Modulation of a - Amino - 3 - hydroxy ~ 5 - rnethyl = 44 soxazole Propionate ( AMPA ) Receptors by a Novel Organic Nitrate Ester Samuel

Positive modulators of the excitatory amino acid receptor a-Amino-3hydroxy-5-methyl-4-isoxazole Propionate (AMPA) has been shown to enhance memory and learning tasks performed by rodents and by human subjects. A new class of AMPA receptor modulators has been recently synthesized. These compounds belong to the class of organic nitrate ester of the nitroglycerine family and are designated GT-2 1-005, GT-11-013, GT-21-038, and GT-21-022. GT-2 1 005 was found to enhance AMPA receptor-mediated responses. The structure of this drug is simple compared to the various positive modulators of the AMPA receptor that have already characterized. GT-21-005 en hanced kainate-evoked currents in cultured and acutely isolated hippocampal neurons. It also enhanced glutamate-evoked currents by reducing desensitization at the receptor and increasing the rate of recovery from desensitization. The presence of GT-21-005 also prolonged the decay of spontaneous miniature excitatory postsynaptic currents (mEPSCs). This shows that GT-21-005 can enhance synaptic responses that may be responsible for encoding rnemory and learning in the hippocampus. GT-21-005 also has inhibitory effects on N-rnethyl-D-aspartate (NMDA) and y-am inobutryic acid (GABA) receptors in the same concentrations that enhance AMPA receptors. This thesis reports the characterization of the effects of GT-21-005 on AMPA receptors using electrophysiological techniques on cultured and acutely isolated neurons from the hippocampus. Acknowledaments I would like to express rny sincere thanks to Dr. John F. MacDonald for his patience and support in rny project. His insightful wisdom and knowledge has been rewarding in my learning experience with this lab. To Dn. Greg Thatcher and James Reynolds, I thank them for their collaboration and support in !his project. I would also like to thank Drs. Zhigang Xiong and Donglin Bai for their friendship and contributions to this project. I also thank Dr. Peter Pennefather for his support as my Graduate Advisor and for enlightening me in kinetic modeling. For Drs. Beverley Oner, WeiYang Lu, Stefanie Roder, and Mike Jackson, I am grateful for their discussions and friendship. As well, I would like to thank my Examination Cornmittee (Drs. J.F. MacDonald, A. Okey, B. Orser, P. Pennefather, and H. Van Tol) for their attendance at my defense, the day snow actually shut the University down. I would also like to thank my parents from the bottom of my heart for al1 their love and support during al1 my years o f study. TABLE OF CON1 EN1 S Abstract .............................................................................................................. i . . Acknowledgments ...................... ................................................................. 11 ... Table Of