THE N-METHYL-D-ASPARTATE ANTAGONISTS PHENCYCLIDINE, KETAMINE AND DIZOCILPINE AS BOTH BEHAVIORAL AND ANATOMICAL MODELS OF THE DEMENTIAS

Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The mod el psychoses these drugs induce mimic a variety of schizophrenic sympt oms, including flattened affect, dissociative thought disorder, depers onalization and catatonic states. These symptoms can persist for prolo nged periods and chronic PCP and ketamine addicts have persisting memo ry deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketami ne in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion-channel. Behavioral observations and drug-discrimination studies in animals in dicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex . Recent studies have indicated that both of these drugs, when given c ontinuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related t o olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, throug h the perforant pathway, to dentate gyrus and other cells in ventral h ippocampus. These degenerative consequences may be excitatory neurotox ic effects, for these compounds also induce an elevation in glucose me tabolism maximal in just those structures where degeneration is observ ed and the degeneration involves entire cells, with all of their proce sses. It has been suggested these non-competitive NMDA antagonists ind uce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce t he same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by s ome schizophrenics and most Alzheimer's patients. This suggests that t hese non-competitive NMDA antagonists may provide a more complete mode l of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect r emain elusive, it appears to be both age and sex dependant. Further st udies of the mechanisms by which NMDA antagonists induce increased glu cose utilization and neurotoxicity in these limbic structures may clar ify these alterations in this simplified Papez-like circuit.