This proposal is concerned with the application of """"""""fast"""""""" electrochemical methods for the determination of real-time serotonin reuptake and release in brain tissue derived from serotonin transporter knockout mice. These mice were produced to gain a clearer understanding of the role of the serotonin transporter in normative behavior, and in anxiety and mood disorders. Serotonin transporter knockout mice display elevations in spontaneous anxiety-like behavior and decreases in locomotor activation in response to 3,4- methylenedioxymethamphetamine (MDMA), a popular drug of abuse. It is hypothesized that these alterations in phenotype are directly attributable to long-term decreases in serotonin transporter function, which ultimately result in neuroadaptive changes in the serotonergic system and its postsynaptic targets. Many of the neurochemical and behavioral parameters studied to date show intermediate levels of change in mice bearing one functional copy of the serotonin transporter gene. However, transporter function initially assessed by [3H]serotonin uptake appears unaltered in heterozygote knockout mice. Therefore, we hypothesize that the characterization of serotonin uptake by classical radiochemical methods does not provide the temporal resolution necessary to detect important variations in the kinetics of the uptake process. The research described will: (1) Evaluate the kinetics of serotonin uptake using high-speed chronoamperometry in synaptosomes derived from serotonin transporter knockout mice; and (2) Characterize the dynamics of serotonin reuptake and release in specific brain regions in slice preparations from serotonin transporter knockout mice using fast scan cyclic voltammetry.
We aim to answer the question of whether intermediate changes in transporter expression lead to significant modifications in transporter function. This proposal represents the novel application of voltammetric techniques to the characterization of changes in serotonergic neurotransmission in transgenic mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064756-02
Application #
6620872
Study Section
Special Emphasis Panel (ZRG1-BECM (01))
Program Officer
Brady, Linda S
Project Start
2001-12-01
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$206,901
Indirect Cost
Name
Pennsylvania State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
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Bressler, Amanda; Blizard, David; Andrews, Anne (2010) Low-stress route learning using the Lashley III maze in mice. J Vis Exp :

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