THE PHARMACOLOGY OF THE NICOTINIC ANTAGONIST, CHLORISONDAMINE, INVESTIGATED IN RAT-BRAIN AND AUTONOMIC GANGLION

1 A single administration of the ganglion blocker, chlorisondamine (10 mg kg(-1), s.c.) is known to produce a quasi-irreversible blockade of the central actions of nicotine in the rat. The mechanism of this per sistent action is not known. It is also unclear whether chlorisondamin e can block neuronal responses to excitatory amino acids and whether c hronic blockade of nicotinic responses also occurs in the periphery. 2 Acute administration of chlorisondamine (10 mg kg(-1), s.c.) to rats resulted in a blockade of central nicotinic effects (ataxia and prostr ation) when tested 1 to 14 days later, but caused no detectable cell d eath in tissue sections sampled throughout the rostrocaudal extent of the brain which were stained in order to reveal neuronal degeneration. 3 Long-term blockade of central nicotinic effects by chlorisondamine was not associated with significant alterations in the density (B-max) of high-affinity [H-3]-nicotine binding to forebrain cryostat-cut sec tions. 4 In cultured dissociated mesencephalic cells of the foetal rat , chlorisondamine and mecamylamine inhibited [H-3]-dopamine release ev oked by N-methyl-D-aspartate (NMDA, 10(-4) M), but only at high concen trations (IC50 approx. 600 and 70 mu M, respectively). A high concentr ation of chlorisondamine (10(-3) M) had no effect on responses to quis qualate (10(-5) M) and only slightly reduced responses to kainate (10( -4) M). Mecamylamine (10(-3) M) was ineffective against both agonists. 5 In adult rat hippocampal slices, chlorisondamine depressed NMDA rec eptor-mediated synaptically-evoked field potentials, but again only at high concentrations (10(-4)-10(-3) M). Synaptic responses that were m ediated by non-NMDA excitatory amino acid receptors were less affected . 6 In rat isolated superior cervical ganglion, electrically-evoked sy naptic transmission was reduced Ih after acute in vivo administration of chlorisondamine (0.1 mg kg(-1), s.c.). However, in vivo administrat ion of a higher dose (10 mg kg(-1) s.c.) did not significantly affect ganglionic transmission when tested two weeks later, despite the conti nued presence of central nicotinic blockade. 7 These results indicate that the persistent CNS nicotinic blockade by chlorisondamine is not a ccompanied by changes in nicotinic [H-3]-nicotine binding site density or by neuronal degeneration in the brain; that at doses sufficient to produce nicotinic receptor blockade, chlorisondamine acts in a pharma cologically selective manner; and that chronic central blockade is not accompanied by long-term peripheral ganglionic blockade.