EVIDENCE THAT NICOTINE CAN ACUTELY DESENSITIZE CENTRAL NICOTINIC ACETYLCHOLINERGIC RECEPTORS

Current concepts concerning nicotine's CNS mechanism(s) of action sugg est that this drug produces its effects via an interaction at nicotini c-cholinergic receptors (nAChRs) sensitive to acetylcholine. In vitro research further suggests that, following its initial agonist effect, this cholinergic drug may also induce a rapid desensitization of the n AChR similar to that of acetylcholine, resulting in termination of its pharmacological effect. Research described in this paper provides evi dence of this secondary desensitization process in vivo by demonstrati ng nicotine's ability to induce acute tolerance in a Discriminative St imulus (DS) paradigm. The ability of nicotine (400 mu g/kg, SC) to eli cit DS control of behavior in a two-lever operant procedure was signif icantly reduced via a challenge dose (800 mu g/kg, SC) of nicotine adm inistered 15-180 min before the training dose. Twenty-three of 52 rats demonstrated this phenomenon. The time to develop acute tolerance var ied, providing additional evidence that these effects may be contingen t upon individual rat variability. In addition, physostigmine was also observed to induce a similar desensitization in a random population o f desensitizing rats. Lastly, there were no differences between desens itizers and non-desensitizers in relation to the ability of mecamylami ne (1000 mu g/kg, SC) to antagonize the DS, while in both populations of rats scopolamine (100 mu g/kg, SC) failed to antagonize the DS.