Abstract
Initial studies in our laboratory suggested that tolerance to nicotine is thought to involve neuronal adaptation not only at the level of the drug-receptor interaction but at postreceptor events such as calcium-dependent second messengers. The present study was undertaken to investigate the hypothesis that L-type calcium channels and calcium-dependent calmodulin protein kinase II are involved in the development and expression of nicotine tolerance. To that end, the effects of modulation of L-type calcium channels (through the use of inhibitors or activators) as well as calcium-dependent calmodulin protein kinase II inactivation were studied in a mouse model of tolerance where mice were infused with nicotine in minipumps (24 mg/kg/day) for 14 days. In addition, the activity of calcium-dependent calmodulin protein kinase II in the lumbar spinal cord region obtained from nicotine-tolerant mice was measured. Our data showed that chronic administration of L-type calcium channel antagonists nimodipine (1 and 5 mg/kg) and verapamil (10 mg/kg) prevented the development of tolerance to nicotine-induced antinociception. In contrast, chronic exposure of BAYK8644 [(±)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester], a calcium channel activator, enhanced nicotine's tolerance. Moreover, a significant increase in both dependent and independent calcium-dependent calmodulin protein kinase II activity was seen in the spinal cord in nicotine-tolerant mice. Finally, spinal administration of 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine (KN-62), a calcium-dependent calmodulin protein kinase II antagonist, reduced the expression of tolerance to nicotine-induced antinociception in mice. In conclusion, our data indicate that calcium-dependent mechanisms such as L-type calcium channels and calcium-dependent calmodulin protein kinase II activation are involved in the expression and development of nicotine tolerance.
Footnotes
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This work was supported by National Institute on Drug Abuse Grants DA-12610 and DA-05274.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.092460.
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ABBREVIATIONS: nAChR, acetylcholine nicotinic receptor; BAYK8644, (±)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester; KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine; KN-04, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine derivative; %MPE, percent maximum possible effect; CL, confidence limit; CREB, cAMP response element-binding protein.
- Received July 11, 2005.
- Accepted August 11, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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