Skip to main content
Log in

Evidence that nicotine can acutely desensitize central nicotinic acetylcholinergic receptors

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Epstein LH, Caggiula AR, Stiller R (1989) Environment-specific tolerance to nicotine. Psychopharmacology 97:235–237

    Google Scholar 

  • Hakan RL, Ksir CJ (1988) Nicotine induced locomotor activity in rats: the role of pavlovian conditioning. Pharmacol Biochem Behav 29:661–665

    Google Scholar 

  • Hakan RL, Ksir CJ (1991) Acute tolerance to the locomotor stimulant effects of nicotine in the rat. Psychopharmacology 104:368–390

    Google Scholar 

  • Hendry JS, Rosecrans JA (1982) Effects of nicotine on conditioned and unconditioned behaviors. Pharmacol Ther 17:431–454

    Google Scholar 

  • James JR (1992) Evidence that nicotine can acutely desensitize central nicotinic cholinergic receptors in vivo PhD Dissertation, Virginia Commonwealth University, Richmond, Virginia

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • Ochoa ELM, Chattopadhyay A, McNamee MG (1989) Desensitization of the acetylcholine receptor: molecular mechanisms and effect of modulators. Cell Mol Neurobiol 9:141–177

    Google Scholar 

  • Rosecrans JA (1989) Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central cholinergic mechanisms. J Subst Abuse 1:287–300

    Google Scholar 

  • 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

    Google Scholar 

  • Tallarida RJ, Murray RB (1981) Manual of pharmacology calculations with computer programs. Springer, New York

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Supported by The German Research Council on Smoking and Health

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02249336

Key words

Navigation