Modulation of nicotine receptors by chronic exposure to nicotinic agonists and antagonists.
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.
Collins
A C
AC
Institute for Behavioral Genetics, School of Pharmacy, University of Colorado, Boulder 80309.
Bhat
R V
RV
Pauly
J R
JR
Marks
M J
MJ
D000818:Animals; D005731:Ganglionic Stimulants / Q000494:pharmacology*; D006801:Humans; D009538:Nicotine / Q000037:antagonists & inhibitors*; D011978:Receptors, Nicotinic / Q000187:drug effects*
D005731:Ganglionic Stimulants; D011978:Receptors, Nicotinic; D009538:Nicotine