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Altered behavioral sensitivity of Ca(2+)-modulating drugs after chronic nicotine administration in mice
1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Abstract:
Numerous studies have demonstrated that tolerance develops to the physiological and behavioral effects of nicotine in animals after chronic administration of the drug. However, the mechanisms underlying tolerance to nicotine are not well known. There are several lines of evidence which support a role for Ca2+ in nicotine's acute pharmacological effects. The objective of the study was to determine whether Ca2+ plays a role in the development of tolerance to nicotine by investigating the behavioral activity of several Ca(2+)-modulating drugs after systemic (BAY K 8644: (+/-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluromethyl)-pheny l] -3-pyridine carboxylic acid methylester) and intrathecal administration (BAY K 8644, Ca2+ and thapsigargin) in nicotine-tolerant mice. The ability of BAY K 8644 to induce motor impairment and hypomotility after i.p. injection was decreased in nicotine-tolerant mice. In addition, tolerance to Ca2+, thapsigargin, and BAY K 8644-induced antinociception after i.t. injection also developed in nicotine-tolerant mice. ED50 values for BAY K 8644 and thapsigargin increased from 3.7 to 12 micrograms/mouse and 0.83 to 19.7 micrograms/mouse, respectively. The greatest tolerance developed to the effects of thapsigargin with an ED50 value that increased from 0.83 to 20 micrograms. Furthermore, chronic nicotine injections did not alter [3H]nitrendipine binding in the brain. These results suggest the involvement of Ca(2+)-dependent mechanisms in nicotine tolerance in mice.
Insights
Calcium (Ca2+) may play a role in nicotine tolerance. Studies in mice show that tolerance develops to Ca2+-modulating drugs, suggesting Ca2+-dependent mechanisms are involved in nicotine tolerance.
Area of Science:
- Neuropharmacology
- Calcium Signaling
Background:
- Chronic nicotine administration leads to tolerance in animals.
- The precise mechanisms underlying nicotine tolerance remain unclear.
- Calcium ions (Ca2+) are implicated in nicotine's acute effects.
Purpose of the Study:
- To investigate the role of Ca2+ in the development of nicotine tolerance.
- To examine the effects of Ca2+-modulating drugs in nicotine-tolerant mice.
Main Methods:
- Systemic and intrathecal administration of Ca2+-modulating drugs (BAY K 8644, Ca2+, thapsigargin) in nicotine-tolerant mice.
- Assessment of motor impairment, hypomotility, and antinociception.
- Measurement of [3H]nitrendipine binding in the brain.
Main Results:
- Tolerance to BAY K 8644-induced motor impairment and hypomotility was observed.
- Significant tolerance to Ca2+, thapsigargin, and BAY K 8644-induced antinociception developed.
- ED50 values for BAY K 8644 and thapsigargin increased substantially in tolerant mice.
- Chronic nicotine did not affect [3H]nitrendipine binding.
Conclusions:
- Ca2+-dependent mechanisms are likely involved in the development of nicotine tolerance.
- Findings suggest a link between calcium signaling pathways and nicotine's long-term effects.