Attenuated nicotine-like effects of varenicline but not other nicotinic ACh receptor agonists in monkeys receiving nicotine daily.
Chronic treatment can differentially impact the effects of pharmacologically related drugs that differ in receptor selectivity and efficacy.



The impact of daily nicotine treatment on the effects of nicotinic ACh receptor (nAChR) agonists was examined in two groups of rhesus monkeys discriminating nicotine (1.78 mg·kg-1base weight) from saline. One group received additional nicotine treatment post-session (1.78 mg·kg-1administered five times daily, each dose 2 h apart; i.e. Daily group), and the second group did not (Intermittent group).



Daily repeated nicotine treatment produced a time-related increase in saliva cotinine. There was no significant difference in the ED50values of the nicotine discriminative stimulus between the Daily and Intermittent group. Mecamylamine antagonized the effects of nicotine, whereas dihydro-β-erythroidine did not. Midazolam produced 0% nicotine-lever responding. The nAChR agonists epibatidine, RTI-36, cytisine and varenicline produced >96% nicotine-lever responding in the Intermittent group. The respective maximum effects in the Daily group were 100, 72, 59 and 28%, which shows that the ability of varenicline to produce nicotine-like responding was selectively decreased in the Daily as compared with the Intermittent group. When combined with nicotine, both varenicline and cytisine increased the potency of nicotine to produce discriminative stimulus effects.



Nicotine treatment has a greater impact on the sensitivity to the effects of varenicline as compared with some other nAChR agonists. Collectively, these results strongly suggest that varenicline differs from nicotine in its selectivity for multiple nAChR subtypes.
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Colin S
CS
Cunningham
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Megan J
MJ
Moerke
Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Martin A
MA
Javors
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC, USA.
F Ivy
FI
Carroll
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Lance R
LR
McMahon
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D000068580:Varenicline / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; C082748:epibatidine; D000068580:Varenicline
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