Mecamylamine prevents tolerance but enhances whole brain [H-3]epibatidine binding in response to repeated nicotine administration in rats

Rationale: Chronic administration of nicotine in rats results in upregulati on of neuronal nicotinic receptors. Upregulation has been proposed to refle ct receptor desensitization, which may underlie functional tolerance to nic otine's effects. However, evidence indicates that tolerance and upregulatio n do not always parallel each other, suggesting that either upregulation do es not always reflect desensitization, or mechanisms other than receptor de sensitization account for tolerance to nicotine. Objectives: The present studies examined tolerance to nicotine-induced anti nociception and changes in receptor binding after two regimens of intermitt ent nicotine injections in rats. The role of receptor activation in upregul ation and tolerance was also examined by co-administering nicotine with the non-competitive antagonist, mecamylamine. Methods: Sprague-Dawley rats wer e administered a short (once-daily, SC for 6 days (0.35 mg/kg)) or long (tw ice-daily for II days (0.66 mg/kg)) series of injections and tolerance to n icotine-induced antinociception and [H-3]epibatidine binding in whole brain were measured. Results: The short series of injections resulted in toleran ce to nicotine-induced antinociception, but failed to increase [H-3]epibati dine binding. In contrast, the long series of injections resulted in both t olerance and increased receptor binding. Once-daily pairings of; mecamylami ne (1 mg/kg, SC) with nicotine (0.35 mg/kg) for 6 days blocked the developm ent of tolerance, indicating receptor activation is necessary for tolerance to occur. Pairing mecamylamine with nicotine (0.66 mg/kg) twice daily for 11 days blocked tolerance but produced a greater increase in [H-3]epibatidi ne binding than nicotine alone. Conclusions: A dissociation of tolerance fr om receptor upregulation was observed in the present study. The finding tha t receptor activation may be necessary for tolerance but not upregulation i s discussed within the context of possible mechanisms controlling tolerance to nicotine.