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Research ArticleArticle

Pharmacological Characterization of Nicotine-Induced Seizures in Mice

M. I. Damaj, W. Glassco, M. Dukat and B. R. Martin
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1284-1291;
M. I. Damaj
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W. Glassco
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M. Dukat
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B. R. Martin
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Abstract

Pharmacological mechanisms involved in nicotine-induced seizures were investigated in mice by testing the ability of several nicotinic agonists in producing seizures after peripheral administration. In addition, nicotinic antagonists such as hexamethonium, mecamylamine, dihydro-β-erythroidine, and methyllycaconitine citrate (MLA) were used in combination with nicotine. We also examined the involvement of calcium channels, N-methyl-d-aspartate receptors, and nitric oxide formation in nicotine-induced seizures. Our results showed that the peripheral administration of nicotine produced seizures in a stereospecific and mecamylamine-sensitive manner. Nicotine-induced seizures are centrally mediated and involve the activation of α7 along with other nicotinic receptor subunits. Indeed, MLA, an α7-antagonist, blocked the effects of nicotine after peripheral and central administration. The extent of α4β2-receptor subtype involvement in nicotine-induced seizures was difficult to assess. On one hand, we observed that dihydro-β-erythroidine (a competitive antagonist) failed to block the effects of nicotine. In addition, a poor correlation was found between binding affinity for3H-nicotine-labeled sites (predominantly α4β2) and seizures potency for several nicotinic agonists. On the other hand, mecamylamine, a noncompetitive antagonist, blocked nicotine-induced seizures more potently than MLA. Furthermore, its potency in blocking seizures was in the same general dose range of other nicotinic effects that are not α7 mediated. These results suggest that this receptor subtype does not play a major role in nicotine-induced seizures. Our findings also suggest that nicotine enhances the release of glutamate either directly or indirectly (membrane depolarization that opens L-type calcium channels). Glutamate release in turn stimulatesN-methyl-d-aspartate receptors, thus triggering the cascade of events leading to nitric oxide formation and possibly seizure production.

Footnotes

  • Send reprint requests to: Dr. M. Imad Damaj, Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613. E-mail:mdamaj{at}hsc.vcu.edu

  • ↵1 This work was supported by National Institute on Drug Abuse Grant DA05274.

  • Abbreviations:
    α-BGTX
    α-bungarotoxin
    nAChR
    nicotinic acetylcholine receptor
    NO
    nitric oxide
    MLA
    methyllycaconitine citrate
    NMDA
    N-methyl-d-aspartate
    L-NNA
    NG-nitro-l-arginine
    D-NNA
    NG-nitro-d-arginine
    L-NAME
    NG-nitro-l-arginine methyl ester HCl
    D-NAME
    NG-nitro-d-arginine methyl ester HCl
    NO
    nitric oxide
    AMP-MP
    3-(N-methyl-N-n-propylaminomethyl)pyridine
    AMP-ME
    3-(N-ethyl-N-n-methylaminomethyl)pyridine
    N-MNP
    1,2,3,4,-tetrahydro-N-methyl)-1,6-naphhyridine
    CPP
    3-(RS)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid
    • Received April 20, 1999.
    • Accepted August 30, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Pharmacological Characterization of Nicotine-Induced Seizures in Mice

M. I. Damaj, W. Glassco, M. Dukat and B. R. Martin
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1284-1291;

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Research ArticleArticle

Pharmacological Characterization of Nicotine-Induced Seizures in Mice

M. I. Damaj, W. Glassco, M. Dukat and B. R. Martin
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1284-1291;
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