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 Previous Article
Volume 17, Number 8,
Issue of April 15, 1997
pp. 2921-2927
Copyright ©1997 Society for Neuroscience
Activation of Glutamatergic Neurotransmission by Ketamine: A
Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic
and Cognitive Disruptions Associated with the Prefrontal Cortex
Received Sept. 23, 1996; revised Nov. 21, 1996; accepted Nov. 22, 1996.
Bita Moghaddam,
Barbara Adams,
Anita Verma, and
Darron Daly
Department of Psychiatry, Yale University School of Medicine, VA
Medical Center 116A/2, West Haven, Connecticut 06516
Subanesthetic doses of ketamine, a noncompetitive NMDA
receptor antagonist, impair prefrontal cortex (PFC) function in the rat
and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that
ketamine may impair PFC function in part by interacting with dopamine
neurotransmission in this region. This study sought to determine the
mechanism by which ketamine may disrupt dopaminergic neurotransmission
in, and cognitive functions associated with, the PFC. A thorough
dose-response study using microdialysis in conscious rats indicated
that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate
outflow in the PFC, suggesting that at these doses ketamine may
increase glutamatergic neurotransmission in the PFC at non-NMDA
glutamate receptors. An anesthetic dose of ketamine (200 mg/kg)
decreased, and an intermediate dose of 50 mg/kg did not affect,
glutamate levels. Ketamine, at 30 mg/kg, also increased the release of
dopamine in the PFC. This increase was blocked by intra-PFC application
of the AMPA/kainate receptor antagonist,
6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of
spatial delayed alternation in the rodent, a PFC-sensitive cognitive
task, was ameliorated by systemic pretreatment with AMPA/kainate
receptor antagonist LY293558. These findings suggest that ketamine may
disrupt dopaminergic neurotransmission in the PFC as well as cognitive
functions associated with this region, in part, by increasing the
release of glutamate, thereby stimulating postsynaptic
non-NMDA glutamate receptors.
Key words:
microdialysis;
phencyclidine;
schizophrenia;
working
memory;
antipsychotic drugs;
AMPA receptors
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