Rats exhibiting acute behavioural tolerance to nicotine have more [I-125]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 dev elop acute tolerance to nicotine. Nicotine (0.8 mg/kg, s.c.) was administer ed to nicotine-trained rats in their home cage and each rat tested as to it s 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 evaluat ing nicotine-correct responding during a 2 min test session. The results of this experiment indicated that 8 out of 31 rats (26%) displayed acute tole rance (desensitizers); 18 rats (58%) did not exhibit acute tolerance (non-d esensitzers) and five rats (16%) fell into a middle group and were designat ed as neither desensitizers or non-desensitizers. The mode time for acute t olerance was 150 min, with each desensitizer rat displaying a unique tempor al profile which was replicable 4-5 weeks later. Receptor autoradiographic analysis indicated no significant differences in [H-3]epibatidine binding s ites in the brains of desensitizers and non-desensitizers. In contrast, [I- 125]alpha-bungarotoxin binding was significantly higher in a number of brai n regions in desensitizers. In situ hybridization analysis revealed no diff erence in alpha 7 nAChR subunit mRNA levels between desensitizers and non-d esensitizers. These observations call be interpreted to suggest that the ab ility to display acute tolerance to nicotine is contingent upon the ability to upregulate alpha 7 nAChRs. These data may also be central to understand ing the variability of tobacco use in humans, which may be contingent on th e ability of the receptors binding to alpha-bungarotoxin to be responsive t o nicotine-induced desensitization. (C) 2000 Elsevier Science B.V. All righ ts reserved.