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Characterization and modulation of acute tolerance to nicotine in mice
M I Damaj1, S P Welch, B R Martin
1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298-0613, USA.
Abstract:
Acute tolerance to the effects of nicotine is believed to play an important role in the development and maintenance of dependence to this drug. The objective of this study was to investigate and characterize the development of acute tolerance to nicotine after systemic and intrathecal administrations. Acute tolerance developed to several centrally mediated pharmacological effects of nicotine after systemic (motor coordination, body temperature, antinociception) and intrathecal (antinociception) injection of the drug. The appearance and the magnitude of acute tolerance varied depending on the response measured. Development of acute tolerance to nicotine-induced hypothermia and motor impairment was blocked after intraperitoneal pretreatment with nimodipine. Similarly, an intrathecal injection of nimodipine blocked the development of acute tolerance to nicotine-induced antinociception. On the other hand, intrathecal administration of calcium and thapsigargin enhanced the acute tolerance to nicotine-induced antinociception. Characterization of the acute tolerance to nicotine in several animal models revealed time and dose dependencies that are consistent with receptor-mediated events. More importantly, acute tolerance was modulated by agents that influence cellular calcium homeostasis.
Insights
Acute tolerance to nicotine, a key factor in dependence, was investigated. This study reveals that nimodipine blocks tolerance development, while calcium influences it, suggesting receptor-mediated events.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Acute tolerance to nicotine is crucial for understanding nicotine dependence.
- Investigating tolerance mechanisms after systemic and intrathecal administration is essential.
Purpose of the Study:
- To characterize the development of acute tolerance to nicotine.
- To examine the role of nimodipine and calcium homeostasis in nicotine tolerance.
Main Methods:
- Systemic and intrathecal administration of nicotine in animal models.
- Assessment of motor coordination, body temperature, and antinociception.
- Administration of nimodipine, calcium, and thapsigargin to modulate tolerance.
Main Results:
- Acute tolerance developed to centrally mediated effects of nicotine, varying by response.
- Nimodipine blocked tolerance to nicotine-induced hypothermia, motor impairment, and antinociception.
- Calcium and thapsigargin enhanced acute tolerance to nicotine-induced antinociception.
Conclusions:
- Acute nicotine tolerance exhibits time and dose dependencies, suggesting receptor-mediated mechanisms.
- Cellular calcium homeostasis significantly modulates acute tolerance to nicotine.
- Findings provide insights into the neurobiological underpinnings of nicotine dependence.