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The Effects of Nicotine Treatment on Striatal Dopamine Neurotransmission after Traumatic Brain Injury

Shin, Samuel Sang-Hyun (2011) The Effects of Nicotine Treatment on Striatal Dopamine Neurotransmission after Traumatic Brain Injury. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Traumatic brain injury (TBI) is a widespread problem in the United States affecting thousands of individuals annually. Due to our lack of understanding of the mechanisms of TBI, medical management of the functional deficits in these patients is difficult. In this study, injury induced deficits in striatal dopamine neurotransmission was studied using rats injured by controlled cortical impact. We identified specific decrease in the levels of phosphorylated tyrosine hydroxylase (TH) measured by Western blots in the striatum and substantia nigra at 1 week following TBI, suggesting a decrease in TH activity. A direct measurement of TH activity by an in-vivo TH activity assay showed a correlating deficit in the injured animals. Striatal dopamine release evoked by potassium stimulus using microdialysis probes was decreased in injured animals compared to shams at 1 week. These results suggest deficits in presynaptic dopamine synthesis and release. To reverse these deficits, nicotine which was previously demonstrated to enhance striatal dopamine signaling, was administered for 1 week following injury. Rats that were treated with nicotine showed recovery of dopamine release and TH activity deficits. We have previously identified that TBI induces deficits in phosphorylation of striatal posynaptic protein: dopamine and cAMP regulated phosphoprotein 32 (DARPP-32), an important regulator of striatal dopamine signaling. To assess if nicotine treatment can also reverse this deficit in DARPP-32 phosphorylation at threonine 34 (pDARPP-32-T34), Western blot was used. There was no enhancement of pDARPP-32-T34 levels by nicotine treatment compared to saline controls. Also, phosphorylation levels of molecules downstream of pDARPP-32-T34: extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) were not affected by nicotine treatment. Behavioral experiments testing motor function by Beam Balance Test and Beam Walking Test and cognitive function by Morris Water Maze test showed no benefits of nicotine treatment. The molecular results in this study suggest that nicotine may lead to activativation of multiple receptor signaling pathways that have opposite modulation of pDARPP-32-T34. This study gives us a better understanding of the complex signaling pathways of striatal dopamine neurotransmission in the setting of TBI.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shin, Samuel Sang-Hyunsss26@pitt.eduSSS26
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGraham, Stevensgra@pitt.eduSGRA
Committee MemberKline, Anthonyklinae@upmc.edu
Committee MemberDixon, C. Edwarddixonec@upmc.eduEDIXON
Committee MemberSutton, Richardrsutton@mednet.ucla.edu
Committee MemberPerez, Ruthpererx@upmc.edu
Committee MemberHastings, Teresahasttx@upmc.edu
Date: 16 March 2011
Date Type: Completion
Defense Date: 1 March 2011
Approval Date: 16 March 2011
Submission Date: 9 March 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: dopamine; traumatic brain injury; nicotine; striatum
Other ID: http://etd.library.pitt.edu/ETD/available/etd-03092011-222046/, etd-03092011-222046
Date Deposited: 10 Nov 2011 19:32
Last Modified: 19 Dec 2016 14:35
URI: http://d-scholarship.pitt.edu/id/eprint/6470

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