Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists

Abstract

Antagonists of the N-methyl-D-aspartate ( Lamotrigine; Serotonin; 5-HT2A; LY354740; M100907; MDL 100,907 The field of schizophrenia research is rapidly moving from a focus on the contributions of single neurotransmitters or brain regions toward an appreciation of the interactions of multiple neurotransmitter systems, neural networks, and intracellular mechanisms (Aghajanian and Marek 1999;Carlsson et al. 1997;Krystal et al. 1999b). Investigators are abandoning oversimplified dopaminergic models suggesting that all activation is detrimental to symptoms in schizophrenic patients. Instead, optimal levels of stimulation of particular dopamine-receptor subtypes are needed to sustain behavior and higher cognitive functions (Arnsten 1997;Goldman-Rakic and Selemon 1997 shortcomings of both typical and atypical neuroleptics (Meltzer 1997). As a result, it is now timely to consider the possibility that the next era in medications development for treating schizophrenia will involve mechanisms other than dopamine-2 (D 2 )-receptor antagonism. This review highlights a novel perspective on the neurobiology and treatment of schizophrenia growing from the study of the effects of the N-methyl-D-aspartate (NMDA) glutamate-receptor antagonists in animals and humans. It considers parallels between the transient symptomatic effects of single doses of NMDA antagonists in healthy human subjects and findings in schizophrenic patients. It then highlights similarities between disturbances in information processing produced by NMDA antagonists and deficits observed in schizophrenic patients. Next, this review attempts to provide some insights into mechanisms that link NMDA-receptor antagonism to glutamatergic activation and information-processing deficits. This review then summarizes evidence that dopaminergic systems have limited contributions to positive and negative symptoms produced by NMDA antagonists. Finally, it considers the utility of facilitation of the glycine-B site of the NMDA-receptor complex and drugs that attenuate glutamate release as pharmacotherapies for schizophrenia based on their capacity to attenuate the effects of NMDA antagonists in animals and humans. Because glutamate has both neurotrophic and neurotoxic effects in the brain, potential implications of glutamatergic pharmacotherapies for the course of schizophrenia is considered. PARALLELS BETWEEN NMDA-ANTAGONIST EFFECTS IN HEALTHY SUBJECTS AND SCHIZOPHRENIC PATIENTSLuby and his colleagues coined the term "schizophrenomimetic" to describe the striking similarities between the effects of phencyclidine (PCP), and the symptoms of schizophrenia (Luby et al. 1959). The identification of NMDA-receptor antagonism as the mechanism of action of PCP, the implication of NMDA receptors in many fundamental aspects of neural plasticity and neurotoxicity, and reports of altered glutamate-receptor binding in postmortem tissue from schizophrenic patients rekindled interest in the effects of PCP (Anis et al. 1983;Krystal et al. 1999b;Madison et al. 1991;Rothman and Olney 198...

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

“…An additional possible explanation for the current findings is that nimodipine attenuated the hyperglutamatergic effects of ketamine without normalizing NMDA receptor function (Krystal et al 1999a). Ketamine appears to disinhibit cortical glutamatergic activity (Grunze et al 1996;Moghaddam et al 1997).…”

“…In addition, these drugs produce effects in healthy human subjects that resemble aspects of the signs and symptoms of schizophrenia or dissociative disorders (Krystal et al 1999a). As a result, ketamine administration may provide a laboratory-based approach that may contribute to the characterization of NMDA receptor contributions to cognitive function and the development of novel pharmacotherapeutic approaches that might ameliorate the consequences of NMDA receptor dysfunction.…”

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

“…As NMDA antagonism enhances both glutamate and dopamine release in components of corticostriato-thalamic circuitry (Moghaddam et al, 1997), it is feasible that this enhancement is responsible for the impairment in procedural learning observed in the current study. Previous research has found that administration of a dopamine antagonist can reverse ketamine-induced impairments on the WCST, which has a procedural learning component (Krystal et al, 1999). However, animal studies have found that working memory deficits following NMDA antagonists are more transient than increases in the prefrontal cortex and nucleus accumbens dopamine levels (Adams and Moghaddam, 1998).…”

“…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.…”

“…It has been proposed that NMDA-receptor-mediated LTP is involved in both working and long-term memory in humans (Lisman et al, 1998). Indeed ketamine, when administered to healthy volunteers, induces deficits in performance on verbal and visual memory tasks (Adler et al, 1998;Harborne et al, 1996;Harris et al, 1975;Hetem et al, 2000;Krystal et al, 1994Krystal et al, , 1999Krystal et al, , 2000Malhotra et al, 1996).…”