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Examining the capacity of nAChR antagonists to block the effects of nicotine in nicotine‐tolerant C57BL/6J mice
Author(s) -
Moura Fernando Barreto,
McMahon Lance Richard
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.986.13
Subject(s) - nicotine , mecamylamine , pharmacology , antagonist , antagonism , medicine , anesthesia , hypothermia , discontinuation , chemistry , receptor
The clinical effectiveness of some nAChR‐based smoking cessation aids is proposed to be due to antagonism of the effects of nicotine. However, it is unclear whether nicotine antagonism varies as a function of repeated nicotine exposure. In the current stidy, nicotine, mecamylamine (nonselective nAChR antagonist), and dihydro‐β‐erythroidine (DHβE; α4β2* nAChR antagonist) were studied in male C57BL/6J mice responding under an FR20 schedule of food delivery before, during, and after discontinuation of daily nicotine treatment consisting of 1.78 mg/kg nicotine administered three times per day. Before daily nicotine treatment, nicotine decreased response rate and rectal temperature with ED 50 values of 0.44 and 0.82 mg/kg, respectively. DHβE significantly antagonized the rate‐decreasing and hypothermic effects of nicotine, evidenced by 2.9‐ and 3.2‐ fold rightward shifts of the nicotine dose‐response functions, respectively. Daily nicotine treatment produced tolerance, as evidenced by 3.6‐ and 4.8‐fold rightward shifts in the nicotine dose‐response functions for rate‐decreasing and hypothermic effects, respectively. During daily nicotine treatment, mecamylamine and DHβE no longer antagonized the rate‐decreasing effects of nicotine, whereas both antagonists continued to block the hypothermic effects of nicotine. After discontinuation of daily nicotine treatment, there was a time‐related loss of tolerance to nicotine; under these conditions, mecamylamine and DHβE retained their capacity to antagonize the rate‐decreasing and hypothermic effects of nicotine. These data suggest that nicotine produces rate‐decreasing and hypothermic effects through different receptor types, and further suggest that nicotine can act at non‐nAChRs in nicotine‐tolerant animals. A potential loss of nicotine antagonist activity in cigarette smokers could underscore a potential limitation in the effectiveness of some nAChR‐based smoking cessation aids. Support or Funding Information Funding: USPHS DA25267