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Research ArticleArticle

Accumulation of Nicotine and Its Metabolites in Rat Brain After Intermittent or Continuous Peripheral Administration of [2′-14C]Nicotine

Omar A. Ghosheh, Linda P. Dwoskin, Dennis K. Miller and Peter A. Crooks
Drug Metabolism and Disposition May 2001, 29 (5) 645-651;
Omar A. Ghosheh
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Linda P. Dwoskin
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Dennis K. Miller
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Peter A. Crooks
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Abstract

Concentrations of nicotine, cotinine, and nornicotine in brain and blood following both intermittent and continuous administration of [2′-14C]nicotine to rats were determined to assess nicotine metabolite accumulation in brain following repeated nicotine administration. For intermittent studies, rats were administered s.c. 1 to 10 doses of nicotine (0.3 mg/kg, 15 or 25 μCi of [2′-14C]nicotine; 30-min interinjection interval). For continuous administration studies, rats were implanted s.c. with an osmotic minipump delivering nicotine (0.8 mg/kg/day, 25 or 50 μCi of [2′-14C]nicotine for 1–21 days). Whole brain and trunk blood was collected. The concentration of [2′-14C]nicotine and its metabolites was determined via high-pressure liquid radiochromatography. Brain concentrations of nicotine, cotinine, and nornicotine increased 2-, 12-, and 9-fold, respectively, following 10 injections, reaching a plateau following the fifth injection. Brain blood ratios indicate an enhanced preferential distribution of nornicotine to brain with increasing numbers of injections. Across the 21-day period of continuous infusion, blood nicotine and nornicotine concentrations remained relatively constant, whereas concentrations in brain increased ∼4-fold. Generally, cotinine concentrations in brain and blood did not change across the infusion period. Brain/blood ratios indicate an increase in nicotine distribution into brain across days of nicotine infusion. Results demonstrate that both nicotine and its metabolites accumulate in brain following repeated nicotine administration, and indicate that brain nicotine concentration can not be extrapolated from plasma cotinine or nicotine concentrations. Thus, nornicotine accumulation following repeated nicotine administration suggests that this metabolite plays a contributory role in the neuropharmacological effects of nicotine.

Footnotes

  • Send reprint requests to: Peter A. Crooks, Ph.D., College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082. E-mail: pcrooks{at}pop.uky.edu

  • This research was supported by National Institutes of Health Grants DA 00399, DA 08656, and DA 06043 and a grant from the Tobacco and Health Research Institute, Lexington, KY.

  • Abbreviations used are::
    HPLC
    high-performance liquid chromatography
    ANOVA
    analysis of variance
    CNS
    central nervous system
    HPLRC
    high-pressure liquid radiochromatography
    UV
    ultraviolet
    • Received October 5, 2000.
    • Accepted January 10, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (5)
Drug Metabolism and Disposition
Vol. 29, Issue 5
1 May 2001
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Research ArticleArticle

Accumulation of Nicotine and Its Metabolites in Rat Brain After Intermittent or Continuous Peripheral Administration of [2′-14C]Nicotine

Omar A. Ghosheh, Linda P. Dwoskin, Dennis K. Miller and Peter A. Crooks
Drug Metabolism and Disposition May 1, 2001, 29 (5) 645-651;

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Research ArticleArticle

Accumulation of Nicotine and Its Metabolites in Rat Brain After Intermittent or Continuous Peripheral Administration of [2′-14C]Nicotine

Omar A. Ghosheh, Linda P. Dwoskin, Dennis K. Miller and Peter A. Crooks
Drug Metabolism and Disposition May 1, 2001, 29 (5) 645-651;
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