https://lsa.umich.edu/psych/research&labs/berridge/publications/Berridge&RobinsonBrResRev1998.pdf

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

A stereotaxic atlas of the rat brain

Biosensors for real-time in vivo measurements.

Neurotransmitters are chemicals that are secreted by neurons and relay messages to target cells. The goal of in vivo electrochemistry is to provide a real-time view of neurotransmitters in the extracellular space of the brain. This may be done in brain slices or the intact brain of anesthetized animals to probe the basic functions that regulate neurotransmitter levels. In other experiments, the measurements need to be made in the brain of behaving animals so that correlations of neurotransmitter fluctuations and specific behaviors can be made. For the neurotransmitter dopamine this can be accomplished today by chemical sensing of this neurotransmitter with fast scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes. Dopamine is an important target because it is a central player in the brain ‘reward’ system, although its precise function is not understood. Proposed roles for dopamine in reward have included the mediation of hedonia (pleasure)1, a messenger of incentive salience (wanting)2, or an error signal that promotes the learning associated with goal-directed behavior3,4. These multiple interpretations of dopaminergic function have arisen because, until recently, a real-time view of dopamine and its actions in an awake, behaving animal was unavailable. At the same time, new electrochemical technologies are being developed to measure other neurotransmitter actions. Electrochemical approaches are well suited for this application because they allow a neurotransmitter to be measured with high time resolution, enabling its precise role in the execution of behavioral tasks to be investigated.

In this review we will describe current methods to detect neurotransmitters and monitor their concentration dynamics within neural tissue. The requirements for these methods are quite stringent. They need to be sufficiently selective so that the measured responses are unequivocally due to a specific molecule. They need to be sufficiently sensitive that they can detect these substances in the physiological range. The best established methodologies are for dopamine, so the majority of the applications of the methods described herein will involve this neurotransmitter. As will be seen, the goals in measuring neurotransmitter functions are diverse. On one hand, investigators are unraveling the mechanisms that control neurotransmitter concentrations. These studies range from examining biochemical synthesis to metabolism. On the other hand, investigators are questioning how the neurotransmitter interacts with its receptors and what message it conveys. Yet a third major interest is the role of a neurotransmitter in specific behaviors. To obtain a complete view of neurotransmission and information processing, chemical sensors need to be combined with traditional neurochemical tools. We will illustrate this approach with some specific examples.

/pdf/monitoring-rapid-chemical-communication-in-the-brain-1tx53qbg66.pdf

Monitoring Rapid Chemical Communication in the Brain

Background: Dopamine is a potent neuromodulator in the brain, influencing a variety of motivated behaviors and involved in several neurologic diseases. Measurements of extracellular dopamine in the brains of experimental animals have traditionally focused on a tonic timescale (minutes to hours). However, dopamine concentrations are now known to fluctuate on a phasic timescale (subseconds to seconds). Approach: Fast-scan cyclic voltammetry provides analytical chemical measurements of phasic dopamine signals in the rat brain. Content: Procedural aspects of the technique are discussed, with regard to appropriate use and in comparison with other methods. Finally, examples of data collected using fast-scan cyclic voltammetry are summarized, including naturally occurring dopamine transients and signals arising from electrical stimulation of dopamine neurons. Summary: Fast-scan cyclic voltammetry offers real-time measurements of changes in extracellular dopamine concentrations in vivo. With its subsecond time resolution, micrometer-dimension spatial resolution, and chemical selectivity, it is the most suitable technique currently available to measure transient concentration changes of dopamine. © 2003 American Association for Clinical Chemistry

Detecting subsecond dopamine release with fast-scan cyclic voltammetry in vivo.

Ultrastructure at carbon fiber microelectrode implantation sites after acute voltammetric measurements in the striatum of anesthetized rats

Carbon fiber microelectrodes either were implanted directly into striatal tissue or were mounted into the outlet of microdialysis probes that were implanted into striatal tissue. This allowed voltammetry and microdialysis to be used under identical in vivo experimental conditions to monitor extracellular dopamine levels during electrical stimulation of the medial forebrain bundle both before and after uptake inhibition with nomifensine. The marked differences between the results obtained with each technique cannot be explained on the basis of their inherent analytical attributes (sensitivity, temporal response, etc.). The results demonstrate that the microdialysis recovery factor for endogenous dopamine increases after uptake inhibition, an observation that stands in contradiction to the existing theory and practice of the microdialysis technique. The observations led to the development of a numerical model that rationalizes the observations reported herein and that allows in vivo voltammetry and in vivo microdialysis results to be interpreted within a single theoretical framework.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.1998.70020584.x

