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Cellular nicotinic receptor desensitization correlates with nicotine-induced acute behavioral tolerance in rats

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Abstract

Rationale

Individuals vary in their susceptibility to nicotine addiction. However, there is little evidence that behavioral sensitivity to nicotine is dependent upon the functional state of nicotinic cholinergic receptors (nAChRs).

Objective

This study aims to determine the relationship between in vivo behavioral desensitization and in vitro desensitization of nAChR function.

Methods

Male Sprague–Dawley rats trained to discriminate nicotine were tested for development of acute behavioral tolerance. The rats were injected with nicotine (0.4 mg/kg free base, s.c.), tested for nicotine discrimination for 2 min, then injected with the same dose of nicotine 90, 180, and 270 min after the first injection and tested for nicotine discrimination after each injection. Susceptibility of nAChRs of individual rats to desensitization was assessed by use of the 86Rb+ efflux assay using synaptosomes prepared from the “thalamus,” which included the hypothalamus and midbrain as well as the thalamic nuclei. To desensitize nAChRs, synaptsosomes were superfused with low concentrations of nicotine (5, 10, 20, and 30 nM) before stimulation of 86Rb+ efflux with nicotine (10 μM).

Results

The slopes of the behavioral desensitization were plotted as a function of the decline of nicotine-stimulated 86Rb+ efflux after in vitro desensitization. A significant correlation was observed between the in vitro desensitization of thalamic 86Rb+ efflux and the extent of behavioral desensitization of individual rats.

Conclusions

These findings are consistent with the idea that production of acute behavioral tolerance by nicotine is related to its ability to induce nAChR desensitization at the cellular level.

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Acknowledgment

This work was supported by the Philip Morris External Research Program and the A.D. Williams Trust. We thank Dr. Michael J. Marks for his invaluable assistance in establishing the 86Rb+ efflux assay in our laboratory. We also thank Dr. Peter Rowell for his loan of equipment for the 86Rb+ efflux assays. The experiments described within this publication are all in compliance with the laws of the USA.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA, 23298-0613, USA

    Susan E. Robinson, Robert E. Vann, Angela F. Britton, Mary M. O’Connell & John A. Rosecrans

  2. Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, 23298-0533, USA

    John R. James

  3. Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298-0310, USA

    Susan E. Robinson & John A. Rosecrans

Authors
  1. Susan E. Robinson
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  2. Robert E. Vann
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  3. Angela F. Britton
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  4. Mary M. O’Connell
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  5. John R. James
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  6. John A. Rosecrans
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Correspondence to Susan E. Robinson.

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Robinson, S.E., Vann, R.E., Britton, A.F. et al. Cellular nicotinic receptor desensitization correlates with nicotine-induced acute behavioral tolerance in rats. Psychopharmacology 192, 71–78 (2007). https://doi.org/10.1007/s00213-006-0687-6

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  • DOI: https://doi.org/10.1007/s00213-006-0687-6

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