Dopamine neurotransmission has been implicated in the modulation of many cognitive processes. Both rapid (phasic) and slower (tonic) changes in its extracellular concentration contribute to its complex actions. Fast in vivo electrochemical techniques can measure extracellular dopamine on a rapid time scale but without the selectivity afforded with slower techniques that use chemical separations. Cyclic voltammetry improves chemical resolution over other electrochemical methods, and it can resolve dopamine changes in the brains of behaving rodents over short epochs (<10 s). With this method, however, selective detection of slower dopamine changes is still elusive. Here we demonstrate that principal component regression of cyclic voltammetry data enables quantification of changes in dopamine and extracellular pH. Using this method, we show that cocaine modifies dopamine release in two ways: dopamine concentration transients increase in frequency and magnitude, whereas a gradual increase in steady-state dopamine concentration occurs over 90 s.cyclic voltammetry ͉ nucleus accumbens ͉ principal component regression F ast changes in the extracellular concentration of neurotransmitter can arise from phasic neuronal firing, whereas longlasting changes are associated with tonic firing (1). Dopaminergic neurons exhibit both of these firing patterns. Phasic activity accompanies salient stimuli, whereas tonic firing regulates the steady-state extracellular concentration (2). For this reason, chemical sensors for dopamine should be able to operate on a wide range of time scales in behaving animals. Microdialysis, a commonly used in vivo chemical sampling technique, is well suited to measure the minute-to-minute changes (tonic) that occur after uptake inhibition by agents such as cocaine (3,4). In vivo voltammetry, another approach for dopamine sampling, can measure much faster events, enabling phasic dopamine changes to be measured (5).A limitation of all voltammetric techniques has been their chemical selectivity. Fast-scan cyclic voltammetry at carbonfiber microelectrodes (6) provides rapid measurements and yields a chemical signature, the cyclic voltammogram, that allows distinction among electroactive molecules that are present in the brain. The electrode is highly sensitive to dopamine relative to dihydroxyphenylacetic acid and ascorbate, two major interferants, and the voltammogram of dopamine is distinct from those for a variety of neurochemical substances, although it is the same as that for norepinephrine (7). However, measurements in behaving rats have revealed that rapid dopamine changes are usually accompanied by other rapid changes in the electrochemical signal (5,8,9). Measurements with ion-selective electrodes demonstrated that these signals arise from a change in the pH of the brain extracellular fluid (10). Therefore, an objective method is needed to resolve the detected chemical events, assign them to specific compounds, and evaluate their temporal characteristics.Voltammetric electrodes are similar to othe...

Many individual neurons within the intact brain fire in stochastic patterns that arise from interactions with the neuronal circuits that they comprise. However, the chemical communication that is evoked by these firing patterns has not been characterized because sensors suitable to monitor subsecond chemical events in micron dimensions have only recently become available. Here we employ a voltammetric sensor technology coupled with principal component regression to examine the dynamics of dopamine concentrations in the nucleus accumbens (NAc) of awake and unrestrained rats. The sensor has submillimeter dimensions and provides high temporal (0.1 s) resolution. At select locations spontaneous dopamine transient concentration changes were detected, achieving instantaneous concentrations of approximately 50 nm. At other locations, transients were absent even though dopamine was available for release as shown by extracellular dopamine increases following electrical activation of dopaminergic neurons. At sites where dopamine concentration transients occur, uptake inhibition by cocaine enhances the frequency and magnitude of the rapid transients while also causing a more gradual increase in extracellular dopamine. These effects were largely absent from sites that did not support ongoing transient activity. These findings reveal an unanticipated spatial and temporal heterogeneity of dopamine transmission within the NAc that may depend upon the firing of specific subpopulations of dopamine neurons.

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post-TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d-amphetamine-induced rotational behavior. Adult male Sprague-Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine-induced rotational behavior was assessed 10 days post-CCI. Fourteen days post-CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in V max (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury-related changes in vesicular monoamine transporter or D 2 receptor expression (DRD 2 ) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.

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.

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Experimental models of traumatic brain injury (TBI) have been utilized to characterize the behavioral derangements associated with brain trauma. Several studies exist characterizing motor function in the controlled cortical impact (CCI) injury model of TBI, but less research has focused on how CCI affects exploratory behavior. The goal of this study was to characterize deficits in three novelty exploration tasks after the CCI. Under anesthesia, 37 adult male Sprague Dawley rats received CCI (2.7 mm and 2.9 mm; 4 m/sec) over the right parietal cortex or sham surgery. For days 1-6 post-surgery, the beam balance and beam walking tasks were used to assess motor deficits. The Open Field, Y-Maze, and Free Choice Novelty (FCN) tasks were used to measure exploratory deficits from days 7-14 post-surgery. Injured rats displayed a significant, but transient, deficit on each motor task (p < 0.0001). Open Field results showed that injured rats had lower activity levels than shams (p < 0.0001), displayed less habituation to the task, and had more anxiety related behaviors (thigmotaxis) across days (p < 0.0001). Y-maze results suggest that injured rats spent less time in the novel arm versus the familiar arms when compared to shams (p < 0.0001). For FCN, injured rats were less active (p < 0.05) and spent less time and had fewer interactions with objects in the novel environment compared to shams (p < 0.05). These results suggest that several ethological factors contribute to exploratory deficits after CCI and can be effectively characterized with the behavioral tasks described. Future work will utilize these tasks to evaluate the neural substrates underlying exploratory deficits after TBI.

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.

Over the last several decades, theoretical and methodological advances in the fields of neuroscience, psychophysiology, and molecular genetics have extended into the study of cross-cultural differences in emotion. These advances have accompanied a rise in the use of biological methods and measures to examine cross-cultural differences of emotion particularly in studies of children. The findings from existing studies using these methods and measures are mixed and inconsistent, across a range of emotion phenotypes. In the present article, we argue that current biocultural models of emotion are limited in their explanatory power to account for differences because they neglect the importance of developmental processes. Here we review the extant literature on cultural studies that have used biological measures with a particular focus on shyness, aggression, and interpersonal processes of emotion. We then propose a revised biocultural model of emotion that attempts to account for developmental processes that we believe has explanatory power to reconcile some of the inconsistencies in the extant literature. We suggest this revised model as a preliminary framework to derive testable hypotheses to guide future studies in the area.