Ketamine-Induced NMDA Receptor Hypofunction as a Model of Memory Impairment and Psychosis

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...

Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers

“…The main findings were that ketamine impaired working and episodic memory with increasing dose, disrupted procedural, and semantic memory regardless of dose while leaving perceptual priming intact. Ketamine also induced schizophrenic and dissociative symptoms, replicating previous studies (Krystal et al, 1994;Malhotra et al, 1996;Newcomer et al, 1999;Adler et al, 1998;Hetem et al, 2000).…”

“…The doses of ketamine used in this experiment are somewhat lower and involved a different infusion style (continuous rather than a bolus then maintenance infusion) than some used in previous studies (eg Krystal et al, 1994;Malhotra et al, 1996;Newcomer et al, 1999). Hence comparisons across these studies are limited.…”

“…Secondly, the continuous infusion style used meant that ketamine levels may have been rising throughout the study, which could result in impairments on certain tasks being an effect of increasing dose rather than ketamine specificity for certain memory systems. Studies using steady-state or pseudosteady-state infusion styles have negated this problem (Hetem et al, 2000;Newcomer et al, 1999). A consequence of rising blood ketamine levels may also have been that sedation was increasing, which would have compounded the effects of ketamine on these tasks.…”

“…Hence deficits in verbal fluency may well reflect semantic memory deficits. Conflicting results have been obtained from ketamine studies with fluency tasks of both impaired (Adler et al, 1998) and preserved (Ghoneim et al, 1985) category fluency, and similar findings of an impairment to verbal fluency in some (Adler et al, 1998;Krystal et al, 1994Krystal et al, , 1998, but not all (Krystal et al, 1999;Newcomer et al, 1999) studies. Findings concerning ketamine's effects on working memory are also conflicting.…”

“…Findings concerning ketamine's effects on working memory are also conflicting. Impairments have been found on the N-back task (Adler et al, 1998), but not on a spatial working memory task (Newcomer et al, 1999). In addition, two studies have found preserved backwards digit span (Ghoneim et al, 1985;Harris et al, 1975), but one study has found impaired forwards digit span (Harris et al, 1975).…”