Inhibition of Nicotinic Responses by Cotinine in Bovine Adrenal Chromaffin Cells

We studied the effects of cotinine, the major metabolite of nicotine, on nicotine-induced increase in [ 3 H]phorbol dibutyrate binding, activation of protein kinase C and [ 3 H]noradrenaline release in primary cultured bovine adrenal chromaffin cells. Cotinine (I mM. 15 min.) and nicotine (10 μM, 5 min.) increased the [ 3 H]phorbol binding by 100% and 150%, respectively. Both a short-term (10 min.) and a long-term (24 hr) pretreatment with cotinine inhibited the effect of nicotine. A 24 hr pretreatment with cotinine (I mM) also reduced the nicotine-induced increase in membrane-bound protein kinase C activity. Cotinine pretreatment (10 min.) dose-dependently inhibited the release of [ 3 H]noradrenaline induced by nicotine and dimethylphenylpiperazinium. Cotinine pretreatment did not reduce the [ 3 H]noradrenaline release induced by high extracellular potassium (56 mM) or veratrine (10 mg l -1 ), The results indicate that cotinine inhibits activation of protein kinase C and noradrenaline release induced by nicotinic agonists in primary cultures of bovine adrenal chromaffin cells. The results suggest that pre-existing cotinine could modify responses to acute exposure to nicotine in neural systems.