Multiple Muscarinic Acetylcholine Receptor Subtypes Modulate Striatal Dopamine Release, as Studied with M1–M5Muscarinic Receptor Knock-Out Mice
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A proper balance between striatal muscarinic cholinergic and dopaminergic neurotransmission is required for coordinated locomotor control. Activation of striatal muscarinic acetylcholine receptors (mAChRs) is known to modulate striatal dopamine release. To identify the mAChR subtype(s) involved in this activity, we used genetically altered mice that lacked functional M1-M5 mAChRs [knock-out (KO) mice]. In superfused striatal slices from wild-type mice, the non-subtype-selective muscarinic agonist oxotremorine led to concentration-dependent increases in potassium-stimulated [3H]dopamine release (by up to 60%). The lack of M1 or M2 receptors had no significant effect on the magnitude of these responses. Strikingly, oxotremorine-mediated potentiation of stimulated striatal [3H]dopamine release was abolished in M4 receptor KO mice, significantly increased in M3 receptor-deficient mice, and significantly reduced (but not abolished) in M5 receptor KO mice. Additional release studies performed in the presence of tetrodotoxin suggested that the dopamine release-stimulating M4 receptors are probably located on neuronal cell bodies, but that the release-facilitating M5 and the release-inhibiting M3 receptors are likely to be located on nerve terminals. Studies with the GABA(A) receptor blocker bicuculline methochloride suggested that M3 and M4 receptors mediate their dopamine release-modulatory effects via facilitation or inhibition, respectively, of striatal GABA release. These results provide unambiguous evidence that multiple mAChR subtypes are involved in the regulation of striatal dopamine release. These findings should contribute to a better understanding of the important functional roles that the muscarinic cholinergic system plays in striatal function.
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M1/M5 receptors can stimulate dopamine release from striatal synaptosomes and postsynaptic M1/M5 receptors can increase excitability of cortical pyramidal neurons.
“In contrast, M1/M5 receptors can stimulate dopamine (DA) release from striatal synaptosomes (Zhang et al., 2002) and postsynaptic M1/M5 receptors can increase excitability of cortical pyramidal neurons (Douglas et al., 2002; McCormick and Prince, 1985).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Zhang et al., 2002
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Cites
Neurotransmitters and neuromodulators in the basal ganglia
Graybiel, A. M. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90104-i · Cited by 1,576 · see citing works
Muscarinic Receptors—Characterization, coupling and function
Caulfield, M. P. (1993) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(93)90027-b · Cited by 1,277 · see citing works
Modulation of neurotransmitter release by presynaptic autoreceptors
Starke, K., Göthert, M., & Kilbinger, H. J. (1989) · Physiological Reviews · doi:10.1152/physrev.1989.69.3.864 · Cited by 927 · see citing works
Levey, A. I., Kitt, C. A., Wf, S., Price, D., & Brann, M. R. (1991) · Journal of Neuroscience · doi:10.1523/jneurosci.11-10-03218.1991 · Cited by 920 · see citing works
Modulation of ion-channel function by G-protein-coupled receptors
Hille, B. (1994) · Trends in Neurosciences · doi:10.1016/0166-2236(94)90157-0 · Cited by 760 · see citing works
Molecular Biology of Muscarinic Acetylcholine Receptors
Wess, J. (1996) · Critical Reviews in Neurobiology · doi:10.1615/critrevneurobiol.v10.i1.40 · Cited by 491 · see citing works
Self-citationExpression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia.
