Effects of cotinine at cholinergic nicotinic receptors of the sympathetic superior cervical ganglion of the mouse.
Nicotine, the principal alkaloid in tobacco, is generally accepted to be responsible for most neuropharmacological effects due to tobacco use. Little is known about the action of cotinine, the major metabolite from nicotine, at neuronal structures. To evaluate the mode of action of cotinine at neuronal receptors, its effect on the surface compound potential of the sympathetic superior cervical ganglion (SCG) of the mouse was studied. The modulation of nicotine induced surface potentials by cotinine was tested. It was found that 2-min applications of cotinine (0.1-30 mmol/l) induced concentration dependent depolarizations at the SCG (EC(50)=1.7 mmol/l) which were followed by hyperpolarizations and weak afterdepolarizations. The intrinsic activity of cotinine compares to that induced by much lower concentrations of nicotine (EC(50)=21 micromol/l). These cotinine effects may be mediated at least in part by nicotine impurities which were found by capillary electrophoresis to be 0.1 and 0.8% in different batches of cotinine. Continuous application of 300 micromol/l cotinine shifted the concentration-response curve of nicotine to the right and reduced (IC(50)=302 micromol/l) the effects of submaximal nicotine concentrations (30 micromol/l). This effect could not be mimicked by continuous application of a nicotine concentration (0.3 micromol/l) equivalent to the lower impurity in cotinine. Therefore, the antagonistic action of cotinine at peripheral neuronal nicotinic receptors is at least in part independent of nicotine impurity. The observed antagonistic effect of cotinine at nicotinic receptors likely contributes to the neuropharmacological effects of smoking.
Schroff
K C
KC
Walther Straub-Institute of Pharmacology and Toxicology, Nussbaumstr. 26, 80336, Munich, Germany. schroff@lrz.uni-muenchen.de
Lovich
P
P
Schmitz
O
O
Aschhoff
S
S
Richter
E
E
Remien
J
J
D000818:Animals; D003367:Cotinine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019075:Electrophoresis, Capillary; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D017933:Peripheral Nervous System / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects*; D017783:Superior Cervical Ganglion / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects*
D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D003367:Cotinine