Nicotinic receptor partial agonists alter catecholamine homeostasis and response to nicotine in PC12 cells

Repeated stress is a major public health concern where many stress responses are mediated by neuronal nicotinic acetylcholine receptors. In the present study we evaluated the effects of the nicotinic receptor partial agonists, cytisine and its derivative 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) on two main biological outputs associated with activation of nAChR-release of neurotransmitters and increase in catecholamine biosynthesis to replenish the releasable pool. We compared these substances to the maximal response triggered by nicotine (full agonist) in PC12 cells. Cytisine, 3-pyr-Cyt or nicotine induced time-, dose- and Ca(2+)-dependent significant release of norepinephrine (NE) into the culture media. These effects were completely inhibited by mecamylamine but not by α-bungarotoxin, and only partially affected by α-conotoxin AulB, consistent with the involvement of α3β4 receptors. Co-application of cytisine (or 3-pyr-Cyt) and nicotine resulted in attenuated nicotine-induced NE release. Cytisine or 3-pyr-Cyt alone induced a modest rise in tyrosine hydroxylase (TH) mRNA levels (index of the cell's catecholamine biosynthetic capacity). We conclude that both, cytisine and 3-pyr-Cyt (i) display typical partial agonist properties at naturally existing ganglionic nAChR (α3β4 and α7 nAChR) with regard to catecholamine homeostasis (i.e. NE release and re-synthesis) and (ii) modulated the effect of nicotine during combined treatment.