Weiner, D. M., Levey, A. I., & Brann, M. R. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.18.7050 · Cited by 481 · see citing works
Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions
Di Chiara, G., Morelli, M., & Consolo, S. (1994) · Trends in Neurosciences · doi:10.1016/0166-2236(94)90005-1 · Cited by 467 · see citing works
Matsui, M., Motomura, D., Karasawa, H., Fujikawa, T., Jiang, J. D., Komiya, Y., Takahashi, S.-I., & Taketo, M. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.17.9579 · Cited by 451 · see citing works
Acetylcholine-mediated modulation of striatal function
Calabresi, P., Centonze, D., Gubellini, P., Pisani, A., & Bernardi, G. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01501-5 · Cited by 440 · see citing works
Hersch, S. M., Gutekunst, C., Rees, H., Heilman, C. J., & Levey, A. I. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-05-03351.1994 · Cited by 404 · see citing works
Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean
Yamada, M., Miyakawa, T., Duttaroy, A., Yamanaka, A., Moriguchi, T., Makita, R., Ogawa, M., Chou, C. J., Xia, B., Crawley, J. N., et al. (2001) · Nature · doi:10.1038/35065604 · Cited by 373 · see citing works
Self-citationHamilton, S. E., Loose, M. D., Qi, M., Levey, A. I., Hille, B., McKnight, G. S., Idzerda, R. L., & Nathanson, N. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.24.13311 · Cited by 366 · see citing works
Miyakawa, T., Yamada, M., Duttaroy, A., & Wess, J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-14-05239.2001 · Cited by 366 · see citing works
Self-citationPronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice
Gomeza, J., Shannon, H. E., Kostenis, E., Felder, C. C., Zhang, L., Brodkin, J. D., Grinberg, A., SHENG, H. Z., & Wess, J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1692 · Cited by 348 · see citing works
Self-citationPhenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes
Bernard, V., Normand, E., & Bloch, B. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-09-03591.1992 · Cited by 327 · see citing works
Gomeza, J., Zhang, L., Kostenis, E., Felder, C. C., Bymaster, F. P., Brodkin, J. D., Shannon, H. E., Xia, B., Deng, C., & Wess, J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.18.10483 · Cited by 321 · see citing works
Self-citationRaiteri, M., Leardi, R., & Marchi, M. (1984) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)21528-2 · Cited by 314 · cited 3× · see citing works
“Consistent with previous findings (Lehmann and Langer, 1982; Raiteri et al., 1984; Schoffelmeer et al., 1986), incubation of W T striatal slices with the non-subtype-selective muscarinic agonist oxotremorine led to concentration-dependent increases in potassium-stimulated [ 3 H]dopamine release…”
BackgroundResultZhang, W., Basile, A. S., Gomeza, J., Volpicelli‐Daley, L. A., Levey, A. I., & Wess, J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01709.2002 · Cited by 314 · see citing works
Self-citationGerber, D., Sotnikova, T. D., Gainetdinov, R., Huang, S., Caron, M., & Tonegawa, S. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.261583798 · Cited by 282 · see citing works
Yamada, M., Lamping, K. G., Duttaroy, A., Zhang, W., Cui, Y., Bymaster, F. P., McKinzie, D. L., Felder, C. C., Deng, C., Faraci, F. M., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.251542998 · Cited by 275 · see citing works
Self-citationVilaró, M. T., Palacios, J., & Mengod, G. (1990) · Neuroscience Letters · doi:10.1016/0304-3940(90)90064-g · Cited by 269 · see citing works
The GABA and substance P input to dopaminergic neurones in the substantia nigra of the rat
Bolam, J. P., & Smith, Y. (1990) · Brain Research · doi:10.1016/0006-8993(90)90811-o · Cited by 260 · see citing works
Fisahn, A., Yamada, M., Duttaroy, A., Gan, J.-W., Deng, C., McBain, C. J., & Wess, J. (2002) · Neuron · doi:10.1016/s0896-6273(02)00587-1 · Cited by 251 · see citing works
Self-citationYasuda, R. P., Ciesla, W., Flores, L. R., et al. (1993) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)13594-3 · Cited by 218 · see citing works
Coordinated expression of muscarinic receptor messenger RNAs in striatal medium spiny neurons
Yan, Z., Flores‐Hernández, J., & Surmeier, D. J. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00039-2 · Cited by 179 · see citing works
Sugita, S., Uchimura, N., Jiang, Z. G., & North, R. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.6.2608 · Cited by 171 · see citing works
Howe, A., & Surmeier, D. J. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-01-00458.1995 · Cited by 171 · see citing works
Synaptic Integration Mediated by Striatal Cholinergic Interneurons in Basal Ganglia Function
Kaneko, S., Hikida, T., Watanabe, D., Ichinose, H., Nagatsu, T., Kreitman, R. J., Pastan, I. H., & Nakanishi, S. (2000) · Science · doi:10.1126/science.289.5479.633 · Cited by 166 · see citing works
Biochemical evidence for the presence of presynaptic receptors on dopaminergic nerve terminals
de Belleroche, J., & Bradford, H. F. (1978) · Brain Research · doi:10.1016/0006-8993(78)90176-2 · Cited by 163 · see citing works
