Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mice lacking the norepinephrine transporter are supersensitive to psychostimulants

Abstract

The action of norepinephrine (NE) is terminated, in part, by its uptake into presynaptic noradrenergic neurons by the plasma-membrane NE transporter (NET), which is a target for antidepressants and psychostimulants. Disruption of the NET gene in mice prolonged the clearance of NE and elevated extracellular levels of this catecholamine. In a classical test for antidepressant drugs, the NET-deficient (NET−/−) animals behaved like antidepressant-treated wild-type mice. Mutants were hyper-responsive to locomotor stimulation by cocaine or amphetamine. These responses were accompanied by dopamine D2/D3 receptor supersensitivity. Thus altering NET expression significantly modulates midbrain dopaminergic function, an effect that may be an important component of the actions of antidepressants and psychostimulants.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted disruption of the NET gene and characterization of wild-type and NET−/− mice.
Figure 2: Neurochemical changes in NE homeostasis in NET−/− mice.
Figure 3: Responses by wild-type and NET−/− mice in the tail-suspension and Porsolt forced-swim tests of ‘behavioral despair’.
Figure 4: Locomotor and rewarding effects of cocaine in wild-type and NET−/− mice.
Figure 5: Presynaptic and postsynaptic changes in striatal dopaminergic function in wild-type and NET−/− mice.

Similar content being viewed by others

References

  1. Feldman, R. S., Meyer, J. S. & Quenzer, L. F. Principles of Neuropsychopharmacology 324–344 (Sinauer, Sunderland, Massachusetts, 1992).

    Google Scholar 

  2. Axelrod, J. & Kopin, I. J. The uptake, storage, release and metabolism of noradrenaline in sympathetic nerves. Prog. Brain Res. 31, 21–32 (1969).

    Article  CAS  Google Scholar 

  3. Lindvall, O. & Bjorklund, A. in Chemical Neuroanatomy (ed. Emson, P. C.) 229–255 (Raven, New York, 1983).

    Google Scholar 

  4. Amara, S. G. & Kuhar, M. J. Neurotransmitter transporters: recent progress. Annu. Rev. Neurosci. 16, 73–93 (1993).

    Article  CAS  Google Scholar 

  5. Giros, B. & Caron, M. G. Molecular characterization of the dopamine transporter. Trends Pharmacol. Sci. 14, 43–49 (1993).

    Article  CAS  Google Scholar 

  6. Pacholczyk, T., Blakely, R. D. & Amara, S. G. Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350, 350–354 (1991).

    Article  CAS  Google Scholar 

  7. Fritz, J. D., Jayanthi, L. D., Thoreson, M. A. & Blakely, R. D. Cloning and chromosomal mapping of the murine norepinephrine transporter. J. Neurochem. 70, 2241–2251 (1998).

    Article  CAS  Google Scholar 

  8. Markou, A., Kosten, T. R. & Koob, G. F. Neurobiological similarities in depression and drug dependence: a self- medication hypothesis. Neuropsychopharmacology 18, 135–174 (1998).

    Article  CAS  Google Scholar 

  9. Robinson, T. E. & Berridge, K. C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Rev. 18, 247–291 (1993).

    Article  CAS  Google Scholar 

  10. Jones, S. R. et al. Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc. Natl. Acad. Sci. USA 95, 4029–4034 (1998).

    Article  CAS  Google Scholar 

  11. Gainetdinov, R. R., Jones, S. R., Fumagalli, F., Wightman, R. M. & Caron, M. G. Re-evaluation of the role of the dopamine transporter in dopamine system homeostasis. Brain Res. Rev. 26, 148–153 (1998).

    Article  CAS  Google Scholar 

  12. Jones, S. R. et al. Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat. Neurosci. 2, 649–655 (1999).

    Article  CAS  Google Scholar 

  13. Bengel, D. et al. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (‘Ecstasy’) in serotonin transporter- deficient mice. Mol. Pharmacol. 53, 649–655 (1998).

    Article  CAS  Google Scholar 

  14. Wang, Y. M. et al. Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19, 1285–1296 (1997).

    Article  CAS  Google Scholar 

  15. Palij P. & Stamford, J. A. Real-time monitoring of endogenous noradrenaline release in rat brain slices using fast cyclic voltammetry: 1. Characterization of evoked noradrenaline efflux and uptake from nerve terminals in the bed nucleus of stria terminalis, pars ventralis. Brain Res. 587, 137–146 (1992).

    Article  CAS  Google Scholar 

  16. Leonard, B. E. The role of noradrenaline in depression: a review. J. Psychopharmacol. 11, S39–S47 (1997).

    CAS  Google Scholar 

  17. Hornig, A. & Van Praag, H. M. Depression: Neurobiological, Psychopathological and Therapeutic Advances (Wiley, New York, 1997).

    Google Scholar 

  18. Porsolt, R. D., Bertin, A. & Jalfre, M. Behavioral despair in mice: a primary screening test for antidepressants. Arch. Int. Pharmacodyn. Ther. 229, 327–336 (1977).

    CAS  Google Scholar 

  19. Steru, L. et al. The automated tail suspension test: a computerized device which differentiates psychotropic drugs. Prog. Neuropsychopharmacol. Biol. Psychiatry 11, 659–671 (1987).

    Article  CAS  Google Scholar 

  20. Richelson, E. Synaptic effects of antidepressants. J. Clin. Psychopharmacol. 16, 1S–7S (1996).

    Article  CAS  Google Scholar 

  21. Giros, B. et al. Delineation of discrete domains for substrate, cocaine and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters. J. Biol. Chem. 269, 15985–15988 (1994).

