Differential regulation by N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors of acetylcholine release from the rat striatum in vivo.

The modulation of striatal cholinergic neurons by glutamatergic inputs was studied by monitoring the output of acetylcholine collected via a transversal microdialysis probe implanted into the striatum of freely moving rats. A transversal microdialysis membrane was inserted in the striatum and acetylcholine or GABA levels in the dialysate were measured. Acetylcholine levels in the dialysate were quantified by a high-performance liquid chromatography method with an electrochemical detector, while GABA levels were measured by a high-performance liquid chromatography method with a fluorescence detector. The dialysis membrane was perfused with Ringer solution containing 7 μM physostigmine sulphate and drugs, dissolved in the perfusion solution, were administered locally via the dialysis membrane. Local administration of the N-methyl-d-aspartate antagonist 3-[(RS)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (25–100 μM) brought about a decrease in striatal acetylcholine output which was dose-dependent, reversible and partially antagonized by 100 μM N-methyl-d-aspartate. On the other hand local administration of the non-N-methyl-d-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoil-benzo(F)quinoxaline was followed by an increase in acetylcholine output which reached a maximum of about +55% at 12.8 μM 2,3-dihydroxy-6-nitro-7-sulfamoil-benzo(F)quinoxaline and was readily reversed when the drug was withdrawn from the perfusion solution. Local administration of the non-N-methyl-d-aspartate receptor agonist (S)-alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (50 and 200 μM) decreased acetylcholine output and this effect was reversed by simultaneous perfusion with the GABA antagonist bicuculline (50 μM). In one set of experiments the effect of the non-N-methyl-d-aspartate antagonist quisqualate was investigated both on acetylcholine and GABA output from the striatum of the same animal. Quisqualate perfused through the striatum resulted in a decrease in acetylcholine output and a concomitant increase in GABA output. These results demonstrate that the activity of the striatal cholinergic neurons receive a differential modulation by glutamatergic inputs, depending on the type of receptor involved. N-methyl-d-aspartate receptors tonically activate cholinergic neurons and increase acetylcholine output while non-N-methyl-d-aspartate receptors indirectly, via a GABAergic link, decrease acetylcholine output.