Rats exhibiting acute behavioural tolerance to nicotine have more [125I]alpha-bungarotoxin binding sites in brain than rats not exhibiting tolerance.
Adult male Sprague-Dawley rats trained to discriminate nicotine (0.4 mg/kg, s.c. vs vehicle) using a two-lever food-reinforced operant discriminative stimulus (DS) paradigm were tested as to the ability of each subject to develop acute tolerance to nicotine. Nicotine (0.8 mg/kg, s.c.) was administered to nicotine-trained rats in their home cage and each rat tested as to its ability to detect a 2nd dose of nicotine (0.4 mg/kg, s.c.) injected at 30 min intervals thereafter (90-180 min). Tolerance was determined by evaluating nicotine-correct responding during a 2 min test session. The results of this experiment indicated that 8 out of 31 rats (26%) displayed acute tolerance (desensitizers); 18 rats (58%) did not exhibit acute tolerance (non-desensitzers) and five rats (16%) fell into a middle group and were designated as neither desensitizers or non-desensitizers. The mode time for acute tolerance was 150 min, with each desensitizer rat displaying a unique temporal profile which was replicable 4-5 weeks later. Receptor autoradiographic analysis indicated no significant differences in [3H]epibatidine binding sites in the brains of desensitizers and non-desensitizers. In contrast, [125I]alpha-bungarotoxin binding was significantly higher in a number of brain regions in desensitizers. In situ hybridization analysis revealed no difference in alpha7 nAChR subunit mRNA levels between desensitizers and non-desensitizers. These observations can be interpreted to suggest that the ability to display acute tolerance to nicotine is contingent upon the ability to upregulate alpha7 nAChRs. These data may also be central to understanding the variability of tobacco use in humans, which may be contingent on the ability of the receptors binding to alpha-bungarotoxin to be responsive to nicotine-induced desensitization.
Zhang
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Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research, Karolinska Institutet, Huddinge University Hospital, Sweden. xiao.zhang@kfcmail.hs.sll.se
Paterson
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D
James
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Gong
Z H
ZH
Liu
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Rosecrans
J
J
Nordberg
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A
D000818:Animals; D001143:Arousal / Q000502:physiology*; D001345:Autoradiography; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D003345:Corticosterone / Q000097:blood; D004193:Discrimination Learning / Q000502:physiology; D004361:Drug Tolerance; D008297:Male; D009042:Motivation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D014029:Tobacco Use Disorder / Q000503:physiopathology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D003345:Corticosterone