title: The discriminative stimulus effects of i.v. nicotine in rhesus monkeys: Pharmacokinetics and apparent pA2analysis with dihydro-β-erythroidine.
abstract: Quantitative analysis of antagonism is infrequently used to identify nAChRs mediating behavioral effects. Here, nicotine (0.032 mg/kg i.v.) was established as a discriminative stimulus in rhesus monkeys responding under a fixed ratio 5 schedule; pharmacokinetics and underlying nAChR mechanism(s) were examined. When measured up to 4 h in venous blood, the training dose resulted in the following mean pharmacokinetic parameters: nicotine Cmax= 71.7 ng/ml, t1/2= 116 min, and clearance = 6.25 ml/min/kg; cotinine Cmax= 191 ng/ml; and 3OH-cotinine Cmax= 63 ng/ml. The ED50value of nicotine to produce discriminative stimulus effects was 0.013 mg/kg. Epibatidine and varenicline increased drug-lever responding to 97% and 95%, respectively (ED50values = 0.00015 and 0.031 mg/kg, respectively), whereas cocaine, midazolam, and morphine produced no more than 28% drug-appropriate responding. Mecamylamine and dihydro-β-erythroidine (DHβE) dose-dependently attenuated the discriminative stimulus effects of the nicotine training dose, whereas methyllycaconitine (MLA) did not. DHβE (0.1 and 0.32) produced rightward shifts of the nicotine and varenicline dose-response functions; Schild plots fitted through individual data resulted in slopes that were not different from unity; the apparent pA2calculated for DHβE did not significantly differ in the presence of nicotine (6.58) or varenicline (6.45). Compared to human cigarette smoking, nicotine blood levels after 0.032 mg/kg nicotine i.v. took a similar time to reach maximal concentration, levels at Cmax were similar to smoking 2-3 cigarettes, while average nicotine levels were comparable to smoking 5-6 cigarettes. Apparent pA2analysis with DHβE under these conditions is consistent with nicotine and varenicline acting through the same nAChRs to produce discriminative stimulus effects.
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Moerke
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: Department of Psychiatry, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Javors
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: mcmahonl@uthscsa.edu.
authors.forename: Lance R
authors.initials: LR
authors.lastname: McMahon
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D003367:Cotinine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D004079:Dihydro-beta-Erythroidine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004597:Electroshock; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009538:Nicotine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D018722:Nicotinic Agonists / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012907:Smoking / Q000097:blood; D000068580:Varenicline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D018722:Nicotinic Agonists; D004079:Dihydro-beta-Erythroidine; C001381:hydroxycotinine; D009538:Nicotine; D003367:Cotinine; D000068580:Varenicline
keywords: DHβE; Drug discrimination; FR; MLA; Nicotine; Rhesus monkey; Schild analysis; Varenicline; dihydro-β-erythroidine; fixed ratio; methyllycaconitine; nAChR; nicotinic acetylcholine receptor