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.

Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission

Abstract

The mesolimbic dopamine system is centrally involved in reward and goal-directed behavior, and it has been implicated in multiple psychiatric disorders. Understanding the mechanism by which dopamine participates in these activities requires comprehension of the dynamics of dopamine release. Here we report dissociable regulation of dopamine neuron discharge by two separate afferent systems in rats; inhibition of pallidal afferents selectively increased the population activity of dopamine neurons, whereas activation of pedunculopontine inputs increased burst firing. Only the increase in population activity increased ventral striatal dopamine efflux. After blockade of dopamine reuptake, however, enhanced bursting increased dopamine efflux three times more than did enhanced population activity. These results provide insight into multiple regulatory systems that modulate dopamine system function: burst firing induces massive synaptic dopamine release, which is rapidly removed by reuptake before escaping the synaptic cleft, whereas increased population activity modulates tonic extrasynaptic dopamine levels that are less influenced by reuptake.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Dopamine neuron activity states can be differentially modulated by subcortical nuclei.
Figure 2: Analysis of the firing rate distributions of dopamine neurons following manipulation of VP and PPTg afferents to the VTA.
Figure 3: Modulation of dopamine release in the nucleus accumbens by manipulations which selectively increase dopamine neuron population activity or burst firing.
Figure 4: Histology.

References

  1. 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 

  2. Grace, A.A. Cortical regulation of subcortical dopamine systems and its possible relevance to schizophrenia. J. Neural. Trans. 91, 111–134 (1993).

    Article  CAS  Google Scholar 

  3. 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 (1993).

    Article  Google Scholar 

  4. Garris, P.A., Ciolkowski, E.L., Pastore, P. & Wightman, R.M. Efflux of dopamine from synaptic cleft in the nucleus accumbens. J. Neurosci. 14, 6084–6093 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Gronier, B. & Rasmussen, K. Activation of midbrain presumed dopaminergic neurones by muscarinic cholinergic receptors: an in vivo electrophysiological study in the rat. Br. J. Pharmacol. 124, 455–464 (1998).

    Article  CAS  Google Scholar 

  7. Kitai, S.T., Shepard, P.D., Callaway, J.C. & Scroggs, R. Afferent modulation of dopamine neuron firing patterns. Curr. Opin. Neurobiol. 9, 690–697 (1999).

    Article  CAS  Google Scholar 

  8. Howland, J.G., Taepavarapruk, P. & Phillips, A.G. Glutamate receptor-dependent modulation of dopamine efflux in the nucleus accumbens by basolateral, but not central, nucleus of the amygdala in rats. J. Neurosci. 22, 1137–1145 (2002).

    Article  CAS  Google Scholar 

  9. Floresco, S.B., Todd, C.L. & Grace, A.A. Glutamatergic afferents from hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J. Neurosci. 21, 4915–4922 (2001).

    Article  CAS  Google Scholar 

  10. Wu, M., Hrycyshyn, A.W. & Brudzynski, S.M. Subpallidal outputs to the nucleus accumbens and ventral tegmental area: anatomical and electrophysiological studies. Brain Res. 740, 151–161 (1996).

    Article  CAS  Google Scholar 

  11. Zahm, D.A. & Heimer, L. Two transpallidal pathways originating in the nucleus accumbens. J. Comp. Neurol. 302, 437–446 (1990).

    Article  CAS  Google Scholar 

  12. Clement, J.R. & Grant, S. Glutamate-like immunoreactivity in neurons of the laterodorsal and pedunculopontine nucleus in the rat. Neurosci. Lett. 120, 70–73 (1990).

    Article  Google Scholar 

  13. Oakman, S.A., Faris, P.L., Kerr, P.E., Cozzari, C. & Hartman, B.K. Distribution of pontomesencephalic cholinergic neurons projecting to substantia nigra differ significantly from those projecting to the ventral tegmental area. J. Neurosci. 15, 5859–5869 (1995).

    Article  CAS  Google Scholar 

  14. Tsai, C.T., Mogenson, G.J., Wu, M. & Yang, C.R. A comparison of the effects of electrical stimulation of the amygdala and hippocampus on subpallidal output neurons to the pedunculopontine nucleus. Brain Res. 49, 422–429 (1985).

    Google Scholar 

  15. Maslowski-Cobuzzi, R.J. & Napier TC. Activation of dopaminergic neurons modulates ventral pallidal responses evoked by amygdala stimulation. Neuroscience 62, 1103–1119 (1994).

    Article  CAS  Google Scholar 

  16. Karreman, M., Westerink, B.H. & Moghaddam, B. Excitatory amino acid receptors in the ventral tegmental area regulate dopamine release in the ventral striatum. J. Neurochem. 67, 601–607 (1996).

    Article  CAS  Google Scholar 

  17. Mayer, M.L., Westbrook, G.L. & Guthrie, P.B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309, 261–263 (1984).

    Article  CAS  Google Scholar 

  18. Nirenberg, M.J. et al. The dopamine transporter: comparative ultrastructure of dopaminergic axons in limbic and motor compartments of the nucleus accumbens. J. Neurosci. 17, 6899–6907 (1997).

    Article  CAS  Google Scholar 

  19. Sesack, S.R. Synaptology of Dopamine Neurons. in Handbook of Experimental Pharmacology: Dopamine in the CNS (ed. Di Chiara G.) 63–119 (Springer-Verlag, Heidelberg, 2002).

