• Natalia Gass, Adam James Schwarz, Alexander Sartorius, Esther Schenker, Celine Risterucci, Michael Spedding, Lei Zheng, Andreas Meyer-Lindenberg, and Wolfgang Weber-Fahr.
• Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
• Neuropsychopharmacology. 2014 Mar 1;39(4):895-906.

AbstractDysfunctional connectivity within the hippocampal-prefrontal circuit (HC-PFC) is associated with schizophrenia, major depression, and neurodegenerative disorders, and both the hippocampus and prefrontal cortex have dense populations of N-methyl-D-aspartate (NMDA) receptors. Ketamine, a potent NMDA receptor antagonist, is of substantial current interest as a mechanistic model of glutamatergic dysfunction in animal and human studies, a psychotomimetic agent and a rapidly acting antidepressant. In this study, we sought to understand the modulatory effect of acute ketamine administration on functional connectivity in the HC-PFC system of the rat brain using resting-state fMRI. Sprague-Dawley rats in four parallel groups (N=9 per group) received either saline or one of three behaviorally relevant, sub-anesthetic doses of S-ketamine (5, 10, and 25 mg/kg, s.c.), and connectivity changes 15- and 30-min post-injection were studied. The strongest effects were dose- and exposure-dependent increases in functional connectivity within the prefrontal cortex and in anterior-posterior connections between the posterior hippocampus and retrosplenial cortex, and prefrontal regions. The increased prefrontal connectivity is consistent with ketamine-induced increases in HC-PFC electroencephalographic gamma band power, possibly reflecting a psychotomimetic aspect of ketamine's effect, and is contrary to the data from chronic schizophrenic patients suggesting that ketamine effect does not necessarily parallel the disease pattern but might rather reflect a hyperglutamatergic state. These findings may help to clarify the brain systems underlying different dose-dependent behavioral profiles of ketamine in the rat.

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