Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation

  1. Anitha P Govind
  2. Yolanda F Vallejo
  3. Jacob R Stolz
  4. Jing-Zhi Yan
  5. Geoffrey T Swanson
  6. William N Green  Is a corresponding author
  1. University of Chicago, United States
  2. National Institute of Dental and Craniofacial Research, National Institutes of Health, United States
  3. Northwestern University, Feinberg School of Medicine, United States

Abstract

To better understand smoking cessation, we examined the actions of varenicline (Chantix) during long-term nicotine exposure. Varenicline reduced nicotine upregulation of α4β2-type nicotinic receptors (α4β2Rs) in live cells and neurons, but not for membrane preparations. Effects on upregulation depended on intracellular pH homeostasis and were not observed if acidic pH in intracellular compartments was neutralized. Varenicline was trapped as a weak base in acidic compartments and slowly released, blocking 125I-epibatidine binding and desensitizing α4β2Rs. Epibatidine itself was trapped; 125I-epibatidine slow release from acidic vesicles was directly measured and required the presence of α4β2Rs. Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic vesicles containing α4β2Rs. We conclude that varenicline as a smoking cessation agent differs from nicotine through trapping in α4β2R-containing acidic vesicles that is selective and nicotine-regulated. Our results provide a new paradigm for how smoking cessation occurs and suggest how more effective smoking cessation reagents can be designed.

Article and author information

Author details

  1. Anitha P Govind

    Department of Neurobiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yolanda F Vallejo

    National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jacob R Stolz

    Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jing-Zhi Yan

    Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Geoffrey T Swanson

    Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. William N Green

    Department of Neurobiology, University of Chicago, Chicago, United States
    For correspondence
    wgreen@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2167-1391

Funding

National Institutes of Health (RO1DA 035430)

  • Anitha P Govind
  • Yolanda F Vallejo
  • Jacob R Stolz
  • Jing-Zhi Yan
  • Geoffrey T Swanson
  • William N Green

University of Chicago (Cance center-Pilot grant)

  • Anitha P Govind
  • William N Green

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Govind et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,372
    views
  • 144
    downloads
  • 18
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Anitha P Govind
  2. Yolanda F Vallejo
  3. Jacob R Stolz
  4. Jing-Zhi Yan
  5. Geoffrey T Swanson
  6. William N Green
(2017)
Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation
eLife 6:e25651.
https://doi.org/10.7554/eLife.25651

Share this article

https://doi.org/10.7554/eLife.25651

Further reading

    1. Neuroscience
    Zhujun Shao, Mengya Zhang, Qing Yu
    Research Article

    When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.