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15. Measurement of dopamine


15. Measurement of dopamine

For various reasons, the measurement of dopamine in relation to psychological contexts is not possible for diagnostic or treatment purposes.
Dopamine cannot cross the blood-brain barrier.

15.1. Dopamine measurements in peripheral body fluids or cerebral spinal fluid

Measuring the concentration of dopamine and its metabolites (e.g. homovanillic acid, HVA) in peripheral body fluids or in cerebral spinal fluid (CSF) is not sensitive enough to say anything about dopamine activity in the brain.
A comparison of HVA concentrations in four brain regions (dorsal frontal cortex, orbital frontal cortex, caudate nucleus and putamen), CSF and blood plasma found a single significant correlation (between CSF and dorsal frontal cortex), so that measurements of HVA concentration in the raw plasma (even when influences by diet or anesthesia are excluded ) show barely any benefit for the assessment of central dopamine metabolism and turnover.1

Peripheral dopamine levels say little about brain dopamine levels because dopamine is not only synthesized and released in the brain, but also by various peripheral tissues, e.g. 2

  • Pancreas
  • Adrenal medulla
  • Kidney
  • peripheral leukocytes.

This also applies to the measurement3

  • the amount of the degradation enzyme MAO in the blood
  • the prolactin stress response

Finally, dopaminergic-mediated influences on behavior do not necessarily require a change in dopamine levels or its metabolites. They can also result from mere changes in receptors or dopamine fluxes.

15.2. Blink rate as an indicator of dopamine level changes

The blink rate (Eyeblink)4

  • correlates with the activity of DRD1 and DRD256
    • basal blink rate may correlate more strongly with DRD2
  • can indicate reduced or increased dopamine activity7 and the normalization of this activity after treatment
    • especially striatal dopamine8
  • can reliably predict individual differences in performance on many cognitive tasks, particularly in relation to reward-driven behavior and cognitive flexibility

Two studies found no correlation between blink rate and dopamine activity.910

15.3. Retina and increased extracellular dopamine

A non-invasive analysis of retinal responses to light revealed an increased extracellular dopamine level resulting from a genetically determined increased DAT dopamine efflux.11

15.4. Dopamine measurement in the laboratory

Dopamine can be measured in vitro (on tissue samples) in various ways:3

  • Measurement of the electrical activity of downstream neurons in response to stimulation of dopaminergic neurons
  • Measurement of the firing rate of individual dopaminergic neurons in response to dopamine-relevant stimuli
  • Measuring the effect of dopamine agonists and dopamine antagonists
  • SPECT examinations measure the binding behavior of radioactively labeled dopamine ligands; this allows an indirect conclusion to be drawn about the dopamine concentration
    • dopamine release can be detected by means of the radioligand [11C]-raclopride by reducing the D2R binding potential
  • Imaging studies can show activity of dopaminergic neurons in response to dopamine-related stimuli

15.4.1. Electrochemical measurement methods

Cyclic fast scan voltammetry (FSCV)12

  • Measurement of the change in dopamine release
    • FSCV requires the subtraction of a baseline current, therefore only suitable for recording dopamine changes
  • In vivo, in vitro
  • Carbon fiber electrode is inserted into tissue and triangular wave is applied (-0.6 to 1 V)
  • Fast sampling rate (> 400 V/s)
    • Sampling rate is relatively slow compared to the speed of exocytosis
  • Detection rate 10 to 100 Hz
  • Different compounds generate oxidation and reduction currents at different voltages during the scan; peak current for dopamine at approx. 0.6 V


  • Similar to FSCV, but uses a constant potential (~0.6 V for dopamine) at the electrode.
  • High temporal resolution, limited only by sampling rate.
  • Limited specificity for dopamine. Can therefore only be used if dopamine is the most important electroactive substance.
  • Oxidation consumes dopamine and can therefore contribute to the signal decay.


