Excitatory amino-acids, a new class of neurotransmitters. Pharmacology and functional properties]

The pharmacology of excitatory amino acids (EAA) like glutamate or aspartate, has defined three main types of receptors: NMDA, quisqualate (now named AMPA) and ka?nate receptors, associated to cationic channels. The NMDA receptor, the best characterized, is a macromolecular complex with multiple specific sites: the agonist binding site (glutamate, aspartate, NMDA); the glycine site and polyamine site mediating allosteric regulations; the site located inside the channel for activity-dependent antagonists (phencyclidine, MK-801). This channel, permeable to calcium, is blocked by magnesium in a voltage-dependent manner. The structural complexity of the NMDA receptor suggests the existence of subtle regulations, but also offers many targets for pharmacological drugs. The calcium influx induced by NMDA receptor stimulation may account for the diversity of its functional properties. First, NMDA receptors modulate neuronal plasticity during the development and even long after. Indeed, NMDA receptor can induce long term potentiation (LTP; an experimental model of synaptic facilitation) and are involved in learning and memory. On the other hand, when over-stimulated, they induce neurotoxicity. The death of the cell occurs after several hours, during which NMDA antagonists can prevent irreversible damages. EAA systems are distributed in the whole brain, interacting with numerous other neurotransmitters, but particularly concentrated in the cortico-striatal and cortico-cortical fibers and in the hippocampus. Several neuro-psychiatric disorders could be related to a glutamatergic dysfunction: acute neuronal lesions (stroke, viral disease like AIDS) and epilepsy; but also chronic neurodegenerative disorders (Alzheimer's dementia, Huntington and Parkinson diseases). A glutamatergic hypothesis of schizophrenia arose from the phencyclidine model of psychosis, arguing for an imbalance between glutamate and dopamine. The therapeutic perspectives of glutamatergic substances in these diseases will be discussed.