Direct Comparison of the Response of Voltammetry and Microdialysis to Electrically Evoked Release of Striatal Dopamine

Voltammetric microelectrodes and microdialysis probes were used simultaneously to monitor extracellular dopamine in rat striatum during electrical stimulation of the medial forebrain bundle. Microelectrodes were placed far away (1 mm) from, immediately adjacent to, and at the outlet of microdialysis probes. In drug-naive rats, electrical stimulation (45 Hz, 25 s) evoked a robust response at microelectrodes far away from the probes, but there was no response at microelectrodes adjacent to and at the outlet of the probes. After nomifensine administration (20 mg/kg i.p.), stimulation evoked robust responses at all three microelectrode placements. These results demonstrate first that evoked release in tissue adjacent to microdialysis probes is suppressed in comparison with evoked release in tissue far away from the probes and second that equilibration of the dopamine concentration in the extracellular fluid adjacent to and far away from the probes is prevented by the high-affinity dopamine transporter. Hence, models of microdialysis, which assume the properties of tissue to be spatially uniform, require modification to account for the distance that separates viable sites of evoked dopamine release from the probe. We introduce new mass transfer resistance parameters that qualitatively explain the observed effects of uptake inhibition on stimulation responses recorded with microdialysis and voltammetry.

Coupled effects of mass transfer and uptake kinetics on in vivo microdialysis of dopamine.

Numerical modeling was used as a means to examine the relationship between the outcome of in vivo voltammetry and microdialysis experiments and dopamine concentrations in the extracellular fluid of rat striatum. In the case of microdialysis, quantitative interpretation of results demands knowledge of the in vivo values for the extraction and recovery ratios of the probes toward dopamine. Equality of the extraction and recovery ratios is a necessary condition for the direct application of the no-net-flux method as a quantitative technique. Recent results have suggested that the extraction and recovery ratios are not equal, and this interpretation is now supported by theory. A new relationship between extraction and recovery is proposed.

Modeling Voltammetry and Microdialysis of Striatal Extracellular Dopamine: The Impact of Dopamine Uptake on Extraction and Recovery Ratios

The objective of this study was to examine whether the limited diffusion distance of dopamine in rat striatum produces spatial heterogeneity in the extracellular dopamine concentration on a dimensional scale of a few micrometers. Such heterogeneity would be significant because it would imply that the concentration of dopamine at a given receptor depends on the receptor's ultrastructural location. Spatially resolved measurements of extracellular dopamine were performed in the striatum of chloral hydrate-anesthetized rats with carbon fiber microdisk electrodes. Dopamine was monitored during electrical stimulation of the nigrostriatal pathway before and after administration of drugs that selectively affect the kinetics of evoked dopamine release and dopamine uptake. The effects of nomifensine (20 mg/kg), L-DOPA (250 mg/kg), and alpha-methyl-p-tyrosine (250 mg/kg) on the amplitude of the stimulation responses were examined. The outcome of these experiments was compared with predictions derived from a mathematical model that combines diffusion with the kinetics of release and uptake. The results demonstrate that the extracellular dopamine concentration is spatially heterogeneous on a micrometer scale and that changing the kinetics of dopamine release and uptake has different effects on this spatial distribution. The impact of these results on brain neurochemistry is considered.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2000.0741563.x

Changes in the kinetics of dopamine release and uptake have differential effects on the spatial distribution of extracellular dopamine concentration in rat striatum.

Jennifer L. Peters

Papers

Ultrastructure at carbon fiber microelectrode implantation sites after acute voltammetric measurements in the striatum of anesthetized rats

Direct Comparison of the Response of Voltammetry and Microdialysis to Electrically Evoked Release of Striatal Dopamine

Coupled effects of mass transfer and uptake kinetics on in vivo microdialysis of dopamine.

Modeling Voltammetry and Microdialysis of Striatal Extracellular Dopamine: The Impact of Dopamine Uptake on Extraction and Recovery Ratios

Changes in the kinetics of dopamine release and uptake have differential effects on the spatial distribution of extracellular dopamine concentration in rat striatum.