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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.

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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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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Shin, Samuel Sang-Hyunsss26@pitt.edu
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairGraham, Stevensgra@pitt.edu
    Committee MemberKline, Anthonyklinae@upmc.edu
    Committee MemberDixon, C. Edwarddixonec@upmc.edu
    Committee MemberSutton, Richardrsutton@mednet.ucla.edu
    Committee MemberPerez, Ruthpererx@upmc.edu
    Committee MemberHastings, Teresahasttx@upmc.edu
    Title: The Effects of Nicotine Treatment on Striatal Dopamine Neurotransmission after Traumatic Brain Injury
    Status: Unpublished
    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.
    Date: 16 March 2011
    Date Type: Completion
    Defense Date: 01 March 2011
    Approval Date: 16 March 2011
    Submission Date: 09 March 2011
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-03092011-222046
    Uncontrolled Keywords: dopamine; traumatic brain injury; nicotine; striatum
    Schools and Programs: School of Medicine > Neurobiology
    Date Deposited: 10 Nov 2011 14:32
    Last Modified: 24 Feb 2012 14:16
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-03092011-222046/, etd-03092011-222046

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