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Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons

Nature Neuroscience volume 4, pages 275–281 (2001)Cite this article

Abstract

Amphetamine is a highly addictive psychostimulant that promotes the release of the catecholamines dopamine and norepinephrine. Amphetamine-induced release of dopamine in the midbrain inhibits the activity of dopamine neurons through activation of D2 dopamine autoreceptors. Here we show that amphetamine may also excite dopamine neurons through modulation of glutamate neurotransmission. Amphetamine potently inhibits metabotropic glutamate receptor (mGluR)-mediated IPSPs in dopamine neurons, but has no effect on ionotropic glutamate receptor-mediated EPSCs. Amphetamine desensitizes the mGluR-mediated hyperpolarization through release of dopamine, activation of postsynaptic α1 adrenergic receptors, and suppression of InsP3-induced calcium release from internal stores. By selectively suppressing the inhibitory component of glutamate-mediated transmission, amphetamine may promote burst firing of dopamine neurons. Through this mechanism, amphetamine may enhance phasic release of dopamine, which is important in the neural processing of reward.

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Figure 1: Amphetamine selectively inhibits the mGluR IPSP without affecting the glutamatergic EPSC in dopamine neurons.
Figure 2: Amphetamine (10 μM), dopamine (100 μM) and norepinephrine (30 μM) inhibit the mGluR IPSP through activation of α1 adrenergic receptors.
Figure 3: Amphetamine, dopamine and norepinephrine suppress the aspartate-induced hyperpolarization through activation of α1 adrenergic receptors.
Figure 4: Activation of α1 adrenergic receptors cause heterologous desensitization of the mGluR-mediated release of Ca2+ and the outward current induced by InsP3.
Figure 5: The amphetamine-induced inhibition of the hyperpolarization evoked by iontophoretically applied aspartate was blocked by the dopamine transporter blocker, GBR 12909.
Figure 6: Amphetamine selectively decreased the mGluR-mediated hyperpolarization.

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References

  1. Fon, E. A., et al. Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19, 1271–1283 (1997).

    Article  CAS  Google Scholar 

  2. Pierce, R. C. & Kalivas, P. W. Repeated cocaine modifies the mechanism by which amphetamine releases dopamine. J. Neurosci. 17, 3254–3261 (1997).

    Article  CAS  Google Scholar 

  3. Jones, S. R., Gainetdinov, R. R., Wightman, R. M. & Caron M. G. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J. Neurosci. 18, 1979–1986 (1998).

    Article  CAS  Google Scholar 

  4. Amara, S. G. & Sonders, M. S. Neurotransmitter transporters as molecular targets for addictive drugs. Drug Alcohol Depend. 51, 87–96 (1998).

    Article  CAS  Google Scholar 

  5. Groves, P. M., Wilson, C. J., Young, S. J. & Rebec, G. V. Self-inhibition by dopaminergic neurons. Science 190, 522–528 (1975).

    Article  CAS  Google Scholar 

  6. Mercuri, N. B., Calabresi, P. & Bernardi, G. The mechanism of amphetamine-induced inhibition of rat substantia nigra compacta neurones investigated with intracellular recording in vitro. Br. J. Phamacol. 98, 127–134 (1989).

    Article  CAS  Google Scholar 

  7. Pan, W .H., Sung, J. C. & Fuh, S. M. Locally application of amphetamine into the ventral tegmental area enhances dopamine release in the nucleus accumbens and the medial prefrontal cortex through noradrenergic neurotransmission. J. Pharmacol. Exp. Ther. 278, 725–731 (1996).

    CAS  PubMed  Google Scholar 

  8. Darracq, L., Blanc, G., Glowinski, J. & Tassin, J. P. Importance of the noradrenaline–dopamine coupling in the locomotor activating effects of d-amphetamine. J. Neurosci. 18, 2729–2739 (1998).

    Article  CAS  Google Scholar 

  9. Shi, W. X., Pun, C. L., Zhang, X. X., Jones, M. D. & Bunney, B. S. Dual effects of d-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors. J. Neurosci. 20, 3504–3511 (2000).

    Article  CAS  Google Scholar 

  10. Jones, S., Kornblum, J. L. & Kauer, J. A. Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J. Neurosci. 20, 5575–5580 (2000).

