OREGON HEALTH & SCIENCE UNIVERSITY
The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of GABAA receptors, and evidence suggests that GABAergic neurosteroids are endogenous modulators of GABAA receptors and of selective effects of ethanol (EtOH). The present proposal builds on results generated in the current period of funding in the selectively bred Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) male mice. The finding that WSP mice had a persistent decrease in endogenous ALLO levels during EtOH withdrawal, in conjunction with tolerance to ALLO's anticonvulsant effect, is consistent with greater neural excitability in the WSP vs. WSR line during EtOH withdrawal. The selected line differences in the modulatory effect of ALLO on EtOH withdrawal severity likely reflects a balance between alterations in local concentration of ALLO at GABAA receptors and the concomitant change in GABAA receptor sensitivity to ALLO during EtOH withdrawal. Thus, the goals of the proposed studies are to determine the mechanism and site(s) of action underlying the tolerance to ALLO during EtOH withdrawal in WSP mice (Aim 3), the relative contribution of altered local endogenous ALLO levels (Aim 2) and altered expression of GABAA receptor subunits (Aim 4) to the line difference in ALLO sensitivity during EtOH withdrawal severity in WSP and WSR mice, and the anatomical localization and regulation of the biosynthetic enzyme 5a-reductase (Srd5a1) during EtOH withdrawal in WSP and WSR mice (Aim 1). The pattern of the results will provide essential information on whether activation of GABAA receptors in particular brain regions will be sufficient to alter EtOH withdrawal severity or sensitivity to ALLO during EtOH withdrawal as well as the critical involvement of local ALLO concentration in a specific brain region on EtOH withdrawal severity. This multidisciplinary approach will further test the hypothesis that a decrease in endogenous ALLO levels, which alters GABAergic tone, in conjunction with a decrease in GABAA receptor sensitivity, contribute to the increased withdrawal severity in WSP mice. The long-term goal of this research is to understand mechanisms underlying a genetic predisposition for increased withdrawal severity. This information will aid in our understanding of the mechanisms underlying alcohol withdrawal and will help in the development of new strategies for the treatment of alcohol dependence.
| AWARD OVERVIEW |
| Award Number |
3R01AA012439-09S1 |
Funding Agency |
Department of Health and Human Services |
| Total Award Amount |
$90,378 |
Project Location - City |
Portland |
| Award Date |
08/17/2009 |
Project Location - State |
OR |
| Project Status |
Completed |
Project Location - Zip |
97239-3098
|
| Jobs Reported |
0.00 |
Congressional District |
01 |
| Project Location - Country |
US |
|
|
Recipient Information
(Grants)
| Recipient Information (Grants) |
|
Recipient Name
|
OREGON HEALTH & SCIENCE UNIVERSITY |
| Recipient DUNS Number |
096997515
|
| Recipient Address |
2525 SOUTHWEST 1ST AVENUE STE 201 |
| Recipient City |
PORTLAND |
| Recipient State |
Oregon |
| Recipient Zip |
97201-4762 |
| Recipient Congressional District |
01 |
| Recipient Country |
USA |
Required to Report Top 5
Highly Compensated Officials |
No |
Projects and Jobs Information
| Projects and Jobs Information |
| Project Title |
NEUROSTEROID MODULATION OF ETHANOL WITHDRAWAL SEVERITY |
| Project Status |
Completed |
| Final Project Report Submitted |
Yes |
| Project Activities Description |
Medical Research, General/Other |
| Quarterly Activities/Project Description |
