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

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.

• Authors: Fernando B de Moura, Takato Hiranita, Lance R McMahon
• Journal: Behavioural pharmacology (Behav Pharmacol) Vol. 31 Issue 6 Pg. 565-573 (09 2020) ISSN: 1473-5849 [Electronic] England
• PMID: 32209809 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Pyridines
• methyllycaconitine
• Dihydro-beta-Erythroidine
• Mecamylamine
• epibatidine
• Aconitine

Topics

• Aconitine (analogs & derivatives, pharmacology)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Dihydro-beta-Erythroidine (pharmacology)
• Discrimination Learning (drug effects)
• Male
• Mecamylamine (pharmacology)
• Mice
• Mice, Inbred C57BL
• Pyridines (pharmacology)