Pharmacological effects of nicotine on norepinephrine metabolism in rat brown adipose tissue: relevance to nicotinic therapies for smoking cessation.
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.
Brees
Dominique J
DJ
Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
Elwell
Michael R
MR
Tingley
F David
FD
Sands
Steven B
SB
Jakowski
Amy B
AB
Shen
Amy C
AC
Cai
Jenny Hon
JH
Finkelstein
Martin B
MB
D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D008067:Lipoma / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D008479:Mediastinal Neoplasms / Q000139:chemically induced / Q000378:metabolism; D009538:Nicotine / Q000819:agonists / Q000494:pharmacology* / Q000633:toxicity; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism*; D011810:Quinoxalines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D016540:Smoking Cessation / Q000379:methods; D000068580:Varenicline
D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D009538:Nicotine; D000068580:Varenicline; D009638:Norepinephrine