    CAS  Google Scholar 

  22. Rossetti, Z. L., D'Aquila, P. S., Hmaidan, Y., Gessa, G. L. & Serra, G. Repeated treatment with imipramine potentiates cocaine-induced dopamine release and motor stimulation. Eur. J. Pharmacol. 201, 243–245 (1991).

    Article  CAS  Google Scholar 

  23. Willner, P. The mesolimbic dopamine system as a target for rapid antidepressant action. Int. Clin. Psychopharmacol. 12 (Suppl. 3), S7–S14 (1997).

    Article  Google Scholar 

  24. Spyraki, C. & Fibiger, H. C. Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine. Eur. J. Pharmacol. 74, 195–206 (1981).

    Article  CAS  Google Scholar 

  25. Nestler, E. J. & Aghajanian, G. K. Molecular and cellular basis of addiction. Science 278, 58–63 (1997).

    Article  CAS  Google Scholar 

  26. Carr, G. D., Fibiger, H. C. & Phillips, A. G. in The Neuropharmacological Basis of Reward (eds. Liebman, J. M. & Cooper, S. J.) 265–319 (Clarendon, Oxford, 1989).

    Google Scholar 

  27. Giros, B., Jaber, M., Jones, S. R., Wightman, R. M. & Caron, M. G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–612 (1996).

    Article  CAS  Google Scholar 

  28. Rocha, B. A. et al. Cocaine self-administration in dopamine-transporter knockout mice. Nat. Neurosci. 1, 132–137 (1998).

    Article  CAS  Google Scholar 

  29. Sora, I. et al. Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc. Natl. Acad. Sci. USA 95, 7699–7704 (1998).

    Article  CAS  Google Scholar 

  30. Reith, M. E. A. & Chen, N. in Neurotransmitter Transporters: Structure, Function and Regulation (ed. Reith, M. E. A.) 345–391 (Humana Press, Totowa, New Jersey, 1997).

    Book  Google Scholar 

  31. Yavich, L., Lappalainen, R., Sirvio, J., Haapalinna, A. & MacDonald, E. Alpha2-adrenergic control of dopamine overflow and metabolism in mouse striatum. Eur. J. Pharmacol. 339, 113–119 (1997).

    Article  CAS  Google Scholar 

  32. Grenhoff, J. & Svensson, T. H. Clonidine modulates dopamine firing in rat ventral tegmental area. Eur. J. Pharmacol. 165, 11–18 (1989).

    Article  CAS  Google Scholar 

  33. Cragg, S. J., Rice, M. E. & Greenfield, S. A. Heterogeneity of electrically evoked dopamine release and reuptake in substantia nigra, ventral tegmental area and striatum. J. Neurophysiol. 77, 863–873 (1997).

    Article  CAS  Google Scholar 

  34. Willner P. Sensitization of dopamine D2- or D3-type receptors as a final common pathway in antidepressant drug action. Clin. Neuropharmacol. 18 (Suppl. 1), S49–S56 (1995).

    Article  Google Scholar 

  35. Mann, J. J. & Kapur, S. A dopaminergic hypothesis of major depression. Clin. Neuropharm. 18, S57–S65 (1995).

    Article  Google Scholar 

  36. Backstrom, I. T., Ross, S. B. & Marcusson, J. O. [3H]desipramine binding to rat brain tissue: binding to both noradrenaline uptake sites and sites not related to noradrenaline neurons. J. Neurochem. 52, 1099–1106 (1989).

    Article  CAS  Google Scholar 

  37. Krobert, K. A., Sutton, R. L. & Feeney, D. M. Spontaneous and amphetamine-evoked release of cerebellar noradrenaline after sensimotor cortex contusion: an in vivo microdialysis study in the awake rat. J. Neurochem. 62, 2233–2240 (1994).

    Article  CAS  Google Scholar 

  38. Gainetdinov, R. R. et al. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283, 397–401 (1999).

    Article  CAS  Google Scholar 

  39. Gong, W., Neill, D. & Justice, J. B. Jr. Conditioned place preference and locomotor activation produced by injection of psychostimulants into ventral pallidum. Brain Res. 707, 64–74 (1996).

    Article  CAS  Google Scholar 

  40. Rinken, A., Finnman, U. B. & Fuxe, K. Pharmacological characterization of dopamine-stimulated [35S]-guanosine 5′-(λ-thiotriphosphate) ([35S]GTPλS) binding in rat striatal membranes. Biochem. Pharmacol. 57, 155–162 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank J. Holt and S. Suter for technical assistance. We are grateful to C. Bock of the Duke University Cancer Center Transgenic Facility for her assistance in the generation of the NET−/− mice. We also thank R. Mortensen (Harvard University, Cambridge, Massachusetts) for providing the pNTK-KO vector and W. Gong (Emory University, Atlanta, Georgia), D. Yang (Eli Lilly, Indianapolis, Indiana), Y. Zhuang (Duke University, Durham, North Carolina) and R. Premont (Duke University) for their help and advice. This work was supported in part by NIH grants NS-19576 and MH-40159 and a Neuroscience Unrestricted Award from Bristol Myers Squibb to M.G.C. M.G.C. is an investigator of the Howard Hughes Medical Institute, W.C.W. is supported in part as a NARSAD Independent Investigator and by NIH grant HD-36015, and R.R. Gainetdinov is a visiting researcher from the Institute of Pharmacology, Russian Academy of Medical Sciences, Baltiyskaya 8, 125315 Moscow, Russia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marc G. Caron.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, F., Gainetdinov, R., Wetsel, W. et al. Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci 3, 465–471 (2000). https://doi.org/10.1038/74839

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/74839

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing