St Andrews Research Repository

St Andrews University Home
View Item 
  •   St Andrews Research Repository
  • Psychology & Neuroscience (School of)
  • Psychology & Neuroscience
  • Psychology & Neuroscience Theses
  • View Item
  •   St Andrews Research Repository
  • Psychology & Neuroscience (School of)
  • Psychology & Neuroscience
  • Psychology & Neuroscience Theses
  • View Item
  •   St Andrews Research Repository
  • Psychology & Neuroscience (School of)
  • Psychology & Neuroscience
  • Psychology & Neuroscience Theses
  • View Item
  • Login
JavaScript is disabled for your browser. Some features of this site may not work without it.

In vivo and in vitro studies of positive allosteric modulation of the NMDA receptor

Thumbnail
View/Open
CasmiraBrazaitisPhDThesis.pdf (13.69Mb)
Date
20/06/2017
Author
Brazaitis, Casmira T.
Supervisor
Brown, Verity Joy
Lambert, Jeremy J.
Funder
Merck Sharp & Dohme. Scottish Life Sciences Fund
Scottish Universities Life Sciences Alliance (SULSA)
Keywords
NMDA receptor
Cognition
Positive allosteric modulation
Huntington's disease
Cerebrosterol
24S-hydroxycholesterol
Metadata
Show full item record
Altmetrics Handle Statistics
Abstract
Dysfunction of the N-methyl-D-aspartate (NMDA) receptor is thought to contribute to the cognitive deficits of many neurodegenerative diseases and psychiatric disorders. Cognitive symptoms of Alzheimer’s disease can be treated with NMDA receptor antagonists or drugs targeting the cholinergic system; however, there are no effective treatments for cognitive deficits of schizophrenia or Huntington’s disease. With the discovery of a potent and selective allosteric modulator of the NMDA receptor, there is the possibility of new treatments based on NMDA receptor functional-enhancement through neuroactive steroids, closely related in structure to the endogenous neurosteroid, cerebrosterol. The aim of this thesis was to examine steroidal modulation of the NMDA receptor both in vitro and in vivo. In chapter 2, NMDA receptor enhancement of both the synthetic and endogenous neuroactive steroids was assessed in neurons maintained in cell culture using calcium imaging techniques. Sulphation of the steroids greatly increased the efficacy of NMDA receptor enhancement compared to the unsulphated steroids. Chapters 3 and 4 investigate the potential for neuroactive steroids to treat cognitive impairments of Huntington’s disease. Using a mouse model, tests were selected that were analogous to those in which patients are impaired; however, no impairments were found in the mouse model. Chapter 5, therefore, used a different model of cognitive impairment – namely, rats with a set-shifting impairment, as is seen in many psychiatric and neurological disorders, including Huntington’s disease – to assess the effect of the synthetic steroid administration. Unfortunately, the rats did not show the expected impairment. The lack of reliable animal models compromised testing the efficacy of these promising NMDA receptor positive allosteric modulators. Nevertheless, the promising in vitro results suggest that there could still be therapeutic potential. In addition, the compound is a useful research tool for exploring NMDA receptor function in health and disease.
Type
Thesis, PhD Doctor of Philosophy
Collections
  • Psychology & Neuroscience Theses
URI
http://hdl.handle.net/10023/10495

Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.

Advanced Search

Browse

All of RepositoryCommunities & CollectionsBy Issue DateNamesTitlesSubjectsClassificationTypeFunderThis CollectionBy Issue DateNamesTitlesSubjectsClassificationTypeFunder

My Account

Login

Open Access

To find out how you can benefit from open access to research, see our library web pages and Open Access blog. For open access help contact: openaccess@st-andrews.ac.uk.

Accessibility

Read our Accessibility statement.

How to submit research papers

The full text of research papers can be submitted to the repository via Pure, the University's research information system. For help see our guide: How to deposit in Pure.

Electronic thesis deposit

Help with deposit.

Repository help

For repository help contact: Digital-Repository@st-andrews.ac.uk.

Give Feedback

Cookie policy

This site may use cookies. Please see Terms and Conditions.

Usage statistics

COUNTER-compliant statistics on downloads from the repository are available from the IRUS-UK Service. Contact us for information.

© University of St Andrews Library

University of St Andrews is a charity registered in Scotland, No SC013532.

  • Facebook
  • Twitter