The effects of spermine on the acquisition and retention of spatial le
arning in the Morris water maze were studied. Spermine 25 and 125 nmol
i.c.v, did not alter the ability of rats to End a hidden platform in
the water maze when administered before training over 5 days, However,
the inhibitory effect of the benzodiazepine, diazepam (3 mg/kg i.p.,3
0 min prior to training), on path length to target was markedly potent
iated by the higher dose of spermine, consistent with spermine acting
as a functional antagonist at the NMDA receptor. This drug combination
did not affect performance on visible platform trials. Administration
of doses of 125 and 250 nmol (but not 62.5 nmol) of spermine i.c.v, i
n the week prior to training (daily for 5 days) dose-dependently inhib
ited subsequent learning of a platform position in the absence of drug
. There higher doses of spermine produced neuronal loss and increased
[H-3]PK11195 binding indicating microglial activation predominantly in
the hippocampus and to a lesser extent in the striatum, septum, thala
mus and amygdala. Spermine 125 nmol i.c.v. (daily for 7 days) also abo
lished retention of a previously learned platform position when admini
stered in an interval between training and retention testing. The inhi
bitory effects of spermine 125 nmol i.c.v. (daily for 7 days) on subse
quent spatial learning were not antagonised by concomitant administrat
ion of 30 nmol dizocilpine. These results demonstrate that spermine pr
oduces a delayed neurotoxic effect in particular neuronal populations
in the brain that selectively impair spatial learning and recall. (C)
1995 Elsevier Science B.V. All rights reserved.