RESUMEN
Current concepts concerning nicotine's CNS mechanism(s) of action suggest that this drug produces its effects via an interaction at nicotinic-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 nAChR similar to that of acetylcholine, resulting in termination of its pharmacological effect. Research described in this paper provides evidence of this secondary desensitization process in vivo by demonstrating nicotine's ability to induce acute tolerance in a Discriminative Stimulus (DS) paradigm. The ability of nicotine (400 micrograms/kg, SC) to elicit DS control of behavior in a two-lever operant procedure was significantly reduced via a challenge dose (800 micrograms/kg, SC) of nicotine administered 15-180 min before the training dose. Twenty-three of 52 rats demonstrated this phenomenon. The time to develop acute tolerance varied, providing additional evidence that these effects may be contingent upon individual rat variability. In addition, physostigmine was also observed to induce a similar desensitization in a random population of desensitizing rats. Lastly, there were no differences between desensitizers and non-desensitizers in relation to the ability of mecamylamine (1000 micrograms/kg, SC) to antagonize the DS, while in both populations of rats scopolamine (100 micrograms/kg, SC) failed to antagonize the DS.
Asunto(s)
Nicotina/farmacología , Antagonistas Nicotínicos , Animales , Aprendizaje Discriminativo/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Tolerancia a Medicamentos , Inyecciones Subcutáneas , Masculino , Mecamilamina/farmacología , Nicotina/administración & dosificación , Nicotina/antagonistas & inhibidores , Fisostigmina/farmacología , Ratas , Ratas Sprague-Dawley , Escopolamina/farmacologíaRESUMEN
The present studies were conducted in order to confirm and extend previous findings that the mechanisms of tolerance to the behaviorally disruptive effects of nicotine in a operant model were primarily pharmacological. Both the traditional methodology employing the determination of dose response curves before and after chronic drug administration and a methodology which omits the generation of dose response curves were utilized in these investigations of nicotine-induced tolerance. Rats developed tolerance to both pre- and post-session administration of nicotine, suggesting that the mechanisms of tolerance to the disruptive effects of nicotine are primarily pharmacological. The mechanisms underlying these effects, however, remain to be evaluated.
RESUMEN
Sprague-Dawley rats were maintained on a daily regimen of nicotine, morphine or saline administration for 28 days. Following the discontinuation of the daily drug regimen, rats were given a choice of tap water or a saccharin-water solution. The rats previously receiving morphine drank significantly less saccharin-water solution than did the rats receiving nicotine or saline injections. The failure of the nicotine rats to display a conditioned aversion to the novel saccharin flavor suggests that nicotine did not produce a physiological withdrawal syndrome analogous to morphine withdrawal in this paradigm.