Real-time measurement of dopamine fluctuations after cocaine in the brain of behaving rats

Abstract

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...

Sensory effects of intravenous cocaine on dopamine and non-dopamine ventral tegmental area neurons

“…Although cocaine has no effect on DA release in vitro (Heikkila et al, 1975), some data suggest that it can increase DA release in vivo. By using fast-cyclic voltammetry in awake, drug-naive rats, iv cocaine was found to increase NAcc extracellular DA levels at surprisingly short latencies (Heien et al, 2005). The effect was clearly evident at 10-20 s post-injection and grew afterwards and, while dose-dependent, it was seen after cocaine at low dose (0.3 mg/kg) similar to that used in our study.…”

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation

“…Principal component regression, a chemometric technique that combines principal component analysis with inverse least-squares regression (Heien et al, 2005), was used to isolate changes in current due to dopamine and pH from the cyclic voltammetric data. We used a standard training set of dopamine, pH, and drift CVs as has been described previously (Aitken et al, 2016;Collins et al, 2016).…”

Adolescent Alcohol Exposure Amplifies the Incentive Value of Reward-Predictive Cues Through Potentiation of Phasic Dopamine Signaling

“…Reward-evoked dopamine release in response to uncued sucrose pellet delivery was used to ensure electrode viability prior to each behavioral session. Dopamine was isolated from the voltammetric signal with chemometric analysis (Heien et al, 2005) using a standard training set based on stimulated dopamine release. Dopamine concentration was estimated based on the average postimplantation electrode sensitivity .…”