    Article  CAS  Google Scholar 

  11. Grace, A. A. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41, 1–24 (1991).

    Article  CAS  Google Scholar 

  12. Schultz, W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1–27 (1998).

    Article  CAS  Google Scholar 

  13. Overton, P. G. & Clark, D. Burst firing in midbrain dopaminergic neurons. Brain Res. Rev. 25, 312–334 (1997).

    Article  CAS  Google Scholar 

  14. Gonon, F. G. Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry. Neuroscience 24, 19–28 (1988).

    Article  CAS  Google Scholar 

  15. Suaud-Chagny, M. F., Chergui, K., Chouvet, G. & Gonon, F. Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area. Neuroscience 49, 63–72 (1992).

    Article  CAS  Google Scholar 

  16. Fiorillo, C. D. & Williams, J. T. Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394, 78–82 (1998).

    Article  CAS  Google Scholar 

  17. Clausing, P., Gough, B., Holson, R. R., Slikker, W. Jr. & Bower, J. F. Amphetamine levels in brain microdialysate, caudate/putamen, substantial nigra and plasma after dosage that produces either behavioral or neurotoxic effects. J. Pharmacol. Exp. Ther. 274, 614–621 (1995).

    CAS  PubMed  Google Scholar 

  18. Yokel, R. A. & Pickens, R. Drug level of d- and l-amphetamine during intravenous self-administration. Psychopharmacology (Berl.) 34, 255–264 (1974).

    Article  CAS  Google Scholar 

  19. Fiorillo, C. D. & Williams, J. T. Selective inhibition by adenosine of mGluR IPSPs in dopamine neurons following cocaine treatment. J. Neurophysiol. 83, 1307–1314 (2000).

    Article  CAS  Google Scholar 

  20. Jones, S. & Kauer, J. A. Amphetamine depresses excitatory synaptic transmission via serotonin receptors in the ventral tegmental area. J. Neurosci. 19, 9780–9787 (1999).

    Article  CAS  Google Scholar 

  21. Grenhoff, J., North, R. A. & Johnson, S. W. Alpha1-adrenergic effects on dopamine neurons recorded intracellularly in the rat midbrain slice. Eur. J. Neurosci. 7, 1707–1713 (1995).

    Article  CAS  Google Scholar 

  22. Ruffolo, R. R. Jr., Goldberg, M. R., & Morgan, E. L. Interactions of epinephrine, noradrenaline, dopamine, and their corresponding alpha-methyl-substituted derivatives with alpha and beta adrenoceptors in the pithed rat. J. Pharmacol. Exp. Ther. 230, 595–600 (1984).

    CAS  PubMed  Google Scholar 

  23. Reader, T. A., Brière, R. & Grondin, L. Alpha-1 and alpha-2 adrenoceptor binding in cerebral cortex: competition studies with [3H]prazocin and [3H]idazoxan. J. Neural Transm. 68, 79–95 (1987).

    Article  CAS  Google Scholar 

  24. Morikawa, H., Imani, F., Khodakhah, K. & Williams, J. T. Inositol 1,4,5-triphosphate-evoked responses in midbrain dopamine neurons. J. Neurosci. 20, RC103 1–5 (2000).

    Article  Google Scholar 

  25. Guatteo, E., Mercuri, N. B., Bernardi, G. & Knopfel, T. Group I metabotropic glutamate receptors mediate an inward current in rat substantia nigra dopamine neurons that is independent from calcium mobilization. J. Neurophysiol. 82, 1974–1981 (1999).

    Article  CAS  Google Scholar 

  26. Scarponi, M., Bernardi, G. & Mercuri, N. B. Electrophysiological evidence for a reciprocal interaction between amphetamine and cocaine-related drugs on rat midbrain dopaminergic neurons. Eur. J. Neurosci. 11, 593–598 (1999).

    Article  CAS  Google Scholar 

  27. Grenhoff, J., Nisell, M., Ferre, S., Aston-Jones, G. & Svensson, T. H. Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J. Neural Transm. Gen. Sect. 93, 11–25 (1993).

    Article  CAS  Google Scholar 

  28. Nicola, S. M., Kombian, S. B. & Malenka, R. C. Psychostimulants depress excitatory synaptic transmission in the nucleus accumbens via presynaptic D1-like dopamine receptors. J. Neurosci. 16, 1591–1604 (1996).

    Article  CAS  Google Scholar 

  29. Harvey, J. & Lacey, M. G. Endogenous and exogenous dopamine depress EPSCs in rat nucleus accumbens in vitro via D1 receptor activation. J. Physiol. (Lond.) 492, 143–154 (1996).

    Article  CAS  Google Scholar 

  30. Travagli, R. A. & Williams, J. T. Endogenous monoamines inhibit glutamate transmission in the spinal trigeminal nucleus of the guinea-pig. J. Physiol. (Lond.) 491, 177–185 (1996).

