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Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380

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Abstract

Rationale

Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists, and antagonists have antidepressant-like effects in rodents and reduce symptoms of depression in humans.

Objectives

The study determined whether the antidepressant-like effect of the nAChR β2* partial agonist sazetidine-A (sazetidine) in the forced swim test was due to activation or desensitization of β2* nAChRs. The study also determined if sazetidine’s behavioral responses in the forced swim test corresponded to β2* nAChRs receptor occupancy and drug bioavailability.

Results

Acute antidepressant-like effects in the forced swim test were seen with sazetidine and the full β2* agonist 5-I-A8350 (BALB/cJ mice) and the less selective β2* partial agonist varenicline in C57BL/6J but not BALB/cJ mice. The role of β2* nAChRs was confirmed by results showing: (1) reversal of sazetidine’s antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-β-erythroidine; (2) absence of sazetidine’s effect in mice lacking the β2 subunit of the nAChR; and (3) a high correspondence between behaviorally active doses of sazetidine and β2* receptor occupancy. β2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 lasted beyond the duration of action in the forced swim test. Sazetidine’s long lasting receptor occupancy did not diminish behavioral efficacy in the forced swim test following repeated dosing.

Conclusions

Results demonstrate that activation of a small population of β2* nAChRs (10–40%) is sufficient to elicit sazetidine’s antidepressant-like actions without producing tolerance and suggest that ligands that activate β2* nAChRs would be promising targets for the development of a new class of antidepressant.

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Acknowledgements

Portions of this work were supported by MH085193 to APK. MRP was supported by MH077681.

Conflicts of interest

There is no actual or potential conflict of interest in relation to this article.

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Authors and Affiliations

  1. PsychoGenics, Inc., 765 Old Saw Mill River Road, Tarrytown, NY, 10591, USA

    Barbara J. Caldarone, Daguang Wang, Neil E. Paterson, Michael Manzano, Allison Fedolak, Katie Cavino, Mei Kwan, Taleen Hanania & Afshin Ghavami

  2. Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL, USA

    Sheela K. Chellappan & Alan P. Kozikowski

  3. Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands

    Berend Olivier

  4. Department of Psychiatry, Yale School of Medicine, 34 Park Street, 3rd Floor Research, New Haven, CT, 06508, USA

    Berend Olivier & Marina R. Picciotto

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  1. Barbara J. Caldarone
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  2. Daguang Wang
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  3. Neil E. Paterson
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  11. Berend Olivier
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Correspondence to Barbara J. Caldarone.

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Caldarone, B.J., Wang, D., Paterson, N.E. et al. Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380. Psychopharmacology 217, 199–210 (2011). https://doi.org/10.1007/s00213-011-2271-y

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