The dopamine hypothesis of schizophrenia, which remains the most prominent theory in the field, can be seen as originating from the fortuitous discovery of the antipsychotic effects of chlorpromazine in the mid-1950s. So too, glutamatergic theories can be dated to a precise observation, in this case the synthesis in the late 1950s of the dissociative anesthestics phencyclidine (PCP) and ketamine (Chen and Weston, 1960
), followed shortly thereafter by the demonstration of their psychotogenic potential in humans (Luby et al, 1962
), the discovery of the PCP receptor (Zukin and Zukin, 1979
), and finally the discovery that these compounds function by blocking the N
-methyl--aspartate receptor (NMDAR) channel (Javitt and Zukin, 1991
). PCP and ketamine induced negative symptoms and cognitive dysfunction similar to that of schizophrenia, suggesting that this model may be particularly relevant to persistent, poor-outcome forms of schizophrenia.
Historically, attempts have been made to attribute PCP- and ketamine-induced psychosis to a wide variety of targets including dopaminergic, monoaminergic, cholinergic, GABAergic, opiatergic, sigma (Javitt and Zukin, 1991
), and, most recently, to high D2 receptors (Seeman, 2010
). However, the behavioral effects of NMDAR antagonists that are relevant to schizophrenia persist in the absence of dopamine activity (Carlsson and Carlsson, 1989
; Adams and Moghaddam, 1998
) or dopamine antagonists (Krystal et al, 1995
). Furthermore, both the absolute concentrations and the rank-order potency with which a range of compounds induce psychotomimetic effects in humans and animal models conforms to their rank order of potency at NMDAR but not other receptor types (Javitt and Zukin, 1991
; Seeman, 2010
To date, all compounds that bind to the PCP site of the NMDAR have been found to induce psychosis when given to humans, whereas the same is not true for proposed alternative non-NMDAR-related targets, so that NMDAR blockade by these agents appears both necessary and sufficient to explain their psychotomimetic effects. Moreover, the effects do not appear to be unique to agents that inhibit NMDAR via the PCP site. Thus, antagonists at both the glutamate binding site (eg CGS-19755) and the glycine modulatory site (eg, CP-101,606) also induce psychotomimetic effects when administered clinically (Muir et al, 1995
; Preskorn et al, 2008
). Finally, it has been observed recently that psychosis related to systemic lupus erythematous and other autoimmune disorders may be due to the production of CNS-penetrant anti-NMDAR antibodies (Omdal et al, 2005
), providing unexpected support to NMDAR models of endogenous psychosis.
The NMDAR model may be considered revolutionary, not only because it proposes a different set of targets than would be predicted by more traditional monoaminergic models, but because it proposes a fundamental reconceptualization of what brain regions to target and what assays may be most effective for continued drug development. In particular, dopamine projections in the brain are relatively discrete. In dopaminergic models, therefore, symptoms are seen as arising from dysfunction within a limited number of brain regions, such as dorsolateral prefrontal cortex (Lesh et al, 2011
) or striatum (Simpson et al, 2010
), with secondary top-down dysregulation elsewhere in the brain.
In contrast to the limited range of dopamine neurotransmission, all cortical efferents and the majority of cortical afferents, and cortico-cortical connections are glutamatergic. In glutamatergic models, therefore, deficits are seen as distributed throughout cortical and subcortical regions, within involvement of sensory as well as higher cortical brain regions (Javitt, 2009b
). For example, mismatch negativity (MMN), an event-related potential that indexes brain function at the level of auditory cortex, has been shown repeatedly to be abnormal in schizophrenia (Javitt et al, 1993
; Naatanen and Kahkonen, 2009
). Deficits similar to those observed in schizophrenia are induced by ketamine administration in normal volunteers (Krystal et al, 1994
; Umbricht et al, 2000
; Heekeren et al, 2008
) and by local administration of NMDAR antagonists into auditory cortex of awake, behaving primates (Javitt et al, 1996
). Most recently, similar effects have been reported in rodents (Ehrlichman et al, 2008
; Tikhonravov et al, 2008
), suggesting that measures such as MMN may be used as translational biomarkers for future drug development research.
Nevertheless, the observation that symptoms, cognitive deficits, and neurophysiological indices of schizophrenia can be reproduced by blocking NMDAR receptors does not, in itself, explain either how such deficits arise or how they best can be treated. In the simplest versions of the NMDAR models, the primary goal of treatment would be the restoration of function at the NMDAR itself. However, in many, if not most, medical conditions, the target of treatment may not be the site of dysfunction. Thus, a goal of ongoing research has been to delineate, not only potential causes of NMDAR dysfunction, but also the steps leading from NMDAR dysfunction to psychosis and cognitive impairment. This research has led to an evolution in the conceptualization of glutamatergic dysfunction over the past 20 years, and elaboration of targets beyond the NMDAR itself.