No abstract

No abstract

No abstract

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...

Several days of exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can-similar to pharmacological GC treatment-reversibly decrease specific elements of memory performance in otherwise healthy individuals.