NMDA-INDUCED GLUTAMATE AND ASPARTATE RELEASE FROM RAT CORTICAL PYRAMIDAL NEURONS - EVIDENCE FOR MODULATION BY A 5-HT1A ANTAGONIST

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.