| Notes: | Advisor: Xiaoxi Zhuang.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and The Pritzker School of Medicine, Committee on Neurobiology, 2014.
Dissertation Abstracts International, Volume: 76-02(E), Section: B.
|
|---|
| Summary: | Parkinson's disease (PD) constitutes the second most prevalent neurodegenerative disorder, with 7-10 million people afflicted worldwide. PD is characterized by the progressive and selective degeneration of the dopamine (DA) neurons that reside in the substantia nigra pars compacta (SNc), which causes motor impairments such as rigidity, bradykinesia/akinesia and the inability to initiate movement. Despite the fact that the underlying cause of DA degeneration remains unknown, epidemiological studies have consistently shown that both caffeine and nicotine use inversely correlates with PD incidence, and several clinical and animal studies have suggested both caffeine and nicotine may alleviate PD symptoms. However, the mechanisms by which caffeine and nicotine act to alleviate PD symptoms and reduce the incidence of PD remains unknown.
Recently, our lab has shown that dopamine blockade induces a learned inhibition of movement that is D2-dependent and encoded as abnormal corticostriatal plasticity at indirect pathway synapses. We have termed this phenomenon aberrant motor learning, and proposed that this learned inhibition of movement may partly underlie PD symptoms. Moreover, we have shown that theophylline, a derivative of caffeine and adenosine 2A receptor (A2A) antagonist, blocks abnormal corticostriatal plasticity at indirect pathway synapses as well as prevents the acquisition of aberrant motor learning.
Because nicotine interferes with endogenous acetylcholine regulation of dopamine release and both acetylcholine and dopamine are critically involved in corticostriatal plasticity, I asked if nicotine could prevent the acquisition of aberrant motor learning similar to theophylline and other A2A antagonists. Chronic nicotine, but not acute nicotine, blocked the initial acquisition of D2-mediated aberrant motor learning in a manner similar to A2A antagonists. This protective effect appeared to be mediated by [beta]2*-containing nicotinic acetylcholine receptors (nAChRs), as mice lacking the [beta]2* nAChR subunit were also protected against D2 antagonist induced aberrant motor learning. Additionally, while the acute effects of nicotine on dopamine release have been well defined, much less is known about how chronic nicotine, and hence repeated and prolonged desensitization of nAChRs, alters ongoing dopamine release dynamics, particularly in the intact animal. Thus, using fast-scan cyclic voltammetry, I examined stimulated dopamine release in anesthetized mice following chronic nicotine exposure, and found both chronic nicotine and genetic deletion of [beta]2* nAChR subunits significantly reduced dopamine release in response to both single pulse and burst stimulation. The results herein suggest that chronic nicotine reduces the dynamic range of dopamine release and that this chronically reduced range of dopamine release can promote neuroadaptations that in turn protect against the acquisition of aberrant motor learning. These results suggest that nicotine may decrease PD incidence by preventing the acquisition of aberrant motor learning, thereby delaying the progression of motor dysfunction, rather than protecting against dopamine cell death.
|
|---|
