The substantia nigra pars compacta and ventral tegmental area contain the two largest populations of dopamine-releasing neurons in the mammalian brain. These neurons extend elaborate projections in the striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output through the release of dopamine to promote and reinforce motor action1,2,3,4. Here we show that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA (γ-aminobutyric acid). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2 and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schultz, W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1–27 (1998)
Wickens, J. R., Reynolds, J. N. & Hyland, B. I. Neural mechanisms of reward-related motor learning. Curr. Opin. Neurobiol. 13, 685–690 (2003)
Gerfen, C. R. & Surmeier, D. J. Modulation of striatal projection systems by dopamine. Annu. Rev. Neurosci. 34, 441–466 (2011)
Palmiter, R. D. Dopamine signaling in the dorsal striatum is essential for motivated behaviors: lessons from dopamine-deficient mice. Ann. NY Acad. Sci. 1129, 35–46 (2008)
Albin, R. L., Young, A. B. & Penney, J. B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375 (1989)
Dagher, A. & Robbins, T. W. Personality, addiction, dopamine: insights from Parkinson’s disease. Neuron 61, 502–510 (2009)
Sulzer, D. How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69, 628–649 (2011)
Bentivoglio, M. & Morei, M. in Handbook of Chemical Neuroanatomy – Dopamine Vol. 21, 1–107 (Elsevier, 2005)
Chuhma, N. et al. Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses. J. Neurosci. 24, 972–981 (2004)
Hnasko, T. S. et al. Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65, 643–656 (2010)
Tecuapetla, F. et al. Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens. J. Neurosci. 30, 7105–7110 (2010)
Stuber, G. D., Hnasko, T. S., Britt, J. P., Edwards, R. H. & Bonci, A. Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J. Neurosci. 30, 8229–8233 (2010)
Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neurosci. 8, 1263–1268 (2005)
Backman, C. M. et al. Characterization of a mouse strain expressing Cre recombinase from the 3′ untranslated region of the dopamine transporter locus. Genesis 44, 383–390 (2006)
Schmitz, Y., Benoit-Marand, M., Gonon, F. & Sulzer, D. Presynaptic regulation of dopaminergic neurotransmission. J. Neurochem. 87, 273–289 (2003)
Sabatini, B. L. & Regehr, W. G. Timing of synaptic transmission. Annu. Rev. Physiol. 61, 521–542 (1999)
Gonzalez-Hernandez, T., Barroso-Chinea, P., Acevedo, A., Salido, E. & Rodriguez, M. Colocalization of tyrosine hydroxylase and GAD65 mRNA in mesostriatal neurons. Eur. J. Neurosci. 13, 57–67 (2001)
Cruikshank, S. J., Urabe, H., Nurmikko, A. V. & Connors, B. W. Pathway-specific feedforward circuits between thalamus and neocortex revealed by selective optical stimulation of axons. Neuron 65, 230–245 (2010)
Wojcik, S. M. et al. A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron 50, 575–587 (2006)
Yelin, R. & Schuldiner, S. The pharmacological profile of the vesicular monoamine transporter resembles that of multidrug transporters. FEBS Lett. 377, 201–207 (1995)
Kozorovitskiy, Y., Saunders, A., Johnson, C. A., Lowell, B. B. & Sabatini, B. L. Recurrent network activity drives striatal synaptogenesis. Nature 485, 646–650 (2012)
Berube-Carriere, N. et al. The dual dopamine-glutamate phenotype of growing mesencephalic neurons regresses in mature rat brain. J. Comp. Neurol. 517, 873–891 (2009)
Matsuda, W. et al. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29, 444–453 (2009)
Ramirez, M. & Gutierrez, R. Activity-dependent expression of GAD67 in the granule cells of the rat hippocampus. Brain Res. 917, 139–146 (2001)
Gonzalez-Hernandez, T., Barroso-Chinea, P. & Rodriguez, M. Response of the GABAergic and dopaminergic mesostriatal projections to the lesion of the contralateral dopaminergic mesostriatal pathway in the rat. Mov. Disord. 19, 1029–1042 (2004)
Hirasawa, H., Puopolo, M. & Raviola, E. Extrasynaptic release of GABA by retinal dopaminergic neurons. J. Neurophysiol. 102, 146–158 (2009)
Maher, B. J. & Westbrook, G. L. Co-transmission of dopamine and GABA in periglomerular cells. J. Neurophysiol. 99, 1559–1564 (2008)
Iijima, K. Chemocytoarchitecture of the rat locus ceruleus. Histol. Histopathol. 8, 581–591 (1993)
Trottier, S. et al. Co-localization of histamine with GABA but not with galanin in the human tuberomamillary nucleus. Brain Res. 939, 52–64 (2002)
Broadbelt, K. G., Paterson, D. S., Rivera, K. D., Trachtenberg, F. L. & Kinney, H. C. Neuroanatomic relationships between the GABAergic and serotonergic systems in the developing human medulla. Auton. Neurosci. 154, 30–41 (2010)
Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003)
Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nature Neurosci. 13, 133–140 (2010)
Tong, Q. et al. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab. 5, 383–393 (2007)
Tong, Q., Ye, C. P., Jones, J. E., Elmquist, J. K. & Lowell, B. B. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nature Neurosci. 11, 998–1000 (2008)
Durieux, P. F. et al. D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nature Neurosci. 12, 393–395 (2009)
Pologruto, T. A., Sabatini, B. L. & Svoboda, K. ScanImage: flexible software for operating laser scanning microscopes. Biomed. Eng. Online 2, 13 (2003)
The authors thank A. Saunders and Y. Kozorovitskiy for generating and characterizing the AAV-DIO-EGFP and AAV-DIO-VGAT constructs, D. Sulzer and H. Zhang for assistance with amperometry, R. Shah and C. Johnson for technical support, and members of the laboratory for discussions. This work was supported by a Nancy Lurie Marks Family Foundation postdoctoral fellowship (N.X.T.) and by grants from the National Institutes of Health (NS046579 to B.L.S. and 4R00NS075136 to J.B.D.).
The authors declare no competing financial interests.
About this article
Cite this article
Tritsch, N., Ding, J. & Sabatini, B. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490, 262–266 (2012). https://doi.org/10.1038/nature11466
Nature Reviews Neuroscience (2021)
Cellular and Molecular Life Sciences (2021)
Journal of Neural Transmission (2021)
Acta Pharmacologica Sinica (2020)
Polysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner
Nature Communications (2020)