PSYCHOTOGENICITY AND N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISM - IMPLICATIONS FOR NEUROPROTECTIVE PHARMACOTHERAPY

The development of neuroprotective agents for the prevention of neuron al loss in acute conditions such as stroke and epilepsy or chronic neu rodegenerative disorders including Parkinson's disease, Alzheimer's di sease, Huntington's chorea, and motor neuron disease is currently focu sing on drugs that inhibit excitatory amino acid neurotransmission or exhibit antioxidant properties. Unfortunately, potent antagonists at t he N-methyl-D-aspartate (NMDA) type glutamate receptor, which is thoug ht to mediate excitotoxic neuronal injury, e.g., MK-801 or phencyclidi ne (PCP) share a high probability of inducing psychotomimetic side eff ects. Further, these drugs have been associated with acute neurotoxici ty in vitro and in vivo, precluding their clinical use. In contrast, l ow affinity NMDA receptor antagonists like amantadine and its dimethyl derivative, memantine, have been administered clinically for the mana gement of Parkinson's disease, dementia, neuroleptic drug-induced side effects, and spasticity. These agents have only rarely induced signif icant psychotomimetic side effects. Recent pharmacologic advances have helped to elucidate how high drug affinity for the PCP binding site o f the NMDA receptor may enhance psychotogenicity. Low affinity and ass ociated fast voltage-dependent channel unblocking kinetics are likely to be responsible for the better tolerance of amantadine and memantine compared with MK-801 and PCP. Further factors apparently modulating p sychotogenicity of glutamate receptor antagonists include differential actions on neuronal populations in various brain regions and interact ions with neurotransmitter receptors other than the NMDA type glutamat e receptor. (C) 1997 Society of Biological Psychiatry