As defined in the Award Description field. Analysis of known quantities of allopregnanolone (ALLO) with BSTFA (N,O - Bis(trimethylsilyl)trifluoroacetamide) derivatizing agent has commenced. We are anticipating that we will have the ability to analyze several neurosteroid levels in brain tissue by the end of summer. a brief description of the procedure is as follows: The principal neuroactive steriod of interest, ALLO, will be prepared with ALLO-d4 and then derived with BSTFA to yield the trimethylsilyl (TMS) species along with the deuterated analogue. Analysis will then be performed on the GC-MS utilizing an electron-impact (El) ionization source under a selective ion monitoring (SIM) mode. Upon confirmation of lowest detection limit, the process will be repeated using negative chemical ionization (NCI) with methane as the ionizing gas. This NCI step will be done inorder to achieve a low background noise mass-spectrogram for higher confidence quantitative analysis of ALLO under SIM mode. Upon successful completion of assay development for ALLO, measures will be repeated with different steroids, building a new mass-spectrogram library of derivatized and deuterated analytes to be utilized in the future multi-analyte seprations and determinations. |
| Jobs Created |
0.00 |
| Description of Jobs Created |
NA |
Purchaser Information
(Grants)
| Purchaser Information |
| Contracting Office ID |
Not Reported |
| Contracting Office Name |
Not Available |
| Contracting Office Region |
Not Available |
| TAS Major Program |
75-0909 |
| Award Information |
| Award Date |
08/17/2009 |
| Award Number |
3R01AA012439-09S1 |
| Order Number |
|
| Award Type |
Grants |
| Funding Agency ID |
75 |
| Funding Agency Name |
Department of Health and Human Services |
| Funding Office Name |
Not Available |
| Awarding Agency ID |
75 |
| Awarding Agency Name |
Department of Health and Human Services |
| Amount of Award |
$90,378 |
| Funds Invoiced/Received |
$90,378 |
| Expenditure Amount |
$90,378 |
| Infrastructure Expenditure Amount |
$0 |
| Infrastructure Purpose and Rationale |
Not Reported |
| Infrastructure Point of Contact Name |
Not Reported |
| Infrastructure Point of Contact Email |
Not Reported |
| Infrastructure Point of Contact Phone |
Not Reported |
| Infrastructure Point of Contact Address |
Not Reported |
| Infrastructure Point of Contact City |
Not Reported |
| Infrastructure Point of Contact State |
Not Reported |
| Infrastructure Point of Contact Zip |
Not Reported |
Product or Service Information
(Grants)
| Product or Service Information |
| Primary Activity Code |
H01 |
| Activity Description |
Medical Research, General/Other |
| Sub-Awards Information |
| Sub-awards to Organizations |
0 |
| Sub-award Amounts to Organizations |
$0 |
| Sub-Awards to Individuals |
0 |
| Sub-Award Amounts to Individuals |
$0 |
| Number of Sub-awards less than $25,000/award |
0 |
| Amount of Sub-awards less than $25,000/award |
$0 |
| Number of payments to vendors greater than $25,000 |
1 |
| Total Amount of payments to vendors greater than $25,000/award |
$86,859 |
| Number of payments to vendors less than $25,000/award |
12 |
| Total Amount of payments to vendors less than $25,000/award |
$3,523 |
AGILENT TECHNOLOGIES INCORPORATED - Award Number 3R01AA012439-09S1 - AGILENT TECHNOLOGIES INCORPORATED
| Award Number |
3R01AA012439-09S1 |
| Sub-Award Number |
N/A |
| Vendor DUNS Number |
Not reported |
| Vendor HQ Zip Code + 4 |
95051-7201 |
| Vendor Name |
AGILENT TECHNOLOGIES INCORPORATED |
| Product and Service Description |
5975C inert XL EI/CI MSD/DS Turbo CI System for use with 7890A, 6890 and 6850 GC. Includes G3174A MSD with Inert EI and CI ion source, ChemStation (Win XP),G1701EA SW, PC, Laser Jet printer, G3397A ion gauge controller. |
| Payment Amount |
$86,859 |
| Location Information |
| Latitude, Longitude |
45º 29' 56",
-122º 41' 15" |
| Congressional District |
01 |
| Address 1 |
|
| Address 2 |
|
| City |
Portland |
| County |
Multnomah |
| State |
OR |
| Zip |
97239-3098 |
|
 |