Pbs. Clarke et al., THE PHARMACOLOGY OF THE NICOTINIC ANTAGONIST, CHLORISONDAMINE, INVESTIGATED IN RAT-BRAIN AND AUTONOMIC GANGLION, British Journal of Pharmacology, 111(2), 1994, pp. 397-405
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.