In this article, we advance a unified hypothesis pertaining to combined dysfunction of dopamine and N-methyl-D-aspartate glutamate receptors that highlights N-methyl-D-aspartate receptor hypofunction as a key mechanism that can help explain major clinical and pathophysiological aspects of schizophrenia. The following fundamental features of schizophrenia are accommodated by this hypothesis: (1) the occurrence of structural brain changes during early development that have the potential for producing subsequent clinical manifestations of schizophrenia, (2) a quiescent period in infancy and adolescence before clinical manifestations are expressed, (3) onset in early adulthood of psychotic symptoms, (4) involvement of dopamine (D2) receptors in some cases but not others that would explain why some but not all patients are responsive to typical neuroleptic therapy, and (5) ongoing neurodegenerative changes and cognitive deterioration in some patients. We propose that since N-methyl-D-aspartate receptor hypofunction can cause psychosis in humans and corticolimbic neurodegenerative changes in the rat brain, and since these changes are prevented by certain antipsychotic drugs, including atypical neuroleptic agents (clozapine, olanzapine, fluperlapine), a better understanding of the N-methyl-D-aspartate receptor hypofunction mechanism and ways of preventing its neurodegenerative consequences in the rat brain may lead to improved pharmacotherapy in schizophrenia.

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Background Brief isoflurane anesthesia induces neuroapoptosis in the developing rodent brain, but susceptibility of nonhuman primates to the apoptogenic action of isoflurane has not been studied. Therefore, we exposed postnatal day 6 (P6) rhesus macaques to a surgical plane of isoflurane anesthesia for 5 h, and studied the brains 3 h later for histopathological changes. Method With the same intensity of physiological monitoring typical for human neonatal anesthesia, five P6 rhesus macaques were exposed for 5 h to isoflurane maintained between 0.7 and 1.5 end tidal Vol% (endotracheally intubated, mechanically ventilated), and five controls were exposed for 5 h to room air without further intervention. Three hours later, the brains were harvested and serially sectioned across the entire forebrain and midbrain, and stained immunohistochemically with antibodies to activated caspase-3 for detection and quantification of apoptotic neurons. Results Quantitative evaluation of brain sections revealed a median of 32.5 (range, 18.0 to 48.2) apoptotic cells per mm3 of brain tissue in the isoflurane group and only 2.5 (range, 1.9 to 3.8) in the control group (difference significant at p = 0.008). Apoptotic neuronal profiles were largely confined to the cerebral cortex. In the control brains, they were sparse and randomly distributed, whereas in the isoflurane brains they were abundant and preferentially concentrated in specific cortical layers and regions. Conclusion The developing nonhuman primate brain is sensitive to the apoptogenic action of isoflurane, and displays a 13-fold increase in neuroapoptosis after 5 h exposure to a surgical plane of isoflurane anesthesia.

Considerable research interest has recently been focused on the role of glutamate and related neural circuitry in the neurobiology of schizophrenia. The results of these investigations have emphasized hypofunction of glutamatergic neurons and/or the N-methyl-D-aspartate (NMDA) glutamate receptor (Tsai et al. 1995;Kim et al. 1980aKim et al. , 1980bSherman et al. 1991;Deutsch et al. 1989;Javitt and Zukin 1991;Olney 1988a;Olney 1988b;Olney and Farber 1995). An important element of several of these theoretical positions is that NMDA receptor hypofunction (NRH) produced by any mechanism can be psychotogenic. This has renewed interest in the clinical effects of NMDA glutamate receptor antagonists.Ketamine and phencyclidine (PCP) are non-competitive NMDA glutamate receptor antagonists (Zukin and Zukin 1979;Vincent et al. 1979;Lodge and Anis 1982;Lodge et al. 1987) which can produce a transient state of NRH in the brain. Early investigators characterized a PCP-induced clinical syndrome of schizophrenia-like Received March 18, 1998; revised June 19, 1998; accepted June 29, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 20 , NO . 2 NMDA Receptor Hypofunction Induced Memory Decrease 107 symptoms, including hallucinations, delusions, idiosyncratic and illogical thinking, poverty of speech and thought, agitation, disturbances of emotion, affect, withdrawal, decreased motivation, and dissociation (Johnstone et al. 1959;Luby et al. 1959;Rosenbaum et al. 1959;Luby et al. 1962;Corssen and Domino 1966;Bakker and Amini 1961;Davies and Beech 1960;Domino and Luby 1981). This PCP-induced syndrome can be indistinguishable from acute presentations of schizophrenia (Yesavage and Freeman 1978;Erard et al. 1980). Ketamine, a PCP analog still used in human anesthesia, has been reported to cause reactions similar to but not as severe as those caused by PCP, including brief, reversible "positive" and "negative" schizophrenia-like symptoms (Krystal et al. 1994;Malhotra et al. 1996). Both PCP and ketamine can exacerbate psychosis in schizophrenia Luby et al. 1962;Lahti et al. 1995a;Lahti et al. 1995b;Malhotra et al. 1997).Declarative, explicit or secondary memory and learning deficits in patients with schizophrenia occur early in the course of the illness and are quantitatively large compared with deficits in other differentiated elements of cognitive performance, showing stability "on" versus "off" antipsychotic medication and over repeated testing (Gruzelier et al. 1988;Saykin et al. 1991Saykin et al. , 1994Cannon et al. 1994). Clinical and preclinical investigations suggest the hypothesis that changes in NMDA glutamate receptor activity in patients with schizophrenia may be causally related to memory impairments found in this disorder. Relevant to this hypothesis, the activation of post-synaptic NMDA receptors is important for the induction of the activity-dependent synaptic modification called long-term potentiation (LTP) (Bliss and Collingridge 1993;Collingridge and Bliss 1995), and hippocampal LTP has been postulated to underlie cert...

Background Exposure of rhesus macaque fetuses for 24 h, or neonates for 9 h, to ketamine anesthesia causes neuroapoptosis in the developing brain. The present study further clarifies the minimum exposure required for, and the extent and spatial distribution of, ketamine-induced neuroapoptosis in rhesus fetuses and neonates. Method Ketamine was administered by intravenous infusion for 5 h to postnatal day 6 rhesus neonates, or to pregnant rhesus females at 120 days gestation (full term = 165 days). Three hours later, fetuses were delivered by caesarian section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining. Results Both the fetal (n = 3) and neonatal (n = 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared to drug-naive controls (fetal n = 4; neonatal n = 5). Loss of neurons due to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age. Conclusion The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration of 5 h is sufficient to induce a significant neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.