NMDA Agonists and Antagonists as Probes of Glutamatergic Dysfunction and Pharmacotherapies in Neuropsychiatric Disorders

Abstract

Antagonists of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors and agonists of the glycine-B coagonist site of these receptors have been important tools for characterizing the contributions of NMDA receptor pathophysiology to a large number of neuropsychiatric conditions and for treating these conditions. Among these disorders are Alzheimer's disease, chronic pain syndromes, epilepsy, schizophrenia, Parkinson's disease, Huntington's disease, addiction disorders, major depression, and anxiety disorders. This review will examine pathophysiological and therapeutic hypotheses generated or supported by clinical studies employing NMDA antagonists and glycine-B agonists and partial agonists. It will also consider ethical issues related to human psychopharmacological studies employing glutamatergic probes.

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

“…One hour after LY354740 administration, a standard breakfast was served to research subjects. This study evaluated the interactive effects of LY354740 and ketamine using cognitive and clinical assessments that have been used previously to evaluate the contribution of NMDA glutamate receptors to executive cognitive functions, memory, and psychosis (Krystal et al 1994(Krystal et al , 1998b(Krystal et al , 1999b, including a study that evaluated the interactive effects of ketamine and another glutamate releaseinhibiting drug, lamotrigine (Anand et al 2000). The positive and negative symptom scale (PANSS) (Kay et al 1989) was administered at 120, 245, 345, 500, and 530 min following LY354740 administration (the latter two ratings were safety measures used only to document the return to baseline before discharge on each test day; since this occurred in all cases, these data are not formally reported here).…”

The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats

“…The main evidence for such a deficit in glutamatergic function is that the NMDA-R antagonists, PCP, MK-801, and ketamine induce cognitive impairment in healthy subjects (Javitt and Zukin 1991;Krystal et al 1999;Lahti et al 2001;Newcomer et al 1999) and increase psychosis in patients with schizophrenia (Lahti et al 1995;. Acute or subchronic administration of PCP and MK-801 has been reported to produce impairments in visual and learning memory, attention, reasoning and problem solving, working memory, and social cognition in rodents (see Neill et al 2010 for review).…”

Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine

“…Data from 295 healthy subjects who participated in a total of 974 test days from 11 separate studies were reviewed. While this study was undertaken to explore a putative pathophysiological process, it also was intended to evaluate both the safety of repeated exposure to ketamine in healthy individuals carefully screened for psychiatric illness (White et al 1982;Reich and Silvay 1989;Haas and Harper 1992) and its potential as a tool for human psychopharmacological research (Krystal et al 1999d). …”