Brain neurotransmitter changes in Parkinson's disease
Hornykiewicz, O. (1981) · Movement Disorders · doi:10.1016/b978-0-407-02295-9.50009-6 · Cited by 160 · see citing works
Lehmann, J. C., & Langer, S. Z. (1982) · Brain Research · doi:10.1016/0006-8993(82)91147-7 · Cited by 138 · see citing works
Xu, M., Mizobe, F., Yamamoto, T., et al. (1989) · Brain Research · doi:10.1016/0006-8993(89)90217-5 · Cited by 103 · see citing works
Kemel, M. L., Desban, M., Glowinski, J., & Gauchy, C. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.22.9006 · Cited by 92 · see citing works
Bernard, V., Levey, A. I., & Bloch, B. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-23-10237.1999 · Cited by 89 · see citing works
Smolders, I. J., Bogaert, L., Ebinger, G., & Michotte, Y. M. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68051942.x · Cited by 89 · see citing works
Klippel, N. D., Sarre, S., Ebinger, G., et al. (1993) · Brain Research · doi:10.1016/0006-8993(93)90642-z · Cited by 79 · see citing works
Ronken, E., Mulder, A. H., & Schoffelmeer, A. N. M. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb09797.x · Cited by 71 · see citing works
Santiago, M., & Potter, L. T. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03170-x · Cited by 71 · see citing works
Schoffelmeer, A. N. M., Vliet, B. J. V., Wardeh, G., et al. (1986) · European Journal of Pharmacology · doi:10.1016/0014-2999(86)90781-8 · Cited by 71 · see citing works
Muscarinic receptors mediate direct inhibition of GABA release from rat striatal nerve terminals
Marchi, M., Sanguineti, P., & Raiteri, M. (1990) · Neuroscience Letters · doi:10.1016/0304-3940(90)90099-u · Cited by 47 · see citing works
Chapter 40 Antimuscarinic drugs in the treatment of movement disorders
Fahn, S., Burke, R. E., & Stern, Y. (1990) · Progress in brain research · doi:10.1016/s0079-6123(08)60922-x · Cited by 39 · see citing works
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Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior
Picciotto, M. R., Higley, M. J., & Mineur, Y. S. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.036 · Cited by 1,404 · see citing works
Striatal dopamine neurotransmission: Regulation of release and uptake
Sulzer, D., Cragg, S. J., & Rice, M. E. (2016) · Basal Ganglia · doi:10.1016/j.baga.2016.02.001 · Cited by 382 · see citing works
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Goldberg, J. A., Ding, J. B., & Surmeier, D. J. (2012) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-23274-9_10 · Cited by 150 · see citing works
Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons
Okada, K., Nishizawa, K., Fukabori, R., Kai, N., Shiota, A., Ueda, M., Tsutsui, Y., Sakata, S., Matsushita, N., & Kobayashi, K. (2014) · Nature Communications · doi:10.1038/ncomms4778 · Cited by 90 · see citing works
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van der Westhuizen, E. T., Choy, K. H. C., Valant, C., McKenzie-Nickson, S., Bradley, S. J., Tobin, A. B., Sexton, P. M., & Christopoulos, A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.606656 · Cited by 63 · see citing works
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Smith, J. E., Co, C., Yin, X., Sizemore, G. M., Liguori, A., Johnson, W. E., & Martin, T. J. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2003.11.002 · Cited by 47 · see citing works
Grilli, M., Patti, L., Robino, F., Zappettini, S., Raiteri, M., & Marchi, M. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05307.x · Cited by 40 · see citing works
Yee, J., Famous, K. R., Hopkins, T. J., McMullen, M. C., Pierce, R. C., & Schmidt, H. D. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.10.045 · Cited by 34 · see citing works
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- Authors
- Zhang, W., Yamada, M., Gomeza, J., Basile, A. S., & Wess, J.
- Affiliations
- National Institutes of Health (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-08-01
- Volume
- 22
- Issue
- 15
- Pages
- 6347-6352
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758135
- OpenAlex
- W1494737704
- Cited by
- 224
- References
- 42
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 9 · 2019: 14 · 2018: 12 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 7 · 2013: 6 · 2012: 7
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- muscarinic receptors, striatal dopamine release, M3 muscarinic receptor, M4 receptor, M5 receptor, M1 receptor, M2 muscarinic receptor, oxotremorine, GABA release, cholinergic-dopaminergic interaction, striatum, locomotion control
- MeSH terms
- Animals, Corpus Striatum, Dopamine, Dose-Response Relationship, Drug, Neurons, Oxotremorine, Potassium, Receptors, Muscarinic, Tetrodotoxin, Mice, Knockout, Muscarinic Agonists, GABA Antagonists, Receptor, Muscarinic M2, Receptor, Muscarinic M3, Receptor, Muscarinic M4, Receptor, Muscarinic M5, Receptor, Muscarinic M1, Mice, GABA-A Receptor Antagonists, In Vitro Techniques
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