To investigate the long-term effects of excitatory amino acid microinj
ections into the basal forebrain and its correlation with a possible C
a2+ imbalance associated with the excitotoxic process, ibotenic acid,
mainly an N-methyl-D-aspartate receptor agonist, and quisqualic acid,
an agonist of non-N-methyl-D-aspartate receptors, were injected into t
wo regions rich in cholinergic neurons, namely the medial septal nucle
us and the ventral globus pallidus. Within the globus pallidus but not
within the medial septal nucleus, 13 days and one year postlesion, ne
rve cell death was associated with the appearance of calcium deposits
within the large putative GABAergic pallidal neurons, being more prono
unced in ibotenic acid than quisqualic acid-lesioned rats. An intermed
iate two month post-lesion study with alpha-amino-3-hydroxy-5-methyl-4
-isoxazole propionic acid (AMPA) and ibotenic acid microinjections in
globus pallidus demonstrated that the AMPA subtype of glutamate recept
or may also be involved in this Ca2+ imbalance, together with the N-me
thyl-D-aspartate and metabotropic subtype receptors. Quisqualic acid l
esions in globus pallidus and medial septum were associated with a sub
stantial disappearance of cholinergic cell bodies and their nerve term
inal networks within the cerebral cortex and hippocampal formation res
pectively, as assessed by choline acetyltransferase and acetylcholine
esterase immunocytochemistry. Ibotenic acid lesions resulted in a lowe
r reduction of cholinergic markers. One year after septal lesions indu
ced either by ibotenic or quisqualic acid, a marked atrophy of the ent
ire dorsolateral septal nucleus was observed. Our results support the
hypothesis that brief and intense glutamate exposure can induce long-t
erm neurodegenerative processes and give evidence that long-term excit
otoxic lesions of the two areas studied result in marked differences i
n neuronal damage, including intracellular calcium deposits which do n
ot correlate with the cholinergic deficits produced by multiple glutam
ate receptor subtypes.