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Modulation of nicotine receptors by chronic exposure to nicotinic agonists and antagonists
A C Collins1, R V Bhat, J R Pauly
1Institute for Behavioral Genetics, School of Pharmacy, University of Colorado, Boulder 80309.
Abstract:
Although numerous studies have demonstrated that chronic nicotine treatment often results in tolerance to this drug, the mechanisms that underlie this tolerance are not well defined. Recent evidence suggests that chronic nicotine treatment results in an up-regulation of brain nicotinic receptors, but the majority of these receptors may be desensitized or inactivated, thereby explaining tolerance. There is evidence that while all mouse strains show increased receptor numbers following chronic nicotine treatment, some mouse strains develop maximal changes in [3H] nicotine binding before any tolerance is detected. Other strains show a high correlation between increase in receptor number and tolerance. Studies with several other nicotinic agonists indicate that up-regulation of nicotine receptors can occur without changes in drug sensitivity. Similarly, chronic antagonists treatment can also elicit changes in receptors without affecting sensitivity to nicotine. Some of these discrepancies may be due to genetically influenced interactions between the adrenal steroid, corticosterone (CCS), and the nicotinic receptors. The addition of CCS in vitro inhibits binding to nicotinic receptors, and chronic CCS treatment results in decreases in the number of brain nicotinic receptors measured by [125I] bungarotoxin binding. Either of these biochemical measures may explain why altering CCS concentrations in vivo results in altered sensitivity to nicotine. It may be that both changes in the number of receptors and altered steroid interactions with the nicotinic receptors explain tolerance to nicotine.
Insights
Chronic nicotine exposure causes tolerance by altering brain nicotinic receptors. These changes, potentially influenced by corticosterone, involve receptor number and function, explaining nicotine tolerance.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Chronic nicotine treatment leads to drug tolerance, but underlying mechanisms remain unclear.
- Evidence suggests nicotine up-regulates brain nicotinic receptors, which may become desensitized, causing tolerance.
Purpose of the Study:
- To investigate the mechanisms of nicotine tolerance.
- To explore the role of nicotinic receptor up-regulation and desensitization in nicotine tolerance.
- To examine the influence of corticosterone on nicotinic receptor function and nicotine sensitivity.
Main Methods:
- Analysis of [3H] nicotine binding and receptor number changes in different mouse strains following chronic nicotine treatment.
- Assessment of nicotinic receptor sensitivity to other agonists and antagonists.
- In vitro and in vivo studies involving corticosterone (CCS) and its interaction with nicotinic receptors, including [125I] bungarotoxin binding assays.
Main Results:
- Mouse strains exhibit varying correlations between increased nicotinic receptor numbers and the development of nicotine tolerance.
- Nicotinic receptor up-regulation can occur independently of changes in drug sensitivity.
- Corticosterone (CCS) inhibits nicotinic receptor binding in vitro and chronic CCS treatment reduces receptor numbers, suggesting a role in altered nicotine sensitivity.
Conclusions:
- Nicotine tolerance may result from both changes in nicotinic receptor number and altered interactions with corticosterone.
- Genetic factors likely influence the interplay between corticosterone and nicotinic receptors, contributing to variations in nicotine tolerance.