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Journal of Neuroscience, Vol 16, 373-379, Copyright © 1996 by Society for Neuroscience
NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine
A Verma and B Moghaddam
Department of Psychiatry, Yale University School of Medicine, West Haven, Connecticut, USA.
The present study was performed to assess the role of excitatory amino acid
and dopamine receptors on associative functions of the prefrontal cortex
(PFC) of the rat. Spatial delayed alternation was used as a PFC- sensitive
cognitive task. In addition, in vivo microdialysis was used to assess the
release of dopamine in the PFC. The noncompetitive NMDA antagonists
ketamine (10-30 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) dose- dependently
impaired the spatial delayed alternation performance compared with the
saline-treated control group. Administration of the dopamine antagonists
raclopride (0.1 and 0.5 mg/kg), SCH-23390 (0.1 mg/kg), or haloperidol (0.1
mg/kg) was without a significant effect. However, haloperidol and
raclopride (but not SCH-23390) reversed the disruptive effect of 30 mg/kg
ketamine on spatial delayed alternation performance. Microdialysis studies
revealed that this dose of ketamine preferentially increased the release of
dopamine in the PFC compared with the striatum. These findings indicate
that attenuation of glutamatergic neurotransmission at the NMDA receptor
impairs PFC- dependent cognitive functions. Furthermore, activation of
dopamine neurotransmission contributes, at least in part, to this
impairment.
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