  • Measurement of the absolute dopamine level
  • Usually with subsequent high-performance liquid chromatography
  • In vivo
  • Sensitive enough to measure basal dopamine levels in the brains of living animals
  • Low temporal resolution, therefore unsuitable for measuring fast dopamine transients
  • Tissue damage due to probe; may affect measurements

15.4.2. Measurement of whole cells

D2 IPSC recording12

  • Indicates the activation of DRD2.
    • other dopamine release is not measured
  • Method uses GPCR signal transduction, which causes a delay of approx. 50 to 100 ms between dopamine release and detection.
  • GIRK (G-protein-activated inwardly rectifying potassium channels) generate an inhibitory postsynaptic current (IPSC) when activated by dopamine, which can be measured.
  • DRD2 is coupled to GIRK in midbrain dopamine neurons
  • In the striatum, DRD2s are not coupled to GIRKs. However, GIRKs can be virally expressed to signal D2 activation.


  • dopamine-sensitive chloride channel in C. elegans
  • Measurement of the chloride current with good sensitivity and specificity for dopamine

15.4.3. Imaging procedures


  • Measurement of the fusion of individual vesicles from individual varicosities
  • VMAT-pHluorin is a pH-sensitive fluorophore that is intraluminally bound to VMAT2
  • Fusion of VMAT-pHluorin-labeled vesicles with plasma membrane increases fluorescence signal
  • Specificity limited; result shows vesicular release of all neurotransmitters released from dopamine neurons

Fluorescent false neurotransmitters (FFN)12

  • FFN are VMAT2 substrates that are selectively loaded into monoamine-containing vesicles
  • Upon release of vesicles, FFN diffusion reduces fluorescence in the varicosities
  • Analysis of individual varicosities
  • Sensitivity is limited, as even with strong stimulation only a small proportion of the vesicles of a terminal are released

Genetically encoded dopamine sensors (dLight; GrabDA)12

  • Analysis of dopamine receptors
  • Fluorescent indicators obtained by engineering dopamine receptors
  • Labeling with circularly permuted GFP
  • In vivo; in vitro
  • High sensitivity
  • High spatio-temporal resolution

Nanotube sensors12

  • Investigation of the spatial and temporal properties of dopamine release
  • Single-walled carbon nanotubes
    • Conjugated with single-stranded oligonucleotides
    • Fluorescent in the near infrared range
  • In vivo; in vitro
  • Direct insertion into tissue
  • Strong increase in fluorescence after binding to dopamine
  • Fast response
  • Very sensitive
  • Specificity limited, as other catecholamines and ascorbic acid are also detected

15.4.4. Dopamine release at surface level

  • Previously, dopamine could only be measured selectively. This only made it possible to record a quantity value at a single point. In the meantime, methods have been developed with which dopamine release can be measured and recorded on an area level. One method describes the observation of dopamine release from whole cells,13 another the area-based observation of dopamine release down to dendrite level.14
    These new techniques enable considerable gains in knowledge.

15.5. DAT promoter methylation in blood could predict DAT expression in the striatum

A measurement of DAT promoter methylation in the blood could possibly serve as an indicator of DAT expression in the striatum.15

  1. Elsworth JD, Leahy DJ, Roth RH, Redmond DE Jr (1987): Homovanillic acid concentrations in brain, CSF and plasma as indicators of central dopamine function in primates. J Neural Transm. 1987;68(1-2):51-62. doi: 10.1007/BF01244639. PMID: 3806086.

  2. DiCarlo GE, Wallace MT. Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neurosci Biobehav Rev. 2022 Feb;133:104494. doi: 10.1016/j.neubiorev.2021.12.017. PMID: 34906613; PMCID: PMC8792250.

