Defense Date

3-10-2008

Availability

Worldwide Access

Submission Type

thesis

Degree Name

MS

Department

Pharmacology-Toxicology

School

School of Pharmacy

Committee Chair

David A. Johnson

Committee Member

Christopher K. Surratt

Committee Member

Robert B. Gibbs

Keywords

AChRs, Aversive stimulus, Cognition, Crossover latency, GABAA receptors, Stress

Abstract

Neurosteroids, such as dehydroepiandrosterone sulfate, (DHEAS) are steroidal compounds synthesized within the central nervous system that modulate its function. Among the effects associated with sulfated neurosteroids is the enhancement of memory. Previous studies have demonstrated that altering the metabolism of neurosteroids via inhibition of the enzyme steroid sulfatase could reverse scopolamine-induced amnesia. p-O-(Sulfamoyl) - tetradecanoyl tyramine (DU-14) is a steroid sulfatase inhibitor (SSI) that prevents the conversion of DHEAS to DHEA thereby increasing the concentration of sulfated neurosteroids to potentiate the effect of endogenous DHEAS. To determine whether DU-14 could enhance memory retention for footshock in rats with hippocampal cholinergic hypofunction, male Sprague-Dawley rats were infused with the immunotoxin 192 IgG-saporin (SAP) into the medial septum, and tested using a step-through passive avoidance paradigm. There was a greater than 80% decrease in ChAT activity in the hippocampi of animals treated with SAP (p < 0.0001). There was also a 24.1% decrease in ChAT activity of in the frontal cortex of SAP animals administered DU-14. However, this small but significant decrease did not affect locomotor behavior in rats. Administration of DU-14 enhanced memory retention for 1.0 mA and not 1.25 mA footshock in animals with SAP lesion compared to vehicle treated SAP animals (p< 0.05). The effect of DU-14 on locomotor activity was also investigated. DU-14 did not affect locomotor activity during acclimation or retention. These results suggest that DU-14 may enhance memory retention in rats with hippocampal cholinergic lesion.

Format

PDF

Language

English

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