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Loss of autoreceptor functions in mice lacking the dopamine transporter

Nature Neuroscience volume 2, pages 649–655 (1999)Cite this article

Abstract

Autoreceptors provide an important inhibitory feedback mechanism for dopamine neurons by altering neuronal functions in response to changes in extracellular levels of dopamine. Elevated dopamine may be a component of several neuropsychiatric disorders. However, evidence concerning the state of autoreceptors in such conditions has remained elusive. The function of dopamine autoreceptors was assessed in mice lacking the dopamine transporter (DAT). Genetic deletion of the DAT gene in mice results in a persistent elevation in levels of extracellular dopamine. Direct assessment of impulse-, synthesis- and release-regulating autoreceptors in these mice reveals a nearly complete loss of function. These findings may provide insight into the neurochemical consequences of hyperdopaminergia.

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Figure 1: D2-type dopamine receptor binding in ventral midbrain.
Figure 2: In-vivo assessment of overall dopamine autoreceptor function.
Figure 3: Effect of quinpirole on the firing rate of VTA neurons.
Figure 4: Effects of GBL (750 mg per kg, i.p.) on extracellular dopamine levels in the striatum of WT and DAT–/– mice.
Figure 5: Ex-vivo application of the GBL protocol for testing synthesis-regulating autoreceptor function.
Figure 6: In-vivo microdialysis application of the GBL model for testing synthesis-regulating autoreceptor function.
Figure 7: Voltammetric evaluation of release-regulating autoreceptors.

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Acknowledgements

We thank Jason Holt and Susan Suter for technical assistance. S.R.J. is the recipient of a Young Investigator Award from NARSAD. This work was supported in part by NIH grant NS 19576, an unrestricted Neuroscience Award from Bristol-Myers Squibb and an unrestricted grant from Zeneca Pharmaceuticals to M.G.C. M.G.C. is an Investigator of the Howard Hughes Medical Institute. R.R.G. is a visiting scientist from the Institute of Pharmacology RAMS, Moscow, Russia.

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Authors and Affiliations

  1. Departments of Cell Biology and Medicine, Howard Hughes Medical Institute, Box 3287, 487 CARL Bldg.

    Sara R. Jones, Raul R. Gainetdinov & Marc G. Caron

  2. Duke University Medical Center, Durham, 27710, North Carolina , USA

    Sara R. Jones, Raul R. Gainetdinov & Marc G. Caron

  3. Finch University of Health Sciences, The Chicago Medical School, 3333 Green Bay Road, North Chicago, 60064-3095, Illinois, USA

    Xiu-Ti Hu, Donald C. Cooper & Francis J. White

  4. Department of Chemistry and Curriculum in Neurobiology CB, #3290 Venable Hall

    R. Mark Wightman

  5. University of North Carolina at Chapel Hill, Chapel Hill, 27599-3290, North Carolina, USA

    R. Mark Wightman

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  1. Sara R. Jones
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Correspondence to Marc G. Caron.

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Jones, S., Gainetdinov, R., Hu, XT. et al. Loss of autoreceptor functions in mice lacking the dopamine transporter . Nat Neurosci 2, 649–655 (1999). https://doi.org/10.1038/10204

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