Capturing the angel in "angel dust": twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans

Abstract

Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the pathophysiology of schizophrenia and identify potential new targets for treatment of schizophrenia. We began these efforts in the late 1980s with a keen sense that, in both human and animal studies, we needed to move beyond the dopamine hypothesis of schizophrenia; if the dopamine hypothesis were correct, the existing dopamine antagonists should have cured the disease but they have not. We used NMDA receptor antagonists, not to produce schizophrenia, but as a tool to provide insights into effects of disturbances in glutamate synaptic function in schizophrenia. Our work has provided insights into potential mechanisms that may contribute to disrupted cortical function in schizophrenia and has helped identify potential treatment targets for the disorder. The translational nature of this study made the clinical testing of the first of these targets feasible. Advances in systems neuroscience approaches in animals and humans make new types of translational research possible; however, our concern is that the current obstacles facing translational research funding and academia-industry collaborations threaten the future progress in this field.

Fig. 1.

Left, Ketamine hydrochloride effects on the brief psychiatric rating scale (BPRS): 4 key positive symptoms in healthy subjects (n = 18). Cluster scores (mean ± SEM) are presented for placebo (open circles), ketamine hydrochloride (0.1mg/kg) (closed circles), and ketamine hydrochloride (0.5mg/kg) (closed squares) test days. Individual time point increases from baseline, by Dunnett’s test: **P < .01. All other statistics are presented in the text. Right, Ketamine effects on the BPRS: 3 key negative symptoms in healthy subjects (n = 18). Cluster scores (mean ± SEM) are presented for placebo (open circles), ketamine hydrochloride (0.1mg/kg) (closed circles), and ketamine hydrochloride (0.5mg/kg) (closed squares) test days. Individual time point increases from baseline, by Dunnett’s test: *P < .05; **P < .01. All other statistics are presented in the text.

Fig. 2.

Ketamine increases glutamate efflux in the prefrontal cortex (PFC).

Fig. 3.

NMDA receptor deficits on GABA interneurons disinhibit glutamate release in PFC and hippocampus promoting disorganized cortical activity.