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Cited by 720Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Long-term potentiation of excitatory inputs to brain reward areas by nicotine

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Mansvelder, Huibert D, McGehee, Daniel S·2000·Neuron
DOI 10.1016/s0896-6273(00)00042-8
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Abstract

Nicotine reinforces smoking behavior by activating nicotinic acetylcholine receptors (nAChRs) in the midbrain dopaminergic (DA) reward centers, including the ventral tegmental area (VTA). Although nicotine induces prolonged excitation of the VTA in vivo, the nAChRs on the DA neurons desensitize in seconds. Here, we show that activation of nAChRs on presynaptic terminals in the VTA enhances glutamatergic inputs to DA neurons. Under conditions where the released glutamate can activate NMDA receptors, long-term potentiation (LTP) of the excitatory inputs is induced. Both the short- and the long-term effects of nicotine required activation of presynaptic alpha7 subunit-containing nAChRs. These results can explain the long-term excitation of brain reward areas induced by a brief nicotine exposure. They also show that nicotine alters synaptic function through mechanisms that are linked to learning and memory.

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  • In a slice preparation, nicotine can potentiate glutamate input to DA neurons through α7 nAChRs, resulting in long-term potentiation of those inputs.

    “In a slice preparation, nicotine can potentiate glutamate input to DA neurons through α7 nAChRs, resulting in long-term potentiation of those inputs (Mansvelder and McGehee 2000).”

    From Mechanisms of Nicotine Addiction (2021) · cites this paper as Mansvelder and McGehee 2000

  • Low level nicotine concentrations experienced by smokers over long periods preferentially desensitize α4β2 nAChRs on GABAergic terminals and not α7 nAChRs on glutamatergic terminals in the VTA, shifting presynaptic effects of nicotine from mixed inhibition and excitation of DA neurons toward the glutamatergic response.

    “The low level nicotine concentrations experienced by smokers over long periods are suggested to preferentially desensitize α4β2 nAChRs on GABAergic terminals and not α7 nAChRs on glutamatergic terminals in the VTA, thus shifting the presynaptic effects of nicotine from a mixed inhibition and excitation of DA neurons, toward the glutamatergic response to nicotine (Mansvelder et al., 2002; Mansvel”

    From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Mansvelder and McGehee, 2000

  • At lower nicotine concentrations (250 nM), β2* nAChRs also desensitize rapidly.

    “However, at lower nicotine concentrations, which may be more similar to those observed at steady state in a smoker's brain (250 nM), β2* nAChRs also desensitize rapidly (Mansvelder et al., 2002; Mansvelder and McGehee, 2000).”

    From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Mansvelder and McGehee, 2000

  • Presynaptic effects of lower concentrations of nicotine blocked by α7* selective agents persist in the continued presence of nicotine in rat and mouse brain slices, whereas presynaptic effects blocked by β2* selective agents desensitize during continued nicotine application.

    “More recent studies have shown that presynaptic effects of lower concentrations of nicotine that are blocked by nicotinic agents that are thought to be selective for α7* nAChRs persist in the continued presence of nicotine in rat (Mansvelder et al., 2002) and mouse (Wooltorton et al., 2003) brain slices, whereas presynaptic effects that are blocked with agents thought to be selective for β2* nAChR”

    From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Mansvelder and McGehee, 2000

  • Bungarotoxin-insensitive nAChR subtypes, including the α4β2-containing subtype, have been extensively implicated in the behavioral effects of nicotine, including dependence-related effects such as nicotine self-administration and neurotransmitter release (dopamine).

    “Of the various types of nAChRs that exist in the central nervous system (CNS), members of the so-called bungarotoxin-insensitive subtypes, which are composed of alpha and beta subunits and includes the ubiquitous α4β2-containing subtype, have been extensively implicated in the behavioral effects of nicotine, including its dependence-related effects such as nicotine self-administration and neurotra”

    From Tobacco addiction (2008) · cites this paper as [25]

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Authors
Mansvelder, H. D., & McGehee, D. S.
Affiliations
University of Chicago (US)
Corresponding author
McGehee, Daniel S
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2000-08
Volume
27
Issue
2
Pages
349-357
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/s0896-6273(00)00042-8
OpenAlex
W2043346837
Cited by
720
References
55
Citations by year
2026: 5 · 2025: 11 · 2024: 10 · 2023: 12 · 2022: 13 · 2021: 27 · 2020: 18 · 2019: 23 · 2018: 29 · 2017: 30 · 2016: 16 · 2015: 24 · 2014: 30 · 2013: 35 · 2012: 29
FWCI
11.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS035090, NS-35090)
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
nicotine, long-term potentiation, nicotinic acetylcholine receptors, ventral tegmental area, dopaminergic neurons, glutamatergic input, NMDA receptor, synaptic plasticity, brain reward, smoking behavior, learning and memory
MeSH terms
Animals, Dopamine, Dose-Response Relationship, Drug, Electric Stimulation, gamma-Aminobutyric Acid, Synaptic Transmission, Neurons, Nicotine, Quinoxalines, Receptors, Nicotinic, Rats, Sprague-Dawley, Ventral Tegmental Area, Presynaptic Terminals, Long-Term Potentiation, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Nicotinic Agonists, Excitatory Postsynaptic Potentials, Rats, In Vitro Techniques

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