    Article  CAS  Google Scholar 

  31. Fiorillo, C. D. & Williams, J. T. Cholinergic inhibition of ventral midbrain dopamine neurons. J. Neurosci. 20, 7855–7860 (2000).

    Article  CAS  Google Scholar 

  32. Hajnoczky, G. & Thomas, A. P. The inositol trisphosphate calcium channel is inactivated by inositol trisphosphate. Nature 370, 474–477 (1994).

    Article  CAS  Google Scholar 

  33. Grace, A. A. & Bunney, B. S. The control of firing pattern in nigral dopamine neurons: burst firing. J. Neurosci. 11, 2877–2890 (1984).

    Article  Google Scholar 

  34. Marinelli, M. & White, F. J. Enhanced vulnerability to cocaine self-administration is associated with elevated impulse activity of midbrain dopamine neurons. J. Neurosci. 20, 8876–8885 (2000).

    Article  CAS  Google Scholar 

  35. Thomas, M. J., Malenka, R. C. & Bonci, A. Modulation of long-term depression by dopamine in the mesolimbic system. J. Neurosci. 20, 5581–5586 (2000).

    Article  CAS  Google Scholar 

  36. Blanc, G. et al. Blockade of prefronto-cortical alpha 1-adrenergic receptors prevents locomotor hyperactivity induced by subcortical D-amphetamine injection. Eur. J. Neurosci. 6, 293–298 (1994).

    Article  CAS  Google Scholar 

  37. Dickinson, S. L., Gadie, B. & Tulloch, I. F. Alpha 1- and alpha 2-adrenoreceptor antagonists differentially influence locomotor and stereotyped behaviour induced by d-amphetamine and apomorphine in the rat. Psychopharmacology (Berl.) 96, 521–527 (1988).

    Article  CAS  Google Scholar 

  38. Mavridis, M., Colpaert, F. C. & Millan, M. J. Differential modulation of (+)-amphetamine-induced rotation in unilateral substantia nigra lesioned rats by alpha 1 as compared to alpha 2 agonists and antagonists. Brain Res. 562, 216–224 (1991).

    Article  CAS  Google Scholar 

  39. Poncelet, M., Chermat, R., Soubrie, P. & Simon, P. The progressive ratio schedule as a model for studying the psychomotor stimulant activity of drugs in the rat. Psychopharmacology (Berl.) 80, 184–189 (1983).

    Article  CAS  Google Scholar 

  40. Snoddy, A. M. & Tessel, R. E. Prazosin: effect on psychomotor-stimulant cues and locomotor activity in mice. Eur. J. Pharmacol. 116, 221–228 (1985).

    Article  CAS  Google Scholar 

  41. Tessel, R. E. & Barrett, J. E. Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin. Psychopharmacology (Berl.) 90, 436–440 (1986).

    Article  CAS  Google Scholar 

  42. Grenhoff, J. & Svensson, T. H. Prazosin modulates the firing pattern of dopamine neurons in rat ventral tegmental area. Eur. J. Pharmacol. 233, 79–84 (1993).

    Article  CAS  Google Scholar 

  43. Williams, J. T., North, R. A., Shefner, S. A., Nishi, S. & Egan, T. M. Membrane properties of rat locus coeruleus neurones. Neuroscience 13, 137–56 (1984).

    Article  CAS  Google Scholar 

  44. Johnson, S. W. & North, R. A. Two types of neurone in the rat ventral tegmental area and their synaptic inputs. J. Physiol.(Lond.) 450, 455–468 (1992).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Khodakhah for instruction and guidance in the flash photolysis experiments, and O. Manzoni for comments on the work and manuscript. This work was supported by NIH grants DA04523 (J.T.W.), DA05793 (C.D.F.) and DA07262 (C.A.P.).

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Author notes

  1. Christopher D. Fiorillo

    Present address: Institute for Physiology, University of Fribourg, Rue du Musèe 5, CH 1700, Fribourg, Switzerland

  2. Carlos A. Paladini and Christopher D. Fiorillo: The first two authors contributed equally to this work

Authors and Affiliations

  1. The Vollum Institute, L474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, 97201, Oregon, USA

    Carlos A. Paladini, Christopher D. Fiorillo, Hitoshi Morikawa & John T. Williams

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  1. Carlos A. Paladini
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  2. Christopher D. Fiorillo
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Correspondence to John T. Williams.

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Paladini, C., Fiorillo, C., Morikawa, H. et al. Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons. Nat Neurosci 4, 275–281 (2001). https://doi.org/10.1038/85124

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