Modeling Fast-scan Cyclic Voltammetry Data from Electrically Stimulated Dopamine Neurotransmission Data Using QNsim1.0

Central dopaminergic (DAergic) pathways have an important role in a wide range of functions, such as attention, motivation, and movement. Dopamine (DA) is ...

University of Pittsburgh

University of Pittsburgh, School of Medicine

Traumatic brain injury (TBI) results in functional deficits that often are effectively treated clinically with the neurostimulant, methylphenidate (MPH). We hypothesized that daily MPH administration would reverse striatal neurotransmission deficits observed in the controlled cortical impact (CCI) model of TBI. CCI or naïve rats received daily injections of MPH (5 mg/kg) or saline for 14 days and were assessed on day 15 using fast scan cyclic voltammetry. Dopamine (DA) transporter (DAT) localization, DA-related proteins, and transcription factor (c-fos) expression were also assessed. CCI resulted in reduced electrically evoked overflow of DA and maximal velocity of DA clearance (V(max)). In contrast, CCI was associated with a decrease in the apparent K(M) of DAT. Daily dose of MPH after CCI resulted in robust increases in evoked DA overflow and V(max) as well as increased apparent K(M). Reductions in total striatal DAT expression occurred after CCI and were not further affected by MPH. In contrast, membrane-bound striatal DAT levels were increased in both CCI groups. MPH post-CCI significantly increased striatal c-fos levels compared with saline. These results support the hypothesis that daily MPH improves striatal DA neurotransmission after CCI. DAT expression and transcriptional changes affecting DA protein function may underlie the injury and MPH-induced alterations in neurotransmission observed.

Chronic methylphenidate treatment enhances striatal dopamine neurotransmission after experimental traumatic brain injury.

Traumatic brain injury features deficits are often ameliorated by dopamine (DA) agonists. We have previously shown deficits in striatal DA neurotransmission using fast scan cyclic voltammetry after controlled cortical impact (CCI) injury that are reversed after daily treatment with the DA uptake inhibitor methylphenidate (MPH). The goal of this study was to determine how a single dose of MPH (5 mg/kg) induces changes in basal DA and metabolite levels and with electrically evoked overflow (EO) DA in the striatum of CCI rats. MPH-induced changes in EO DA after a 2-week daily pre-treatment regime with MPH was also assessed. There were no baseline differences in basal DA or metabolite levels. MPH injection significantly increased basal [DA] output in dialysates for control but not injured rats. Also, MPH injection increased striatal peak EO [DA] to a lesser degree in CCI (176% of baseline) versus control rats (233% of baseline). However, daily pre-treatment with MPH resulted in CCI rats having a comparable increase in EO [DA] after MPH injection when compared with controls. The findings further support the concept that daily MPH therapy restores striatal DA neurotransmission after CCI.

Controlled cortical impact injury influences methylphenidate-induced changes in striatal dopamine neurotransmission.

Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can assess real-time in vivo dopamine (DA) concentration changes to study the kinetics of DA neurotransmission. Electrical stimulation of dopaminergic (DAergic) pathways can elicit FSCV DA responses that largely reflect a balance of DA release and reuptake. Interpretation of these evoked DA responses requires a framework to discern the contribution of DA release and reuptake. The current, widely implemented interpretive framework for doing so is the Michaelis-Menten (M-M) model, which is grounded on two assumptions- (1) DA release rate is constant during stimulation, and (2) DA reuptake occurs through dopamine transporters (DAT) in a manner consistent with M-M enzyme kinetics. Though the M-M model can simulate evoked DA responses that rise convexly, response types that predominate in the ventral striatum, the M-M model cannot simulate dorsal striatal responses that rise concavely. Based on current neurotransmission principles and experimental FSCV data, we developed a novel, quantitative, neurobiological framework to interpret DA responses that assumes DA release decreases exponentially during stimulation and continues post-stimulation at a diminishing rate. Our model also incorporates dynamic M-M kinetics to describe DA reuptake as a process of decreasing reuptake efficiency. We demonstrate that this quantitative, neurobiological model is an extension of the traditional M-M model that can simulate heterogeneous regional DA responses following manipulation of stimulation duration, frequency, and DA pharmacology. The proposed model can advance our interpretive framework for future in vivo FSCV studies examining regional DA kinetics and their alteration by disease and DA pharmacology.

Neurobiological model of stimulated dopamine neurotransmission to interpret fast-scan cyclic voltammetry data.

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury. Currently, little is understood about chronic changes in striatal dopamine (DA) systems after hypoxic-ischemic brain injury. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal (60Hz, 10s MFB stimulation) electrical stimulations in rats to characterize presynaptic components of DA neurotransmission in dorsal striatum (D-Str) and nucleus accumbens (NAc) 14 days after a 5-minute VF-CA when compared to Sham or Naïve. VF-CA increased D-Str evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (Vmax). Methylphenidate (MPH) (10mg/kg), a DA transporter (DAT) inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60Hz, 5s stimulation response. MPH increased initial evoked overflow [DA] more-so in VF-CA versus sham and reduced D-Str Vmax in VF-CA but not Shams; these findings are consistent with upregulated striatal DAT in VF-CA versus Sham. Our work demonstrates that 5-minute VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions. This article is protected by copyright. All rights reserved.

Rashed Harun

Center for Neuroscience,
Safar Center for Resuscitation Research

University of Pittsburgh

Modeling Fast-scan Cyclic Voltammetry Data from Electrically Stimulated Dopamine Neurotransmission Data Using QNsim1.0

Rashed Harun

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Center for Neuroscience,Safar Center for Resuscitation Research

University of Pittsburgh

Modeling Fast-scan Cyclic Voltammetry Data from Electrically Stimulated Dopamine Neurotransmission Data Using QNsim1.0

Center for Neuroscience,
Safar Center for Resuscitation Research