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.
|Stein, Murray B; Andrews, Anne M (2015) Serotonin States and Social Anxiety. JAMA Psychiatry 72:845-7|
|Yang, Hongyan; Sampson, Maureen M; Senturk, Damla et al. (2015) Sex- and SERT-mediated differences in stimulated serotonin revealed by fast microdialysis. ACS Chem Neurosci 6:1487-501|
|Altieri, Stefanie C; Yang, Hongyan; O'Brien, Hannah J et al. (2015) Perinatal vs genetic programming of serotonin states associated with anxiety. Neuropsychopharmacology 40:1456-70|
|Carkaci-Salli, Nurgul; Salli, Ugur; Tekin, Izel et al. (2014) Functional characterization of the S41Y (C2755A) polymorphism of tryptophan hydroxylase 2. J Neurochem 130:748-58|
|Yang, Hongyan; Thompson, Andrew B; McIntosh, Bryan J et al. (2013) Physiologically relevant changes in serotonin resolved by fast microdialysis. ACS Chem Neurosci 4:790-8|
|Moya, Pablo R; Wendland, Jens R; Rubenstein, Liza M et al. (2013) Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder. Mov Disord 28:1263-70|
|Beikmann, Brendan S; Tomlinson, Ian D; Rosenthal, Sandra J et al. (2013) Serotonin uptake is largely mediated by platelets versus lymphocytes in peripheral blood cells. ACS Chem Neurosci 4:161-70|
|Singh, Y S; Altieri, S C; Gilman, T L et al. (2012) Differential serotonin transport is linked to the rh5-HTTLPR in peripheral blood cells. Transl Psychiatry 2:e77|
|Singh, Yogesh S; Sawarynski, Lauren E; Dabiri, Pasha D et al. (2011) Head-to-head comparisons of carbon fiber microelectrode coatings for sensitive and selective neurotransmitter detection by voltammetry. Anal Chem 83:6658-66|
|Bressler, Amanda; Blizard, David; Andrews, Anne (2010) Low-stress route learning using the Lashley III maze in mice. J Vis Exp :|
Showing the most recent 10 out of 17 publications