title: The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat.
abstract: Nicotinic acetylcholine receptor (nAChR) antagonists have been shown previously to decrease nicotine self-administration and precipitate elevations in brain reward thresholds and somatic signs of withdrawal in animals chronically exposed to nicotine. Both the positive-reinforcing effects of acute nicotine and the negative effects of nicotine withdrawal have been hypothesized to contribute to the development and maintenance of nicotine dependence. The aim of the present study was to use methyllycaconitine (MLA), an alpha 7 nAChR antagonist, to investigate the role of alpha 7 receptors in the reinforcing effects of nicotine and nicotine withdrawal. MLA was administered to animals allowed to self-administer nicotine intravenously, and also to animals that had been prepared with nicotine-containing osmotic mini-pumps and trained on a brain stimulation reward procedure. The results indicated that pretreatment with the highest doses of MLA used (3.9 and 7.8 mg/kg) significantly reduced nicotine self-administration at two doses of self-administered nicotine (0.03 and 0.06 mg/kg/infusion). Nevertheless, MLA administration, at all doses tested, had no effect on brain reward thresholds or the number of somatic signs of withdrawal observed in rats chronically exposed to either nicotine or saline. In conclusion, the alpha 7 nAChR subtype appears to play a significant role in the reinforcing effects of acute nicotine administered intravenously, but not in nicotine dependence, as reflected in the lack of precipitation of the nicotine withdrawal syndrome in nicotine-treated animals.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037, USA. amarkou@scripps.edu
authors.forename: A
authors.initials: A
authors.lastname: Markou
authors.forename: N E
authors.initials: NE
authors.lastname: Paterson
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D008297:Male; D009538:Nicotine / Q000009:adverse effects; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000175:diagnosis / Q000209:etiology; D014029:Tobacco Use Disorder / Q000188:drug therapy*
chemical_list: D018733:Nicotinic Antagonists; C054634:methyllycaconitine; D009538:Nicotine; D000157:Aconitine