  3. Müller (2007): Dopamin und kognitive Handlungssteuerung: Flexibilität und Stabilität in einem Set-Shifting Paradigma. Dissertation

  4. Jongkees BJ, Colzato LS (2016): Spontaneous eye blink rate as predictor of dopamine-related cognitive function-A review. Neurosci Biobehav Rev. 2016 Dec;71:58-82. doi: 10.1016/j.neubiorev.2016.08.020. PMID: 27555290. REVIEW

  5. Demiral ŞB, Manza P, Biesecker E, Wiers C, Shokri-Kojori E, McPherson K, Dennis E, Johnson A, Tomasi D, Wang GJ, Volkow ND (2022): Striatal D1 and D2 receptor availability are selectively associated with eye-blink rates after methylphenidate treatment. Commun Biol. 2022 Sep 26;5(1):1015. doi: 10.1038/s42003-022-03979-5. PMID: 36163254; PMCID: PMC9513088.

  6. Elsworth JD, Lawrence MS, Roth RH, Taylor JR, Mailman RB, Nichols DE, Lewis MH, Redmond DE Jr (1991): D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey. J Pharmacol Exp Ther. 1991 Nov;259(2):595-600. PMID: 1682479.

  7. Chen EY, Lam LC, Chen RY, Nguyen DG (1996): Blink rate, neurocognitive impairments, and symptoms in schizophrenia. Biol Psychiatry. 1996 Oct 1;40(7):597-603. doi: 10.1016/0006-3223(95)00482-3. PMID: 8886292.

  8. Sadibolova R, Monaldi L, Terhune DB (2022): A proxy measure of striatal dopamine predicts individual differences in temporal precision. Psychon Bull Rev. 2022 Aug;29(4):1307-1316. doi: 10.3758/s13423-022-02077-1. PMID: 35318580; PMCID: PMC9436857.

  9. van den Bosch R, Hezemans FH, Määttä JI, Hofmans L, Papadopetraki D, Verkes RJ, Marquand AF, Booij J, Cools R (2023): Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity. Elife. 2023 Apr 21;12:e83161. doi: 10.7554/eLife.83161. PMID: 37083626; PMCID: PMC10162803.

  10. van der Post J, de Waal PP, de Kam ML, Cohen AF, van Gerven JM (2004): No evidence of the usefulness of eye blinking as a marker for central dopaminergic activity. J Psychopharmacol. 2004 Mar;18(1):109-14. doi: 10.1177/0269881104042832. PMID: 15107193.

  11. Dai H, Jackson CR, Davis GL, Blakely RD, McMahon DG (2017): Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model. J Neurodev Disord. 2017 Dec 28;9(1):38. doi: 10.1186/s11689-017-9215-8. PMID: 29281965; PMCID: PMC5745861.

  12. Liu C, Kaeser PS (2019): Mechanisms and regulation of dopamine release. Curr Opin Neurobiol. 2019 Aug;57:46-53. doi: 10.1016/j.conb.2019.01.001. PMID: 30769276; PMCID: PMC6629510. REVIEW

  13. Zeng S, Wang S, Xie X, Yang SH, Fan JH, Nie Z, Huang Y, Wang HH. Live-Cell Imaging of Neurotransmitter Release with a Cell-Surface-Anchored DNA-Nanoprism Fluorescent Sensor. Anal Chem. 2020 Nov 17;92(22):15194-15201. doi: 10.1021/acs.analchem.0c03764. PMID: 33136382.

  14. Bulumulla, Krasley, Cristofori-Armstrong, Valinsky, Walpita, Ackerman, Clapham, Beyene (2022): Visualizing synaptic dopamine efflux with a 2D composite nanofilm. Elife. 2022 Jul 4;11:e78773. doi: 10.7554/eLife.78773. PMID: 35786443; PMCID: PMC9363124.

  15. Wiers CE, Lohoff FW, Lee J, Muench C, Freeman C, Zehra A, Marenco S, Lipska BK, Auluck PK, Feng N, Sun H, Goldman D, Swanson JM, Wang GJ, Volkow ND (2018): Methylation of the dopamine transporter gene in blood is associated with striatal dopamine transporter availability in ADHD: A preliminary study. Eur J Neurosci. 2018 Aug;48(3):1884-1895. doi: 10.1111/ejn.14067. PMID: 30033547; PMCID: PMC6113083.

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