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The Journal of Neuroscience, January 12, 2005, 25(2):524-531; doi:10.1523/JNEUROSCI.3800-04.2005

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Neurobiology of Disease
Ketamine Induces Dopamine-Dependent Depression of Evoked Hippocampal Activity in the Nucleus Accumbens in Freely Moving Rats

Mark J. Hunt, Karima Kessal, and Rene Garcia

Neurobiologie Comportementale, Institut National de la Santé et de la Recherche Médicale, Université de Nice-Sophia Antipolis, 06108 Nice, France

Noncompetitive NMDA receptor antagonists, such as ketamine, induce a transient schizophrenia-like state in healthy individuals and exacerbate psychosis in schizophrenic patients. In rodents, noncompetitive NMDA receptor antagonists induce a behavioral syndrome that represents an experimentally valid model of schizophrenia. Current experimental evidence has implicated the nucleus accumbens in the pathophysiology of schizophrenia and the psychomimetic actions of ketamine. In this study, we have demonstrated that acute systemic administration of ketamine, at a dose known to produce hyperlocomotion and stereotypy, depressed the amplitude of the monosynaptic component of fimbria-evoked field potentials recorded in the nucleus accumbens. A similar effect was observed using the more selective antagonist dizocilpine maleate, indicating the depression was NMDA receptor dependent. Paired-pulse facilitation was enhanced concomitantly with, and in proportion to, ketamine-induced depressed synaptic efficacy, indicative of a presynaptic mechanism of action. Notably, the depression of field potentials recorded in the nucleus accumbens was markedly reduced after a focal 6-hydroxydopamine lesioning procedure in the nucleus accumbens. More specifically, pretreatment with the D₂/D₄ antagonist haloperidol, but not the D₁ antagonist SCH23390 blocked ketamine-induced depression of nucleus accumbens responses. Our findings provide supporting evidence for the contemporary theory of schizophrenia as aberrant excitatory neurotransmission at the level of the nucleus accumbens.

Key words: ketamine; NMDA; nucleus accumbens; evoked field potentials; dopamine; schizophrenia

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Received June 1, 2004; revised November 22, 2004; accepted November 22, 2004.

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