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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 [160–162].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [162]
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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. (2021) · IUPHAR/BPS Guide to Pharmacology CITE · doi:10.2218/gtopdb/f2/2021.3
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“The robust calcium responses to DHPG and carbachol are consistent with previous reports of expression of mGluR5 and m5AchR in VTA-DA neurons (Merrill et al., 2015; Yeomans et al., 2001).”
Metadata
- 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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