Transient surges of dopamine in the nucleus accumbens are associated with drug seeking. Using a voltammetric sensor with high temporal and spatial resolution, we demonstrate differences in the temporal profile of dopamine concentration transients caused by acute doses of nicotine, ethanol, and cocaine in the nucleus accumbens shell of freely moving rats. Despite differential release dynamics, all drug effects are uniformly inhibited by administration of rimonabant, a cannabinoid receptor (CB 1 ) antagonist, suggesting that an increase in endocannabinoid tone facilitates the effects of commonly abused drugs on subsecond dopamine release. These time-resolved chemical measurements provide unique insight into the neurobiological effectiveness of rimonabant in treating addictive disorders.
Dopamine concentrations fluctuate on a subsecond time scale in the nucleus accumbens (NAc) of awake rats. These transients occur in resting animals, are more frequent following administration of drugs of abuse, and become time-locked to cues predicting reward. Despite their importance in various behaviors, the origin of these signals has not been demonstrated. Here we show that dopamine transients are evoked by neural activity in the ventral tegmental area (VTA), a brain region containing dopaminergic cell bodies. The frequency of naturally occurring dopamine transients in a resting, awake animal was reduced by a local VTA microinfusion of either lidocaine or (Ϯ)2-amino,5-phosphopentanoic acid (AP-5), an NMDA receptor antagonist that attenuates phasic firing. When dopamine increases were pharmacologically evoked by noncontingent administration of cocaine, intra-VTA infusion of lidocaine or AP-5 significantly diminished this effect. Dopamine transients acquired in response to a cue during intracranial self-stimulation were also attenuated by intra-VTA microinfusion of AP-5, and this was accompanied by an increase in latency to lever press. The results from these three distinct experiments directly demonstrate, for the first time, how neuronal firing of dopamine neurons originating in the VTA translates into synaptic overflow in a key terminal region, the NAc shell.Key words: in vivo voltammetry; neurotransmission; carbon-fiber microelectrode; cocaine; intracranial self-stimulation; burst firing IntroductionDopaminergic neurons provide a critical modulatory influence in reward seeking (Everitt and Robbins, 2000;Phillips et al., 2003a), prediction error (Schultz et al., 1997 and reinforcement (Wise, 2004). Real-time dopamine neurotransmission in awake animals, monitored with fast-scan cyclic voltammetry at carbonfiber microelectrodes, has revealed naturally occurring, subsecond dopamine concentration fluctuations (transients) in the nucleus accumbens (NAc) (Robinson et al., 2002;Wightman et al., 2007). Under basal conditions these transients occur at highly variable frequencies with amplitudes of ϳ50 nM and durations of ϳ1 s . They are enhanced upon administration of drugs of abuse (Stuber et al., 2005), and become timelocked to cues that predict reward availability (Phillips et al., 2003a;Roitman et al., 2004;Day et al., 2007;Owesson-White et al., 2008). Despite their importance, the origin of dopamine transients in the NAc is unclear.The most likely cause of dopamine transients is phasic firing of dopaminergic neurons in the ventral tegmental area (VTA).These neurons normally fire in a tonic pattern (ϳ5 Hz) and periodically discharge in short bursts (ϳ20 Hz). Bursts are particularly apparent at presentation of primary rewards or their associated cues (Schultz et al., 1997;Hyland et al., 2002). The activity of dopaminergic neurons is regulated by multiple inputs (Floresco et al., 2003;Lodge and Grace, 2006), and in brain slices that lack these inputs, phasic activity is not observed (Overton and Clark, 1997). In t...
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.
Fast-scan cyclic voltammetry has been used in a variety of applications and has been shown to be especially useful to monitor chemical fluctuations of neurotransmitters such as dopamine within the mammalian brain. A major limitation of this procedure, however, is the large amplitude of the background current relative to the currents for the solution species of interest. Furthermore, the background tends to drift, and this drift limits the use of digital background subtraction techniques to intervals less than 90 s before distortion of dopamine signals occurs. To minimize the impact of the background, a procedure termed analog background subtraction is reported here. The background is recorded, and its inverse is played back to the current transducer during data acquisition so that it cancels the background in subsequent scans. Background drift still occurs and is recorded, but its magnitude is small compared to the original background. This approach has two advantages. First it allows the use of higher gains in the current transducer, minimizing quantization noise. Second, because the background amplitude is greatly reduced, principal component regression could be used to separate the contributions from drift, dopamine, and pH when appropriate calibrations were performed. We demonstrate the use of this approach with several applications. First, transient dopamine fluctuations were monitored for 15 min in a flowing injection apparatus. Second, evoked release of dopamine was monitored for a similar period in the brain of an anesthetized rat. Third, dopamine was monitored in the brain of freely moving rats over a 30 min interval. By analyzing the fluctuations in each resolved component, we were able to show that cocaine causes significant fluctuations in dopamine concentration in the brain while those for the background and pH remain unchanged from their predrug value.
Hydrogen peroxide is a reactive oxygen species that is implicated in a number of neurological disease states and that serves a critical role in normal cell function. It is commonly exploited as a reporter molecule enabling the electrochemical detection of non-electroactive molecules at electrodes modified with substrate-specific oxidative enzymes. We present the first voltammetric characterization of rapid hydrogen peroxide fluctuations at an uncoated carbon fiber microelectrode, demonstrating unprecedented chemical and spatial resolution. The carbon surface was electrochemically conditioned on the anodic scan and the irreversible oxidation of peroxide was detected on the cathodic scan. The oxidation potential was dependent on scan rate, occurring at +1.2 V vs. Ag/AgCl at a scan rate of 400 V·sec -1 . The relationship between peak oxidation current and concentration was linear across the physiological range tested, with deviation from linearity above 2 mM and a detection limit of 2 μM. Peroxide was distinguished from multiple interferents, both in vitro and in brain slices. The enzymatic degradation of peroxide was monitored, as was peroxide evolution in response to glucose at a glucose oxidase modified carbon fiber electrode. This novel approach provides the requisite sensitivity, selectivity, spatial and temporal resolution to study dynamic peroxide fluctuations in discrete biological locations.
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