Ketamine, at a Dose that Disrupts Motor Behavior and Latent Inhibition, Enhances Prefrontal Cortex Synaptic Efficacy and Glutamate Release in the Nucleus Accumbens
- 8 March 2006
- journal article
- Published by Springer Science and Business Media LLC in Neuropsychopharmacology
- Vol. 32 (3), 719-727
- https://doi.org/10.1038/sj.npp.1301057
Abstract
Noncompetitive N-methyl-D-aspartate (NMDA) antagonists such as ketamine represent useful pharmacological tools to model, in both healthy humans and rodents, behavioral and cerebral abnormalities of schizophrenia. These compounds are thought to exert some of their disruptive effects by impairing glutamatergic transmission in corticolimbic circuits including the nucleus accumbens (NAc). In this study, we investigated in freely moving rats behavioral changes as well as electrophysiological and neurochemical alterations in the NAc following acute systemic injection of a subanesthetic dose (25 mg/kg) of ketamine. We found that ketamine induced an immediate behavioral activation, characterized by hyperlocomotion, stereotypies and ataxia, and abolished latent inhibition in a conditioned-fear paradigm when injected at the pre-exposure stage. We also observed that during expression of motor effects which are thought to be related to the positive symptoms of schizophrenia, ketamine potentiated synaptic efficacy in the prefrontal-accumbens pathway and increased the extracellular levels of glutamate in the NAc. These results, taken together with previous findings, suggest that the psychotic-like effects of noncompetitive NMDA antagonists may be, in part, mediated by an increase in glutamate release in the NAc associated with synaptic changes in accumbens glutamatergic inputs including enhancement of synaptic efficacy in the prefrontal input.Keywords
This publication has 52 references indexed in Scilit:
- Alterations of Benzodiazepine Receptors in Type II Alcoholic Subjects Measured With SPECT and [123I]IomazenilAmerican Journal of Psychiatry, 1998
- Corticolimbic Dopamine Neurotransmission Is Temporally Dissociated from the Cognitive and Locomotor Effects of PhencyclidineJournal of Neuroscience, 1998
- Glutamate Receptor Dysfunction and SchizophreniaArchives of General Psychiatry, 1995
- Effects of the NMDA receptor antagonist ketamine on flavor memory: Conditioned aversion, latent inhibition, and habituation of neophobiaBehavioral and Neural Biology, 1994
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in HumansArchives of General Psychiatry, 1994
- Hypofrontality in Neuroleptic-Naive Patients and in Patients With Chronic SchizophreniaArchives of General Psychiatry, 1992
- Recent advances in the phencyclidine model of schizophreniaAmerican Journal of Psychiatry, 1991
- Physiologic Dysfunction of Dorsolateral Prefrontal Cortex in SchizophreniaArchives of General Psychiatry, 1986
- Basal Ganglia and Limbic System Pathology in SchizophreniaArchives of General Psychiatry, 1985
- Study of a New Schizophrenomimetic Drug—SernylArchives of Neurology & Psychiatry, 1959