Mechanisms involved in the Development Behavioural supersensitivity

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Short Term Objectives and Long Term Goals: The short term objectives of this program are to (1) gain an in-depth understanding of the molecular mechanisms involved in the development of behavioural supersensitivity following dopamine D2 receptor (D2R) antagonism and (2) to investigate the protective mechanisms of novel Peptide A designed in our lab. The long-term goals are to (3) investigate the changes in dopamine transporters and receptors induced by oxidative stress (OS) using brain imaging in live rats and (4) to enhance neuroprotection by developing novel microgels for targeted delivery of Peptide A to the brain.****Aims & Approaches****Short term 5 years: 1. To investigate the effects of novel Peptide A for neuroprotection against haloperidol-induced OS, various groups of rats will be treated with haloperidol, haloperidol + Peptide A, and inactive Peptide B for 28 days. Behavioural supersensitivity will be monitored by recording stereotyped behavior, vacuous chewing movements (VCMs) and locomotor activity. 2. To establish whether Peptide A prevents AIF translocation in striatopallidal neurons, striatoentopenduncular neurons, and astroglial cells, groups of rats will be treated with haloperidol, haloperidol + Peptide A, and vehicle solution for 28 days. At the end of treatment, brain regions will be dissected and labeled with specific antibodies for neurons and astroglial cells. 3. To establish whether there is an increase in glutamate release and decrease in GABA, rats will be treated as described above in Aim 2. Glutamate and GABA will be measured in live rats by microdialysis. 4. To investigate molecular mechanisms of Peptide A in cellular models, D2R-transfected human neuroblastoma SH SY5Y cells will be used to measure free radical formation, MEF2 and Nrf2 expression, and cell viability upon treatment with environmental toxin, paraquat, and haloperidol.****Long-term goals, beyond 5 years: 1. To determine whether intransal delivery of Peptide A prevents downregulation of dopamine transporters and D2Rs during oxidative stress using brain imaging. 2. To develop novel microgels for targeted delivery of Peptide A to the brain using our patented technology (Patent # 62/362,105,2016).****Novelty, Significance, and Impact:****This program uses technology ranging from cellular models to animal testing to advance our knowledge of oxidative stress and cell death. This research is essential as the mechanisms involved in cell death caused by certain compounds and environmental toxins are not known. Additionally, new insights into neuroprotection will help advance the development of more effective compounds. Combined with the production of novel microgels for enhanced targeted brain delivery, the patentable technology that will be developed in this project represents exciting opportunities for Canada to further increase its contribution to novel biological and engineering knowledge and techniques.***