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Differential regulation of alcohol taking and seeking by antagonism at α4β2 and α3β4 nAChRs

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Abstract

Rationale

Alcoholism is a serious public health problem throughout the world. Current pharmacotherapies for the treatment of this disorder are poorly effective. Preclinical and clinical findings point to nicotinic acetylcholine receptors (nAChRs) as a promising target for the development of novel and effective medications. Assuage Pharmaceuticals, in collaboration with Torrey Pines Institute for Molecular Studies, has discovered a new class of potent and selective α4β2 nAChR antagonists.

Objective

Here, it was hypothesized that α4β2 nAChR antagonism is a viable approach for treatment of alcohol use disorders.

Results

When tested in rats, one lead compound, AP-202, attenuated both operant alcohol and nicotine self-administration in a paradigm in which the two reinforcers were concurrently available. The conotoxin TP2212-59, a selective α3β4 nAChR antagonist, was only effective in reducing nicotine self-administration. AP-202 also reduced alcohol but not food responding when alcohol was presented as the only reinforcer, whereas the commercially available α4β2 nAChR antagonist dihydro-β-erythroidine failed to alter alcohol self-administration. AP-202 did not block relapse-like behavior induced by previously alcohol-associated stimuli or yohimbine stress. In a reinstatement paradigm, in which alcohol seeking was triggered by a nicotine challenge, a behavior successfully inhibited by the nonselective nAChR antagonist mecamylamine, AP-202 was not effective, while pretreatment with TP2212-59 abolished nicotine-induced reinstatement of alcohol seeking.

Conclusions

These findings suggest differential roles for α4β2 and α3β4 nAChR on alcohol taking and seeking with selective blockade of α4β2 nAChR being more implicated in modulating alcohol taking while selective blockade of α3β4 nAChR is involved in nicotine-induced alcohol seeking.

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Acknowledgements

We are thankful to Shannon Ortiz-Umpierre and Roman Ramirez for animal care and Ginamarie Debevec for support in analytical chemistry.

Funding

This work was supported by NIH grants R41 AA025298 and R44 DA036968.

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Authors and Affiliations

  1. Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL, 34987, USA

    Andrea Cippitelli, Gloria Brunori, Jennifer Schoch, Christopher J. Armishaw, Jinhua Wu, Marc A. Giulianotti, Gregory S. Welmaker & Lawrence Toll

  2. Assuage Pharmaceuticals, Inc., 11350 SW Village Parkway, Port St. Lucie, FL, 34987, USA

    Jinhua Wu, Marc A. Giulianotti, Gregory S. Welmaker & Lawrence Toll

  3. Astraea Therapeutics, LLC, 320 Logue Avenue, Mountain View, CA, 94043, USA

    Nurulain T. Zaveri

Authors
  1. Andrea Cippitelli
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  2. Gloria Brunori
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  3. Jennifer Schoch
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  4. Christopher J. Armishaw
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  5. Jinhua Wu
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  6. Nurulain T. Zaveri
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  7. Marc A. Giulianotti
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  8. Gregory S. Welmaker
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  9. Lawrence Toll
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Corresponding author

Correspondence to Andrea Cippitelli.

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The authors declare that they have no conflict of interest.

Additional information

Christopher J. Armishaw’s current affiliation is with Eli Lilly & Company, Indianapolis, IN 46285.

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Cippitelli, A., Brunori, G., Schoch, J. et al. Differential regulation of alcohol taking and seeking by antagonism at α4β2 and α3β4 nAChRs. Psychopharmacology 235, 1745–1757 (2018). https://doi.org/10.1007/s00213-018-4883-y

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