CHOLINOMIMETICS INCREASE GLUTAMATE OUTFLOW VIA AN ACTION ON THE CORTICOSTRIATAL PATHWAY - IMPLICATIONS FOR ALZHEIMERS-DISEASE

Physostigmine, the acetylcholinesterase inhibitor (0.3 mg/kg, i.m.), i ncreased extracellular glutamate but not aspartate concentrations in t he striatum of anaesthetised rats, determined using microdialysis and HPLC. The rise was both tetrodotoxin and calcium dependent. In contras t, neither physostigmine(10 mu M) added to the perfusion fluid nor veh icle (injected intramuscularly) affected amino acid concentrations. To obtain evidence that the action of acetylcholine was to modulate posi tively cortical pyramidal neurone activity via the M(1) receptor, the selective M(1) agonist PD 142505-0028 (10 mu M) was topically applied to the frontal cortex. Like physostigmine, PD 142505-0028 rapidly incr eased glutamate but not aspartate concentrations in the striatum. More over, the effect of intramuscular physostigmine was blocked by a topic ally applied M(1) antagonist. These new data add to our hypothesis tha t cholinomimetics increase pyramidal neurone function.