    Google Scholar 

  20. Meiergerd, S.M., Patterson, T.A. & Schenk, J.O. D2 receptors may modulate the function of the striatal transporter for dopamine: kinetic evidence from studies in vitro and in vivo. J. Neurochem. 61, 764–767 (1993).

    Article  CAS  Google Scholar 

  21. Wightman, R.M. & Robinson, D.L. Transient changes in mesolimbic dopamine and their association with 'reward'. J. Neurochem. 82, 721–735 (2002).

    Article  CAS  Google Scholar 

  22. O'Donnell, P. & Grace, A.A. Tonic D2-mediated attenuation of cortical excitation in nucleus accumbens neurons recorded in vitro. Brain Res. 634, 105–112 (1994).

    Article  CAS  Google Scholar 

  23. Richfield, E.K., Penney, J.B. & Young, A.B. Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system. Neuroscience 30, 767–777 (1989).

    Article  CAS  Google Scholar 

  24. Redgrave, P., Prescott, T.J. & Gurney, K. Is the short-latency dopamine response too short to signal reward error? Trends Neurosci. 22, 146–151 (1999).

    Article  CAS  Google Scholar 

  25. Floresco, S.B., Blaha, C.D., Yang, C.R. & Phillips, A.G. Modulation of hippocampal and amygdalar-evoked activity of nucleus accumbens neurons by dopamine: cellular mechanisms of input selection. J. Neurosci. 21, 2851–2860 (2001).

    Article  CAS  Google Scholar 

  26. Wickens, J.R., Begg, A.J. & Arbuthnott GW Dopamine reverses the depression of rat corticostriatal synapses which normally follows high-frequency stimulation of cortex in vitro. Neuroscience 70, 1–5 (1996).

    Article  CAS  Google Scholar 

  27. Datla, K.P., Ahier, R.G., Young, A.M.J., Gray, J.A. & Joseph, M.H. Conditioned appetitive stimulus increases extracellular dopamine in the nucleus accumbens of the rat. Eur. J. Neurosci. 16, 1987–1993 (2002).

    Article  CAS  Google Scholar 

  28. Phillips, A.G., Atkinson, L.J., Blackburn, J.R. & Blaha, C.D. Increased extracellular dopamine in the nucleus accumbens of the rat elicited by a conditional stimulus for food: an electrochemical study. Can. J. Physiol. Pharmacol. 71, 387–393 (1993).

    Article  CAS  Google Scholar 

  29. Shenton, M.E., Dickey, C.C., Frumin, M. & McCarley, R.W. A review of MRI findings in schizophrenia. Schizophr. Res. 49, 1–52 (2001).

    Article  CAS  Google Scholar 

  30. Shim, S.S., Bunney, B.S. & Shi, W-X. Effects of lesions in the medial prefrontal cortex on activity of midbrain dopamine neurons. Neuropsychopharmacology 15, 437–441 (1996).

    Article  CAS  Google Scholar 

  31. Laruelle, M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res. Rev. 1, 371–384 (2000).

    Article  Google Scholar 

  32. Kitamura, M., Ikeda, H., Koshikawa, N. & Cools, A.R. GABAA agents injected into the ventral pallidum differentially affect dopaminergic pivoting and cholinergic circling elicited from the shell of the nucleus accumbens. Neuroscience 104, 117–127 (2001).

    Article  CAS  Google Scholar 

  33. Samson, H.H. & Chappell, A. Injected muscimol in pedunculopontine tegmental nucleus alters ethanol self-administration. Alcohol 23, 41–48 (2001).

    Article  CAS  Google Scholar 

  34. Milner, K.L. & Mogenson, G.J. Electrical and chemical activation of the mesencephalic and subthalamic locomotor regions in freely moving rats. Brain Res. 452, 273–285 (1988).

    Article  CAS  Google Scholar 

  35. Yang, C.R. & Mogenson, G.J. Hippocampal signal transmission to the mesencephalic locomotor regions and its regulation by dopamine D2 receptors in the nucleus accumbens: an electrophysiological and behavioral study. Neuroscience 23, 1041–1055 (1987).

    Article  CAS  Google Scholar 

  36. Grace, A.A. & Bunney, B.S. Intracellular and extracellular electrophysiology of nigral dopaminergic neurons. Neuroscience 10, 301–315 (1983).

    Article  CAS  Google Scholar 

  37. West, A.R. & Grace, A.A. Striatal nitric oxide signaling regulates the neuronal activity of midbrain dopamine neurons. J. Neurophysiol. 83, 1796–1808 (2000).

    Article  CAS  Google Scholar 

  38. Moore, H., Todd, C.L. & Grace, A.A. Striatal extracellular dopamine levels in rats with haloperidol-induced depolarization block of substantia nigra dopamine neurons. J. Neurosci. 18, 5068–5077 (1998).

    Article  CAS  Google Scholar 

  39. West, A.R. & Galloway, M.P. Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: role of ionotropic glutamate receptor-dependent mechanisms. Neuropharmacology 36, 1571–1581 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank N. McMurdo and C. Smolar for their assistance with histology, and A. Charara for discussions. Support was provided by a US National Institutes of Health grant. S.B.F. is a recipient of a Human Frontiers Post Doctoral Fellowship.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Stan B Floresco or Anthony A Grace.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Floresco, S., West, A., Ash, B. et al. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci 6, 968–973 (2003). https://doi.org/10.1038/nn1103

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1103

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