Mecamylamine blacks the development of tolerance to nicotine in rats: implications for the mechanisms of tolerance

Chronic injections of nicotine in rats produce upregulation of nicotinic ch olinergic receptors. It has been proposed that this upregulation is a refle ction of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicot inic receptors, does not prevent upregulation produced by nicotine injectio ns. This suggests that receptor activation is not a prerequisite for nicoti ne-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of toleran ce to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicoti ne did block the development of tolerance to nicotine-induced antinocicepti on (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.6 6 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no ev idence that after six pairings of mecamylamine with nicotine, the cues asso ciated with mecamylamine delivery took on conditioned antagonistic properti es. These findings suggest that, unlike the receptor upregulation that resu lts from either continuous or repeated nicotine administration, the toleran ce following a short series of intermittent nicotine injections is dependen t on receptor activation.