Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area
Open accessAbstract
Systemic exposure to nicotine induces glutamatergic synaptic plasticity on dopamine (DA) neurons in the ventral tegmental area (VTA), but mechanisms are largely unknown. Here, we report that single, systemic exposure in rats to nicotine (0.17 mg/kg free base) increases the ratio of DA neuronal currents mediated by AMPA relative to NMDA receptors (AMPA/NMDA ratio) assessed 24 h later, based on slice-patch recording. The AMPA/NMDA ratio increase is evident within 1 h and lasts for at least 72 h after nicotine exposure (and up to 8 d after repeated nicotine administration). This effect cannot be prevented by systemic injection of either α7-nAChR (nicotinic ACh receptor)-selective [methyllycaconitine (MLA)] or β2*-nAChR-selective [mecamylamine (MEC)] antagonists but is prevented by coinjection of MLA and MEC. In either nAChR α7 or β2 subunit knock-out mice, systemic exposure to nicotine still increases the AMPA/NMDA ratio. Preinjection in rats of a NMDA receptor antagonist MK-801((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), but neither DA receptor antagonists [SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) plus haloperidol] nor a calcineurin inhibitor (cyclosporine), prevents the nicotine-induced increase in AMPA/NMDA ratio. After systemic exposure to nicotine, glutamatergic (but not GABAergic) transmission onto rat VTA DA neuronal inputs is enhanced. Correspondingly, DA neuronal firing measured 24 h after nicotine exposure using extracellular single-unit recording in vivo is significantly faster, and there is conversion of silent to active DA neurons. Collectively, these findings demonstrate that systemic nicotine acting via either α7- or β2*-nAChRs increases presynaptic and postsynaptic glutamatergic function, and consequently initiates glutamatergic synaptic plasticity, which may be an important, early neuronal adaptation in nicotine reward and reinforcement.
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Repeated nicotine exposure produces heterologous adaptations, including increased AMPA/NMDA current ratios at DA neurons and increased high-affinity D2 receptors in the NAcc.
“Besides altering cholinergic function, repeated nicotine exposure produces heterologous adaptations. For example, nicotine increases AMPA/NMDA current ratios (a hallmark of long-term potentiation) at DA neurons [94–96] and other locations involved in drug-associated memory [97–99]. In the NAcc, nicotine leads to an increase in high affinity DA D2 receptors [100].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [94]
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- Authors
- Gao, M., Jin, Y., Yang, K., Zhang, D., Lukas, R. J., & Wu, J.
- Affiliations
- Barrow Neurological Institute (US)
- Corresponding author
- Wu, Jie
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-10-13
- Volume
- 30
- Issue
- 41
- Pages
- 13814-13825
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2995497
- OpenAlex
- W2154854636
- Cited by
- 99
- References
- 60
- Citations by year
- 2026: 6 · 2025: 4 · 2023: 1 · 2022: 6 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 9 · 2017: 4 · 2016: 4 · 2015: 10 · 2014: 13 · 2013: 8 · 2012: 5
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Barrow Neurological Foundation
- Philip Morris International
- Arizona Biomedical Research Commission
- National Institutes of Health
- National Institute on Drug Abuse (R01DA015389)
- National Institute of Neurological Disorders and Stroke (R01NS040417)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- dopaminergic neurons, ventral tegmental area, AMPA/NMDA ratio, nicotinic acetylcholine receptors, alpha7 nAChR, beta2 nAChR, nicotine dependence, calcineurin inhibition, dopamine antagonists, neuronal firing rate
- MeSH terms
- Analysis of Variance, Animals, Dopamine, Dose-Response Relationship, Drug, Electrophysiology, Genotype, Neuronal Plasticity, Neurons, Nicotine, Receptors, Nicotinic, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Wistar, Ventral Tegmental Area, Receptors, AMPA, Mice, Knockout, Glutamic Acid, Excitatory Postsynaptic Potentials, Reverse Transcriptase Polymerase Chain Reaction, Mice, Rats, alpha7 Nicotinic Acetylcholine Receptor
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