Time course study of the effects of chronic nicotine infusion on drug response and brain receptors
Abstract
The experiments reported here examined the time course of the development and loss of tolerance to nicotine as well as the time course for the up-regulation and return to basal levels of brain nicotinic receptors. Nicotine was administered by continuous i.v. infusion through cannulae implanted in the right jugular veins of DBA mice. Tolerance to the effects of nicotine on Y-maze activity and rears, body temperature and heart rate was seen accompanying the infusion of 4 mg/kg/hr of nicotine. Maximal tolerance was obtained in 4 days and was paralleled by increases in the number of brain nicotine binding sites. The binding of alpha-bungarotoxin was also increased by chronic nicotine treatment but increases in binding preceded the development of detectable tolerance to the challenge dose of nicotine. Chronic nicotine treatment had no effect on quinuclidinyl benzilate binding. Tolerance to the effects of nicotine was lost at different rates for the various tests in that base-line response was attained for the Y-maze activity and rearings test in 8 days, whereas 12 to 16 days were required to regain control response for the body temperature test. Tolerance for the heart rate test persisted throughout the 20-day withdrawal period. Brain nicotine binding sites had returned to control levels by 8 days after treatment whereas the alpha-bungarotoxin binding sites were at control levels at the earliest time of postinfusion testing (4 days). Brain quinuclidinyl benzilate binding sites were unaffected by nicotine treatment and did not change during the withdrawal period. The changes in nicotine binding in the various brain regions during the onset and offset experiments were virtually identical. These changes in binding correlated highly with the acquisition and loss of tolerance to the effects of nicotine on the Y-maze locomotor activity and body temperature tests. The correlations between changes in nicotine binding and the Y-maze rearings and the heart rate tests were lower but some association is suggested. Although changes in nicotine binding may explain some of the tolerance observed, other explanations for tolerance must be sought as well.
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Previous preclinical studies demonstrated that in chronically nicotine treated animals, nAChR levels returned to levels observed in control animals after termination of nicotine, but with variable timing ranging between 1 and 3 weeks.
“Previous preclinical studies demonstrated that in chronically nicotine treated animals, nAChR levels returned to levels observed in control animals after termination of nicotine, but with variable timing ranging between 1 and 3 weeks15, 80, 81.”
From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [80]
Animals exposed to nicotine chronically exhibit increased levels of nAChRs in the brain.
“animals exposed to nicotine chronically exhibit increased levels of nAChRs in the brain (Marks et al., 1983(Marks et al., , 1985(Marks et al., , 1992;;Schwartz and Kellar, 1983)”
From Human Tobacco Smokers in Early Abstinence Have Higher Levels of β<sub>2</sub>* Nicotinic Acetylcholine Receptors than Nonsmokers (2006) · cites this paper as Marks et al., 1985
These α4β2* binding changes are related to the development and loss of tolerance.
“Similarly, a study in mice indicated that α4β2* nAChRs binding sites increased during chronic nicotine treatment and returned to control levels following cessation of treatment; these changes were related to the development and loss of tolerance (Marks et al., 1985).”
From The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation (2012) · cites this paper as Marks et al., 1985
In mice, α4β2* nAChR binding sites increase during chronic nicotine treatment and return to control levels after cessation.
“Similarly, a study in mice indicated that α4β2* nAChRs binding sites increased during chronic nicotine treatment and returned to control levels following cessation of treatment; these changes were related to the development and loss of tolerance (Marks et al., 1985).”
From The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation (2012) · cites this paper as Marks et al., 1985
Non-α7 nAChRs remain upregulated longer than α7 nAChRs, which return to baseline almost immediately after nicotine cessation.
“Non-α7 nAChRs show a longer lasting upregulation than α7 nAChRs, which return to baseline almost immediately after cessation of nicotine treatment (Marks et al., 1985).”
From The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation (2012) · cites this paper as Marks et al., 1985
The time scale (48 h) is relevant to the initial stages of nicotine-induced up-regulation in the brains of mice.
“The time scale is also relevant to the initial stages of nicotine-induced up-regulation in the brains of mice (Marks et al., 1985).”
From Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning (2011) · cites this paper as Marks et al., 1985
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- Authors
- Marks, M. J., Stitzel, J. A., & Collins, A. C.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1985-12
- Volume
- 235
- Issue
- 3
- Pages
- 619-628
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2155400043
- Cited by
- 265
- References
- 0
- Citations by year
- 2025: 1 · 2022: 2 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 8 · 2015: 11 · 2014: 9 · 2013: 7 · 2012: 6
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institute on Drug Abuse (DA 03194)
- National Center for Research Resources (RR07013-19)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- nicotine tolerance, receptor down-regulation, alpha-bungarotoxin binding, quinuclidinyl benzilate binding, nicotine withdrawal, locomotor activity, heart rate, body temperature, DBA mice
- MeSH terms
- Animals, Body Temperature, Brain Chemistry, Bungarotoxins, Drug Tolerance, Female, Mice, Inbred DBA, Motor Activity, Nicotine, Receptors, Nicotinic, Substance Withdrawal Syndrome, Time Factors, Mice
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