Sn. Dijk et al., NMDA-INDUCED GLUTAMATE AND ASPARTATE RELEASE FROM RAT CORTICAL PYRAMIDAL NEURONS - EVIDENCE FOR MODULATION BY A 5-HT1A ANTAGONIST, British Journal of Pharmacology, 115(7), 1995, pp. 1169-1174
1 We have investigated an aspect of the regulation of cortical pyramid
al neurone activity. Microdialysis was used to assess whether topical
application of drugs (in 10 mu l) to fill a burr hole over the frontal
cortex, where part of the corticostriatal pathway originates, would c
hange concentrations of the excitatory amino acids glutamate and aspar
tate in the striatum of the anaesthetized rat. 2 Topical application o
f N-methyl-D-aspartate (NMDA, 2 and 20 mM) dose-dependently increased
glutamate and aspartate concentrations in the striatum. Coapplication
of tetrodotoxin (10 mu M) blocked the NMDA-evoked rise in these amino
acids. A calcium-free medium, perfused through the probe also blocked
the rise, indicating that it was due to an exocytotic mechanism in the
striatum. 3 It was hypothesized that the rise observed was due to an
increase in the activity of the corticostriatal pathway. As 5-hydroxyt
ryptamine(1A) (5-HT1A) receptors are enriched on cell bodies of cortic
ostriatal neurones, a selective 5-HT1A-antagonist (WAY 100135) was coa
pplied with the lower dose of NMDA. Compared to NMDA alone, coapplicat
ion of 50 mu M WAY 100135 significantly increased glutamate release. T
his effect was sensitive to tetrodotoxin and calcium-dependent. Applic
ation of 50 mu M WAY 100135 alone significantly enhanced glutamate rel
ease above baseline; this was also tested at 100 mu M (not significant
). 4 Compared to NMDA alone, coapplication of WAY 100135 (20 mu M) sig
nificantly enhanced aspartate release; the mean value was also increas
ed (not significantly) with 50 mu M. This rise was calcium-dependent,
but not tetrodotoxin-sensitive. WAY 100135 (100 mu M) reduced NMDA-ind
uced aspartate release. Application of the drug alone had no effect on
basal aspartate release. 5 Coapplication of the 5-HT1A agonist, 8-OHD
PAT (5 mM) with NMDA did not affect the NMDA-evoked increase in glutam
ate and aspartate. 6 Topical application of high potassium (100 mM) to
the surface of the cortex did not result in a detectable rise in stri
atal glutamate or aspartate. 7 Perfusion of WAY 100135 (tested at 50 m
u M) through the dialysis probe did not affect glutamate or aspartate
concentrations. 8 It was concluded that a selective 5-HT1A-antagonist
can increase the activity of corticostriatal pyramidal neurones. As in
Alzheimer's disease hypoactivity of pyramidal neurones almost certain
ly exists, a selective 5-HT1A-antagonist may be potentially useful in
the treatment of the cognitive symptoms of this disease.