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Toxicologic Pathology
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Articles

Pharmacological Effects of Nicotine on Norepinephrine Metabolism in Rat Brown Adipose Tissue: Relevance to Nicotinic Therapies for Smoking Cessation

Dominique J. Brees, Michael R. Elwell, F. David Tingley, III, Steven B. Sands, Amy B. Jakowski, Amy C. Shen, Jenny Hon Cai and Martin B. Finkelstein

Pfizer Global Research and Development, Groton, Connecticut, USA

Correspondence: Martin B. Finkelstein, Pfizer Global Research and Development, P.O. Box 8012, Eastern Point Road, Groton, CT 06340-8012, USA; e-mail:martin.b.finkelstein{at}pfizer.com.

In a two-year carcinogenicity study with administration of high doses of the partial nicotinic agonist varenicline (recently approved for smoking cessation), mediastinal hibernomas occurred in three male rats. To investigate potential mechanisms for partial and full nicotinic agonists to contribute to development of hibernomas, the effects of nicotine on rat brown adipose tissue (BAT) were studied. Male and female rats were administered nicotine at doses of 0, 0.3, and 1 mg/kg subcutaneously for fourteen days. Intrathoracic (mediastinal periaortic and mediastinal perithymic) BAT and interscapular BAT were examined microscopically, and determinations of uncoupling protein-1 (UCP-1) expression and norepinephrine (NE) content were made. Additionally, NE turnover was measured in mediastinal periaortic and perithymic BAT. Nicotine (1 mg/kg) administration resulted in decreased vacuolation only in mediastinal periaortic and mediastinal perithymic BAT of males and elevated UCP-1 in mediastinal periaortic BAT of males and females. Increased NE content occurred only in mediastinal periaortic BAT of males given 0.3 and 1 mg/kg doses, whereas NE turnover was decreased in both males and females given 1 mg/kg. Together, these data demonstrate that nicotine primarily affects mediastinal BAT in male rats, consistent with the gender and location of the hibernomas observed in the two-year carcinogenicity study.

Key Words: nicotine • nAChR • brown adipose tissue • rats • norepinephrine • hibernoma • varenicline

Abbreviations: ANOVA, analysis of variance • Arbp, acidic ribosomal phosphoprotein P0 • BAT, brown adipose tissue • GAPDH, glyceraldehyde-3-phosphate dehydrogenase • HPLC, high performance liquid chromatography • IHC, immunohistochemistry • LSC, laser scanning cytometry • MHPG, 3-methoxy-4-hydroxyphenylglycol • mRNA, messenger ribonucleic acid • nAChR, nicotinic acetylcholine receptor • NE, norepinephrine • RT-PCR, reverse transcriptase polymerase chain reaction • UCP-1, uncoupling protein-1

This version was published on June 1, 2008

Toxicologic Pathology, Vol. 36, No. 4, 568-575 (2008)
DOI: 10.1177/0192623308317424
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 Toxicol PatholHome page
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