M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation
Abstract
Mesopontine cholinergic neurons (Ch5 and Ch6 cell groups) activate the cerebral cortex via thalamic projections, and activate locomotion and reward via dopamine neurons in the substantia nigra and ventral tegmental area (VTA). Nicotinic receptors in VTA activate dopamine neurons quickly, and are needed for the stimulant and rewarding effects of nicotine in rats. Muscarinic receptors in VTA activate dopamine neurons slowly, and are needed for the rewarding effects of hypothalamic stimulation, but do not increase locomotion. Antisense oligonucleotides targetting M5 mRNA, when infused into the VTA, inhibited M5 receptor binding and rewarding hypothalamic stimulation. Mutant mice with truncated M5 muscarinic receptor genes drank more water than wild-type controls. Spontaneous locomotion and locomotor responses to amphetamine and scopolamine were unchanged. Electrical stimulation near Ch6 induced dopamine release in the nucleus accumbens in two phases, an early phase (0-2 min after stimulation) dependent on nicotinic and gluatamatergic receptors in VTA, and a late phase (8-50 min after stimulation) dependent on muscarinic receptors in VTA. The late phase was lost in M5 mutant mice, while the early phase was unchanged. M5 muscarinic receptors bind slowly to muscarinic ligands, and appear to mediate slow secretions.
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Both muscarinic and nicotinic ACh receptors are present on VTA dopamine neurons, as well as on cholinergic and glutamatergic terminals regulating different aspects of dopamine release in output sites such as the striatum and NAc.
“Both muscarinic and nicotinic ACh receptors are present on VTA dopamine neurons, as well as on cholinergic and glutamatergic terminals regulating different aspects of dopamine release in output sites, such as the striatum and NAc [160–162].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [162]
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“Furthermore, M5R activation in the VTA is necessary to produce the tonic excitation and prolonged mesolimbic NAc DA release that sustains rewarding brain stimulation and motivational behaviors (Yeomans et al., 2001; Forster et al., 2002; Miller and Blaha, 2005).”
BackgroundResultOff the Beaten Path: Drug Addiction and the Pontine Laterodorsal Tegmentum
Kohlmeier, K. A. (2013) · ISRN Neuroscience · doi:10.1155/2013/604847 · Cited by 17 · see citing works
“[67] J.”
Separating analgesia from reward within the ventral tegmental area
Schifirnet, E., Bowen, S. E., & Borszcz, G. S. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.01.009 · Cited by 15 · see citing works
“Cholinergic activation of VTA following electrical stimulation of LTDg (Forster and Blaha, 2000; Yeomans et al., 2001; Forster et al., 2002; Lester et al., 2010) or intra-VTA administration of carbachol (Westerink et al.”
BackgroundCharacteristics of Vocalization in Adult Mice
Ehret, G. (2018) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-12-809600-0.00018-4 · Cited by 15 · see citing works
Huang, X., Zheng, G., & Zhan, C. (2011) · The Journal of Physical Chemistry B · doi:10.1021/jp210579b · Cited by 15 · see citing works
“For a better understanding of the binding affinity difference between Solifenacin and SVT-40776, the MM-PBSA calculations were performed to estimate the binding free energy change, i.e. ΔΔGbind in Eq.”
MethodInfluentialSakata, K., & Overacre-Delgoffe, A. E. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14129 · Cited by 15 · see citing works
“…selected regions/ cells (Weiner et al. 1990), including the hippocampal CA1 pyramidal neurons (Vilaro et al. 1990) and the nigrostriatal dopaminergic neurons (Weiner et al. 1990; Reever et al. 1997), where M5 mAChR controls prolonged dopamine release (Yeomans et al. 2001; Forster et al. 2002).”
Brudzyński, S. M. (2010) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-12-374593-4.00026-7 · Cited by 16 · see citing works
Muscarinic Agonists and Antagonists in Schizophrenia
Bolbecker, A. R., & Shekhar, A. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-23274-9_8 · Cited by 13 · see citing works
Wrona, D., Klejbor, I., & Trojniar, W. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.06.016 · Cited by 13 · see citing works
Galaj, E., Nisanov, R., & Ranaldi, R. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.04.037 · Cited by 12 · see citing works
Nunes, E. J., Kebede, N., Haight, J. L., Foster, D. J., Lindsley, C. W., Conn, P. J., & Addy, N. (2023) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.122.001438 · Cited by 11 · see citing works
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Functional characterization of muscarinic receptor subtypes in human duodenal secretion
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Acetylcholine receptors (muscarinic) in GtoPdb v.2023.1
Birdsall, N. J. M., Bradley, S. J., Brown, D. A., Buckley, N. J., Challiss, R. A. J., Christopoulos, A., Eglen, R. M., Ehlert, F. J., Felder, C. C., Hammer, R., et al. (2023) · IUPHAR/BPS Guide to Pharmacology CITE · doi:10.2218/gtopdb/f2/2023.1 · Cited by 4 · see citing works
Cholinergic Receptor Knockout Mice
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Muscarinic and NMDA Receptors in the Substantia Nigra Play a Role in Reward-Related Learning
Galaj, E., Barrera, E. D., Lynch, O. L., Diodati, R., Thomas, A., Schneider, P., Lenhard, H., Vashisht, A., & Ranaldi, R. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac076 · Cited by 3 · see citing works
“This is something that could be explored in future studies because these receptor subtypes are known for their roles in neuroplasticity related to learning and memory (Yeomans et al., 2001; Leaderbrand et al., 2016; Baez et al., 2018).”
Birdsall, N. J. M., Bradley, S. J., Brown, D. A., Buckley, N. J., Challiss, R. A. J., Christopoulos, A., Eglen, R. M., Ehlert, F. J., Felder, C. C., Hammer, R., et al. (2019) · IUPHAR/BPS Guide to Pharmacology CITE · doi:10.2218/gtopdb/f2/2019.4 · Cited by 3 · see citing works
The genetics of latent inhibition: studies of inbred and mutant mice
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Learning Deficits and Depressionlike Behaviors Associated with Developmental Methylmercury Exposures
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Dopaminergic Transmission and Wake-Promoting Effects of Central Nervous System Stimulants
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“VTA dopamine neurons are strongly excited by cholinergic brainstem neurons via activation of nicotinic and muscarinic M5 receptors (Yeomans and Baptista 1997; Yeomans et al. 2001; Pidoplichko et al. 1997).”
BackgroundMuscarinic Acetylcholine Receptors
Enz, A. (2007) · xPharm: The Comprehensive Pharmacology Reference · doi:10.1016/b978-008055232-3.60209-0 · Cited by 2 · see citing works
- Authors
- Yeomans, J., Forster, G., & Blaha, C.
- Affiliations
- University of Toronto (CA)
- Macquarie University (AU)
- Corresponding author
- Yeomans, John
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 2001-04
- Volume
- 68
- Issue
- 22-23
- Pages
- 2449-2456
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W1999928356
- Cited by
- 124
- References
- 0
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 6 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 2
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- M5 muscarinic receptor, dopaminergic neurons, ventral tegmental area, nicotinic acetylcholine receptors, reward, brain stimulation, substantia nigra, nucleus accumbens dopamine release, antisense oligonucleotides, locomotion
- MeSH terms
- Acetylcholine, Animals, Corpus Striatum, Dopamine, Electric Stimulation, Humans, Hypothalamus, Neurons, Receptors, Muscarinic, Receptors, Nicotinic, Reward, Receptor, Muscarinic M5
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