The discriminative stimulus effects of epibatidine in C57BL/6J mice

Fernando B. De Moura, Takato Hiranita, Lance R Mcmahon

Research output: Contribution to journalArticlepeer-review

Abstract

The α4β2∗ nicotinic acetylcholine receptor (nAChR) subtypes are targeted for the development of smoking cessation aids, and the use of drug discrimination in mice provides a robust screening tool for the identification of drugs acting through nAChRs. Here, we established that the α4β2∗ nAChR agonist epibatidine can function as a discriminative stimulus in mice. Male C57BL/6J mice discriminated epibatidine (0.0032 mg/kg, subcutaneously) and were tested with agonists varying in selectivity and efficacy for α4β2∗ nAChRs. The discriminative stimulus effects of epibatidine were characterized with the nonselective, noncompetitive nicotinic antagonist mecamylamine, with the selective β2-substype-containing nAChR antagonist dihydro-β-erythroidine hydrobromide (DHβE), and the α7 antagonist methyllycaconitine (MLA). Nicotine (0.32-1.0 mg/kg, subcutaneously), the partial nAChR agonist cytisine (1.0-5.6 mg/kg, subcutaneously), and the α7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (10-56 mg/kg, intraperitoneally) produced no more than 33% epibatidine-appropriate responding. The partial α4β2∗ nAChR agonists varenicline and 2′-fluoro-3′-(4-nitro-phenyl)deschloroepibatidine produced 61 and 69% epibatidine-appropriate responding, respectively. DHβE and mecamylamine, but not MLA, significantly antagonized the discriminative stimulus effects of epibatidine. These results show that epibatidine may be trained as a discriminative stimulus in mice and has utility in elucidating the in-vivo pharmacology of α4β2∗ nAChR ligands.

Original languageEnglish (US)
Pages (from-to)565-573
Number of pages9
JournalBehavioural pharmacology
Volume31
Issue number6
DOIs
StatePublished - Sep 1 2020
Externally publishedYes

Keywords

  • alpha4beta2
  • C57BL/6J mice
  • discriminative stimulus effects
  • epibatidine
  • nicotine

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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