Vol. 288, Issue 3, 905-911, March 1999

(S)-()-Cotinine, the Major Brain Metabolite of Nicotine, Stimulates Nicotinic Receptors to Evoke [³H]Dopamine Release from Rat Striatal Slices in a Calcium-Dependent Manner¹

Linda P. Dwoskin, Lihong Teng, Susan T. Buxton and Peter A. Crooks

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.