(S)-(-)-cotinine, the major brain metabolite of nicotine, stimulates nicotinic receptors to evoke [H-3]dopamine release from rat striatal slices in acalcium-dependent manner

Cotinine, a major peripheral metabolite of nicotine, has recently been show n to be the most abundant metabolite in rat brain after peripheral nicotine administration. However, little attention has been focused on the contribu tion of cotinine to the pharmacological effects of nicotine exposure in eit her animals or humans. The present study determined the concentration-respo nse relationship for (S)-(-)-cotinine-evoked H-3 overflow from superfused r at striatal slices preloaded with [3H]dopamine ([H-3]DA) and whether this r esponse was mediated by nicotinic receptor stimulation. (S)-(-)-Cotinine (1 mu M to 3 mM) evoked H-3 overflow from [H-3]DA-preloaded rat striatal slic es in a concentration-dependent manner with an EC50 value of 30 mu M, indic ating a lower potency than either (S)-(-)-nicotine or the active nicotine m etabolite, (S)-(-)-nornicotine. As reported for (S)-(-)-nicotine and (S)-(- )-nornicotine, desensitization to the effect of (S)-(-)-cotinine was observ ed. The classic nicotinic receptor antagonists mecamylamine and dihydro-bet a-erythroidine inhibited the response to (S)-(-)-cotinine (1-100 mu M). Add itionally. H-3 overflow evoked by (S)-(-)-cotinine (10-1000 mu M) was inhib ited by superfusion with a low calcium buffer. Interestingly, over the same concentration range, (S)-(-) -cotinine did not inhibit [H-3]DA uptake into striatal synaptosomes. These results demonstrate that (S)-(-)-cotinine, a constituent of tobacco products and the major metabolite of nicotine, stimu lates 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 .