N-methyl-D-aspartate antagonists as drug models of schizophrenia: a surprising link to tobacco smoking.

The pros and cons of N-methyl-D-aspartate (NMDA) antagonists as drug models of schizophrenia are discussed in relation to the neuropathology of this complex mental spectrum of diseases. The role of acetylcholine, dopamine, gamma aminobutyric acid, glutamic acid, and serotonin emphasizes that multiple neurotransmitter system abnormalities are involved, even though current drug therapy involves primarily dopamine (D(2))/serotonin (5 HT(2)) antagonists. Only some of the fundamental aspects of schizophrenia are replicated by NMDA receptor antagonists of glutamic acid. Subchronic NMDA antagonism in an animal model results in decreased levels of dopamine in prefrontal cortex and increased D(1) receptor binding. The results of PET studies of schizophrenic patients imply decreased dopamine levels in their prefrontal cortex. Tobacco-smoking schizophrenic patients transiently normalize prepulse inhibition. Nicotine appears to be one factor that may help explain some of these phenomena.