The pathophysiology, etiology, and treatment of schizophrenia remain elusive, but research is closing the gap. Schizophrenia globally affects less than 1% of the population and presents with positive, negative, and cognitive symptoms. As treatment for schizophrenia is not completely and meaningfully effective at treating all of the symptoms, without eliciting side effects, the current thesis aimed to evaluate a new drug candidate. PAOPA is a novel allosteric modulator that increases dopamine binding to the dopamine D2 receptor. It has previously shown positive findings in preventing and reversing behaviours proposed to model phenotypes of schizophrenia. However, it has not yet been tested to improve cognitive deficits in animal models, nor has its effects on other animals models been investigated. Lastly, its mechanism of action has not yet been comprehensively answered. In three separate studies, PAOPA was tested on ameliorating attentional deficits using the 5-choice serial reaction time task in an amphetamine model, deficits in novel objection recognition memory, sensorimotor gating, social interaction, and locomotor activity using a PCP model, and its effects on proteins regulating G protein-coupled receptors (GRK2 and arrestin-3), downstream signalling (ERK1 and ERK2), and synaptic vesicular control (synapsin II) were investigated. Although the sample sizes were too small to draw valid interpretations, the results suggested that PAOPA partially attenuated deficits in attention, novel object recognition memory, social interaction, sensorimotor gating, but not locomotor. Furthermore PAOPA increased the protein expression of GRK2, arrestin-3, ERK1 and 2, and synapsin IIa in the medial prefrontal cortex, striatum, and the nucleus accumbens. The results suggest that PAOPA influences the dopaminergic system in the striatum to change behaviour via receptor internalization and possibly downstream signalling. The present studies illuminate new insights, and point to future explorations for the potential development of PAOPA as a therapeutic for schizophrenia. / Thesis / Master of Science (MSc)

The nematode C. elegans is a multicellular model organism to study the neuronal-basis of behaviour. C. elegans demonstrates an innate response to swim towards the cathode in the presence of a DC electric field(EF), a behaviour known as “electrotaxis”. We examined mutants affecting sensory and dopaminergic neurons and found that these mutants moved with reduced speed with intermittent pauses, abnormal turning, and slower body bend. A similar phenotype was observed in worms treated with neurotoxins 6-OHDA, MPTP and rotenone. Pre-exposing worms to a known neuroprotective compound acetaminophen could suppress the effects of neurotoxin on movement. Further, this study demonstrates that dopamine and the D2-type dopamine receptor are necessary to modulate electrotactic movements in worms. A reduction in extracellular dopamine leads to a significant increase in the swimming speed as judged by the analysis of bas-1(dopa decarboxylase) and cat-1(VMAT) mutants. The dopamine transporter dat-1 acts genetically downstream of bas-1 and cat-1 since dat-1 mutants efficiently suppress bas-1 and cat-1 phenotypes. We also found that DOP-3(D2-type receptor) acts as the sole receptor for dopamine-mediated regulation of electrotaxis. Interestingly, we found that prolonged exposure to EF resulted in a gradual decline in the swimming speed such that animals were 40% slower at the end of ten minutes exercise period. This change is mediated by DOP-3 since dop-3 mutants continue to swim at the initial speed and don’t slow down. This conclusion is supported by the analysis of animals treated with Heloperidol(D2 antagonist) and SKF38393(D1 agonist). Overall, our work demonstrates that D2 receptor-mediated neuronal signalling is required to restrict muscle activity not only during the initial phase of electrotaxis swimming but also for the entire duration of the assay. We suggest that such a role of dopamine signalling might serve as an important and conserved mechanism to limit muscle overuse during prolonged physical exercise. / Thesis / Doctor of Science (PhD)

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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