhibition. The GABAA-R alpha4 subunit is expressed at high levels in the dentate gyrus and thalamus and when partnered with the delta subunit, it is suspected to contribute to tonic inhibition. In vitro studies have found that GABAA-Rs containing alpha4 and delta are highly sensitive to ethanol and to competitive GABAA-R agonists such as gaboxadol and muscimol. In light of these findings, the central hypothesis tested in this thesis was that extrasynaptic GABAA-Rs mediate the depressant effects of these drugs. To provide a model for understanding the precise role of alpha4 containing GABAA-Rs in drug action, mice were engineered to lack the alpha4 subunit by targeted disruption of the Gabra4 gene. alpha4 Subunit knockout mice were viable and superficially indistinguishable from wild-type mice. In electrophysiological recordings, alpha4 knockout mice showed a lack of tonic inhibition in dentate granule cells and thalamic relay neurons. alpha4 knockout mice were also less sensitive to the behavioral effects of gaboxadol and muscimol. However, alpha4 knockout mice did not differ in ethanol-induced changes in anxiety, locomotion, ataxia, coordination, analgesia, or thermoregulation. These data demonstrate that tonic inhibition in dentate granule cells and thalamic relay neurons is mediated by extrasynaptic GABAA-Rs containing the alpha4 subunit and that gaboxadol and muscimol likely achieve their effects via the activation of this GABAA-R subtype. These data also suggest that GABAA-Rs containing the alpha4 subunit are not necessary for many acute behavioral responses to ethanol.
|
| Files |
| Filename |
Size |
Approximate Download Time
(Hours:Minutes:Seconds)
|
| 28.8 Modem |
56K Modem |
ISDN (64 Kb) |
ISDN (128 Kb) |
Higher-speed Access |
| |
ETDChandraD2008.pdf |
2.16 Mb |
00:09:59 |
00:05:08 |
00:04:29 |
00:02:14 |
00:00:11 |
|
