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Nicotine-induced tolerance and receptor changes in four mouse strains
Abstract:
The effects of chronic infusion of 3.0 mg/kg/hr of nicotine on the behavioral responses of four mouse strains (C3H, C57BL, BALB and DBA) to challenge doses of nicotine and on the levels of cholinergic receptors and enzymes were determined. Mice of the C57BL, BALB and DBA strains developed tolerance to the effects of nicotine on Y-maze activity, Y-maze rearing and body temperature. The C3H mice did not exhibit any evidence of tolerance to the effects of nicotine on these measures, but this strain did show tolerance to the effects of nicotine on acoustic startle response. None of the strains developed tolerance to the effects of nicotine on respiration rate, and only the BALB mice demonstrated tolerance to nicotine-induced bradycardia. Chronic nicotine treatment also elicited changes in putative brain nicotinic receptors. Increased binding of L-[3H]nicotine was seen in six brain regions in all four mouse strains. The changes in binding were similar for all the strains. The binding of alpha-[125I]bungarotoxin was also elevated in the four mouse strains, and modest differences among the strains were evident in this measure, with the C3H strain showing the smallest increases in four of the six brain regions. Chronic nicotine treatment did not alter brain muscarinic receptors, as measured with L-[3H]quinuclidinyl benzilate binding, nor were the activities of acetylcholinesterase or choline acetyltransferase altered, except that a small change in hippocampal choline acetyltransferase activity may have occurred. These results indicate that tolerance to nicotine is regulated by genetic factors and that changes in brain nicotinic receptor numbers are not sufficient to explain the development of tolerance.
Insights
Genetic factors influence nicotine tolerance, with varying responses across mouse strains. Chronic nicotine alters nicotinic receptors but doesn't fully explain tolerance development.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Nicotine addiction is a major public health concern.
- Understanding the mechanisms of nicotine tolerance is crucial for developing effective cessation strategies.
- Genetic variability may influence individual responses to nicotine.
Purpose of the Study:
- To investigate the effects of chronic nicotine exposure on behavioral responses and cholinergic systems in different mouse strains.
- To determine the role of genetic factors in the development of nicotine tolerance.
- To examine changes in nicotinic and muscarinic receptors and related enzymes following chronic nicotine administration.
Main Methods:
- Chronic nicotine infusion (3.0 mg/kg/hr) in four mouse strains (C3H, C57BL, BALB, DBA).
- Assessment of behavioral responses (Y-maze activity, rearing, body temperature, acoustic startle, respiration, heart rate).
- Measurement of brain nicotinic and muscarinic receptor binding (L-[3H]nicotine, alpha-[125I]bungarotoxin, L-[3H]quinuclidinyl benzilate) and enzyme activities (acetylcholinesterase, choline acetyltransferase).
Main Results:
- Tolerance to nicotine's effects on Y-maze activity, rearing, and body temperature varied among strains; C3H mice showed less tolerance.
- Tolerance to acoustic startle response was observed in C3H mice, but not to respiration rate changes in any strain.
- Chronic nicotine increased nicotinic receptor binding (L-[3H]nicotine and alpha-[125I]bungarotoxin) across all strains, with minor strain-specific differences.
- Muscarinic receptors and key cholinergic enzyme activities remained largely unchanged, except for a potential minor alteration in hippocampal choline acetyltransferase.
Conclusions:
- Nicotine tolerance is significantly influenced by genetic factors, as evidenced by differential responses across mouse strains.
- While chronic nicotine alters nicotinic receptor binding, these changes alone are insufficient to account for the observed tolerance.
- Further research is needed to elucidate the complex neurobiological mechanisms underlying nicotine tolerance.