Ketamine, at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens.
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.
Razoux
Florence
F
INSERM Equipe Avenir, Laboratoire de Neurobiologie et Psychopathologie, Université de Nice-Sophia Antipolis, Parc Valrose, Nice cedex 2, France.
Garcia
René
R
Léna
Isabelle
I
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005071:Evoked Potentials / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D007266:Inhibition, Psychological; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007649:Ketamine