Cholinergic modulation of N-methyl-D-aspartate-evoked [3H]norepinephrine release from rat cortical slices.

Previous work has shown that N-methyl-D-aspartate (NMDA) receptor activation inhibits muscarinic receptor-mediated phosphoinositide hydrolysis in brain slices. To further explore the potential interactions between NMDA receptors and cholinergic receptors, the effects of cholinergic agonists and NMDA on [3H]norepinephrine (NE) release from rat cortical slices were determined. Slices were labeled with [3H]NE, washed and treated with various agonists by transferring the slices through a series of vials at 1-min intervals. Radioactivity remaining in the medium was then quantitated to determine the fractional release of [3H]NE from the slices. Carbachol (30-3000 microM) slightly stimulated [3H]NE release from a basal level of 0.10 to approximately 0.35 fractional release by itself and significantly enhanced the effect of 250 microM NMDA (3.6 fractional release for NMDA and 5.3 for carbachol + NMDA) in a concentration-dependent manner. Carbachol (1 mM) increased the maximal response but had no effect on the EC50 of NMDA. Atropine (1 microM) significantly attenuated the effect of carbachol alone and the potentiation of NMDA-evoked [3H]NE release by carbachol, whereas d-tubocurarine (10 microM) inhibited the effect of carbachol alone but had no effect on the enhancement of the NMDA response by carbachol. Mecamylamine (100 microM) inhibited the effect of carbachol alone, but also inhibited the NMDA-evoked response with an IC50 of 16 microM. The nicotinic agonist, dimethylphenylpiperazinium (DMPP) stimulated [3H]NE release (approximately 0.4 fractional release at 30 microM) and also potentiated NMDA-stimulated [3H]NE release (2.0 above NMDA alone). d-Tubocurarine, but not atropine, partially inhibited DMPP-stimulated [3H]NE release, but neither antagonist altered the enhancement of NMDA-stimulated [3H]NE release by DMPP.(ABSTRACT TRUNCATED AT 250 WORDS)