![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 288, Issue 3, 905-911, March 1999
)-Cotinine, the Major Brain Metabolite of
Nicotine, Stimulates Nicotinic Receptors to Evoke
[3H]Dopamine Release from Rat Striatal Slices in a
Calcium-Dependent Manner1
College of Pharmacy and Graduate Center for Toxicology, University
for Kentucky, Lexington, Kentucky
Cotinine, a major peripheral metabolite of nicotine, has recently been
shown to be the most abundant metabolite in rat brain after peripheral
nicotine administration. However, little attention has been focused on
the contribution of cotinine to the pharmacological effects of nicotine
exposure in either animals or humans. The present study determined the
concentration-response relationship for
(S)-(
)-cotinine-evoked 3H overflow from
superfused rat striatal slices preloaded with [3H]dopamine ([3H]DA) and whether this
response was mediated by nicotinic receptor stimulation.
(S)-()-Cotinine (1 µM to 3 mM) evoked 3H
overflow from [3H]DA-preloaded rat striatal slices in a
concentration-dependent manner with an EC50 value of 30 µM, indicating a lower potency than either
(S)-()-nicotine or the active nicotine metabolite, (S)-()-nornicotine. As reported for
(S)-()-nicotine and
(S)-()-nornicotine, desensitization to the effect of
(S)-()-cotinine was observed. The classic nicotinic
receptor antagonists mecamylamine and dihydro-
-erythroidine inhibited the response to (S)-()-cotinine (1-100
µM). Additionally, 3H overflow evoked by
(S)-()-cotinine (10-1000 µM) was inhibited by
superfusion with a low calcium buffer. Interestingly, over the same
concentration range, (S)-()-cotinine did not inhibit [3H]DA uptake into striatal synaptosomes. These results
demonstrate that (S)-()-cotinine, a constituent of
tobacco products and the major metabolite of nicotine, stimulates
nicotinic receptors to evoke the release of DA in a calcium-dependent
manner from superfused rat striatal slices. Thus,
(S)-()-cotinine likely contributes to the
neuropharmacological effects of nicotine and tobacco use.
This article has been cited by other articles:
|
|
 |
|
  K. P. Cosgrove, J. Batis, F. Bois, P. K. Maciejewski, I. Esterlis, T. Kloczynski, S. Stiklus, S. Krishnan-Sarin, S. O'Malley, E. Perry, et al. {beta}2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking Arch Gen Psychiatry, June 1, 2009; 66(6): 666 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. O'Leary, N. Parameswaran, J. M. McIntosh, and M. Quik Cotinine Selectively Activates a Subpopulation of {alpha}3/{alpha}6{beta}2 Nicotinic Receptors in Monkey Striatum J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 646 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. C. K. Siu and R. F. Tyndale Characterization and Comparison of Nicotine and Cotinine Metabolism in Vitro and in Vivo in DBA/2 and C57BL/6 Mice Mol. Pharmacol., March 1, 2007; 71(3): 826 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. A. Ghosheh, L. P. Dwoskin, D. K. Miller, and P. A. Crooks Accumulation of Nicotine and Its Metabolites in Rat Brain After Intermittent or Continuous Peripheral Administration of [2'-14C]Nicotine Drug Metab. Dispos., April 13, 2001; 29(5): 645 - 651. [Abstract] [Full Text]
|
|
|
|
|
|
O. Ghosheh, L. P. Dwoskin, W.-K. Li, and P. A. Crooks Residence Times and Half-Lives of Nicotine Metabolites in Rat Brain after Acute Peripheral Administration of [2'-14C]Nicotine Drug Metab. Dispos., December 1, 1999; 27(12): 1448 - 1455. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
