N-METHYL-D-ASPARTATE (NMDA)-STIMULATED NORADRENALINE (NA) RELEASE IN RAT-BRAIN CORTEX IS MODULATED BY PRESYNAPTIC H-3 RECEPTORS

In superfused rat brain cortex slices and synaptosomes preincubated with [H-3]noradrenaline the effect of agonists or antagonists at presynaptic H-3 receptors on NMDA-evoked [H-3]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H-3 receptor agonist R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mu mol/l or 0.032 mu mol/l, respectively); S-(+)-alpha-methylhistamine (up to 10 mu mol/l) as well as the selective H-1, receptor agonist (2-(2-thiazolyl)ethylamine and the selective H-2 receptor agonist dimaprit (each up to 10 mu mol/l) were ineffective. The H-3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H-1 receptor antagonist dimetindene and the preferential H-2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of omega-conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(-)-alpha-methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H-3 receptors. NMDA receptors and H-3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H-3 receptor stimulation.