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Differential Antagonism and Nicotine‐Induced Tolerance/Cross‐Tolerance Among nAChR Agonists in Mice
Author(s) -
Moura Fernando Barreto,
McMahon Lance Richard
Publication year - 2016
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.30.1_supplement.1187.5
Subject(s) - cytisine , varenicline , epibatidine , nicotine , mecamylamine , pharmacology , chemistry , agonist , partial agonist , nicotinic agonist , medicine , nicotinic acetylcholine receptor , receptor , biochemistry
β2* nAChRs mediate the behavioral effects of nicotine; the extent to which β2* nAChRs also mediate the behavioral effects of other nAChR agonists including FDA approved smoking cessations aids (e.g., varenicline) has not been established. The goal of this study was to identify differences in nAChR mechanism(s) underlying the behavioral effects of nicotine, epibatidine, varenicline, and cytisine in male C57Bl/6J mice (n=7). Mice responded under an FR20 schedule of liquid food delivery; rectal temperature was assessed before and after operant conditioning sessions. The effects of nAChR agonists were tested alone, in combination with mecamylamine or DHβE, and after daily nicotine treatment consisting of 3 doses per day, 1.78 mg/kg per dose, 90 min apart. Nicotine, epibatidine, varenicline, and cytisine dose‐dependently decreased rate of FR responding; the respective ED 50 values were 0.44 mg/kg, 0.0027 mg/kg, 2.8 mg/kg, and 4.0 mg/kg. Nicotine, epibatidine, varenicline, and cytisine dose‐dependently decreased rectal temperature; respective decreases in rectal temperature at the largest doses studied were −5.9°C, −3.4°C, −3.5°C, and −3.4°C. Mecamylamine (1 mg/kg) significantly antagonized the rate‐decreasing and hypothermic effects of each agonist. DHβE (3.2 mg/kg) antagonized the rate‐decreasing and hypothermic effects of nicotine and epibatidine, as evidenced by a maximum 3.5‐fold rightward shift in the nicotine and epibatidine dose‐response functions. In contrast, DHβE did not antagonize the effects of varenicline and cytisine. Daily nicotine treatment produced significant rightward shifts in the nicotine dose‐response functions (i.e., tolerance) of 4.1‐fold for rate‐decreasing effects and 4.0‐fold for hypothermic effects, as well as significant rightward shifts in the epibatidine dose‐response functions (i.e., cross‐tolerance) of 2.2‐ and 2.9‐fold, respectively. In contrast, daily nicotine treatment did not significantly modify the potency of varenicline and cytisine to produce either rate‐decreasing or hypothermic effects. To the extent that DHβE is a selective β2* nAChR antagonist, these results suggest that β2* nAChRs mediate the rate‐decreasing and hypothermic effects of nicotine and epibatidine, whereas non‐β2*, mecamylamine‐sensitive nAChRs mediate the effects of varenicline and cytisine. Chronic nicotine treatment appears to decrease the responsiveness of β2* nAChRs, but not the responsiveness of the non‐β2*, mecamylamine‐sensitive nAChRs that mediate the effects of varenicline and cytisine. These results suggest that nAChRs mediating the effects of varenicline and cytisine are different from the nAChRs mediating the effects of nicotine and epibatidine. Support or Funding Information Supported by USPHS grant DA25267