Abstract
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 µg/kg, SC) to elicit DS control of behavior in a two-lever operant procedure was significantly reduced via a challenge dose (800 µg/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 µg/kg, SC) to antagonize the DS, while in both populations of rats scopolamine (100 µg/kg, SC) failed to antagonize the DS.
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References
Epstein LH, Caggiula AR, Stiller R (1989) Environment-specific tolerance to nicotine. Psychopharmacology 97:235–237
Hakan RL, Ksir CJ (1988) Nicotine induced locomotor activity in rats: the role of pavlovian conditioning. Pharmacol Biochem Behav 29:661–665
Hakan RL, Ksir CJ (1991) Acute tolerance to the locomotor stimulant effects of nicotine in the rat. Psychopharmacology 104:368–390
Hendry JS, Rosecrans JA (1982) Effects of nicotine on conditioned and unconditioned behaviors. Pharmacol Ther 17:431–454
James JR (1992) Evidence that nicotine can acutely desensitize central nicotinic cholinergic receptors in vivo PhD Dissertation, Virginia Commonwealth University, Richmond, Virginia
Marks MJ, Burch JB, Collins AC (1983) Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther 226 [3]:817–825
Meltzer LT, Rosecrans JA (1988) Nicotine and arecoline as discriminative stimuli: involvement of a non-cholinergic mechanism for nicotine. Pharmacol Biochem Behav 29:587–593
Ochoa ELM, Chattopadhyay A, McNamee MG (1989) Desensitization of the acetylcholine receptor: molecular mechanisms and effect of modulators. Cell Mol Neurobiol 9:141–177
Rosecrans JA (1989) Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central cholinergic mechanisms. J Subst Abuse 1:287–300
Rosecrans JA, Karan L (1993) Neurobehavioral mechanisms of nicotine action: role in the initiation and maintanance of tobacco dependence. J Subst Abuse 10:161–170
Tallarida RJ, Murray RB (1981) Manual of pharmacology calculations with computer programs. Springer, New York
Tonner PH, Wood SC, Miller KW (1992) Can nicotine self-inhibition account for its low efficacy at the nicotinic acetylcholine receptor from Torpedo? Mol Pharmacol 42[5]:890–897
Villanueva HF, Arezo S, James JR, Rosecrans JA (1992) A characterization of nicotine-induced tolerance: evidence of pharmacological tolerance in the rat. Behav Pharmacol 3:255–260
Wonnacott S, Drasdo A, Sanderson E, Rowell P (1990) Presynaptic nicotinic receptors and the modulation of transmitter release. In: Bock G, Marsh J (eds) The biology of nicotine dependence. Wiley, Chichester, pp 87–105
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Supported by The German Research Council on Smoking and Health
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James, J.R., Villanueva, H.F., Johnson, J.H. et al. Evidence that nicotine can acutely desensitize central nicotinic acetylcholinergic receptors. Psychopharmacology 114, 456–462 (1994). https://doi.org/10.1007/BF02249336
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DOI: https://doi.org/10.1007/BF02249336