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Discriminative stimulus and hypothermic effects of some derivatives of the nAChR agonist epibatidine in mice

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Abstract

Rationale

Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential.

Objective

This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4β2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2′-fluoro-3′-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2′-fluorodeschloroepibatidine (RTI-7527-36), and 3′-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76).

Methods

Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature.

Results

In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12 ºC. The rank-order potency in the discrimination and hypothermia assays was epibatidine > RTI-7527-36 > nicotine > RTI-7527-102 > varenicline = cytisine = RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The β2-subunit selective nAChR antagonist dihydro-β-erythroidine (DHβE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine.

Conclusions

The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing β2-subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4β2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists.

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Abbreviations

DHβE:

Dihydro-β-erythroidine

nAChR:

Nicotinic acetylcholine receptor

RTI-7527-36:

2′-Fluorodeschloroepibatidine

RTI-7527-76:

3′-(3″-Dimethylaminophenyl)-epibatidine

RTI-7527-102:

2′-Fluoro-3′-(4-nitrophenyl)deschloroepibatidine

ANOVA:

Analysis of variance

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Funding

DA025267 to LRM

Conflict of interest

All authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Jesse S. Rodriguez, Colin S. Cunningham, Fernando B. Moura & Lance R. McMahon

  2. Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina, 27709, USA

    Pauline Ondachi & F. Ivy Carroll

Authors
  1. Jesse S. Rodriguez
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  2. Colin S. Cunningham
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  3. Fernando B. Moura
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  4. Pauline Ondachi
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  5. F. Ivy Carroll
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  6. Lance R. McMahon
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Corresponding author

Correspondence to Lance R. McMahon.

Additional information

Jesse S. Rodriguez and Colin S. Cunningham indicate equal contribution.

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Rodriguez, J.S., Cunningham, C.S., Moura, F.B. et al. Discriminative stimulus and hypothermic effects of some derivatives of the nAChR agonist epibatidine in mice. Psychopharmacology 231, 4455–4466 (2014). https://doi.org/10.1007/s00213-014-3589-z

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  • DOI: https://doi.org/10.1007/s00213-014-3589-z

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