The striatum interfaces with cortical and subcortical structures to affect cognitive function. Previous work suggests that in the controlled cortical impact (CCI) model of experimental traumatic brain injury (TBI), spatial memory and exploratory behavior in novel environments is impaired. The therapeutic benefits of dopamine (DA) agonists following clinical and experimental models of TBI suggest a role for DA systems in mediating these deficits post-injury. Motivated by these observations, we have used in vivo electrochemical monitoring with fast scan cyclic voltammetry (FSCV) to assess alterations in electrically evoked extracellular DA levels after CCI. After CCI, in vivo evoked overflow of DA is impaired. Additionally there are decrements in DA clearance that correspond to decreased DAT expression after CCI. Additionally, the effects of the neurostimulant, methylphenidate, on DAT function are moderated by CCI. In awake rats after CCI, it also appears that regulation of basal DA levels is impaired. When examining tissue damage sustained directly around striatal placement of microdialysis probes, this type of trauma also suppresses evoked DA release and affects autoregulation of basal DA levels around the injury site. While the effects of CCI and direct striatal injury (DSI) from microdialysis probes on stimulated DA release and basal DA levels is significant, it is critically important to extend these investigations regarding TBI on DA neurotransmission. Currently, we can monitor tonic changes in [DA] in awake animals after pharmacological manipulation using FSCV. However, Mark Wightman has recently improved the performance of his voltammetric recording techniques such that he can now detect spontaneous DA transients, presumably associated with the burst firing of midbrain DA neurons. Wightman's approach has been refined, in part, through the implementation of principle components regression (PCR) to resolve DA signals from other interferents observed in the voltammetric trace. We speculate that adapting this technique would be a viable approach for objectively assessing and refining measurement of tonic changes in DA measured over several minutes, and thus, would provide an additional tool for measuring not only phasic, but also, tonic aspects of DA transmission. Our central hypothesis is that spontaneous striatal DA transients and regulatory mechanisms affecting basal DA are impaired after TBI. Hence, we have the following long-range scientific objectives: 1) to characterize the effects of trauma on naturally occurring, as opposed to electrically evoked, extracellular DA; 2) to characterize the state of regulatory mechanisms governing basal DA after TBI 3) to characterize the effects of DAT inhibitors on striatal extracellular DA post-injury; 4) to temporally link behavioral performance in cognitive tasks with spontaneous DA transients after CCI. In support of these scientific objectives, the technical aim of this R21, is to incorporate this new voltammetric system, including chemometrics with PCR, in to our own studies of phasic and tonic DA transmission in two models of TBI. These scientific objectives derived from adapting in vivo voltammetry monitoring to awake rats with CCI will lay the ground-work for evaluating a number of rehabilitation relevant, dopaminergic, and other therapeutic interventions and the mechanisms by which they restore DA neurotransmission and cognition after injury. The overarching goal is to gain insight into potential mechanisms of action and efficacy of these interventions on cognition and recovery for the clinical population with TBI. ? ? ?
| Wagner, Amy K; Sokoloski, Joshua E; Chen, Xiangbai et al. (2009) Controlled cortical impact injury influences methylphenidate-induced changes in striatal dopamine neurotransmission. J Neurochem 110:801-10 |
