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.
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References
Feldman, R. S., Meyer, J. S. & Quenzer, L. F. Principles of Neuropsychopharmacology 324–344 (Sinauer, Sunderland, Massachusetts, 1992).
Axelrod, J. & Kopin, I. J. The uptake, storage, release and metabolism of noradrenaline in sympathetic nerves. Prog. Brain Res. 31, 21–32 (1969).
Lindvall, O. & Bjorklund, A. in Chemical Neuroanatomy (ed. Emson, P. C.) 229–255 (Raven, New York, 1983).
Amara, S. G. & Kuhar, M. J. Neurotransmitter transporters: recent progress. Annu. Rev. Neurosci. 16, 73–93 (1993).
Giros, B. & Caron, M. G. Molecular characterization of the dopamine transporter. Trends Pharmacol. Sci. 14, 43–49 (1993).
Pacholczyk, T., Blakely, R. D. & Amara, S. G. Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350, 350–354 (1991).
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).
Markou, A., Kosten, T. R. & Koob, G. F. Neurobiological similarities in depression and drug dependence: a self- medication hypothesis. Neuropsychopharmacology 18, 135–174 (1998).
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).
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).
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).
Jones, S. R. et al. Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat. Neurosci. 2, 649–655 (1999).
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).
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).
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).
Leonard, B. E. The role of noradrenaline in depression: a review. J. Psychopharmacol. 11, S39–S47 (1997).
Hornig, A. & Van Praag, H. M. Depression: Neurobiological, Psychopathological and Therapeutic Advances (Wiley, New York, 1997).
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).
Steru, L. et al. The automated tail suspension test: a computerized device which differentiates psychotropic drugs. Prog. Neuropsychopharmacol. Biol. Psychiatry 11, 659–671 (1987).
Richelson, E. Synaptic effects of antidepressants. J. Clin. Psychopharmacol. 16, 1S–7S (1996).
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).
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).
Willner, P. The mesolimbic dopamine system as a target for rapid antidepressant action. Int. Clin. Psychopharmacol. 12 (Suppl. 3), S7–S14 (1997).
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).
Nestler, E. J. & Aghajanian, G. K. Molecular and cellular basis of addiction. Science 278, 58–63 (1997).
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).
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).
Rocha, B. A. et al. Cocaine self-administration in dopamine-transporter knockout mice. Nat. Neurosci. 1, 132–137 (1998).
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).
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).
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).
Grenhoff, J. & Svensson, T. H. Clonidine modulates dopamine firing in rat ventral tegmental area. Eur. J. Pharmacol. 165, 11–18 (1989).
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).
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).
Mann, J. J. & Kapur, S. A dopaminergic hypothesis of major depression. Clin. Neuropharm. 18, S57–S65 (1995).
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).
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).
Gainetdinov, R. R. et al. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283, 397–401 (1999).
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).
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).
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.
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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
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DOI: https://doi.org/10.1038/74839
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