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Ketamine effects on CNS responses assessed with MEG/EEG in a passive auditory sensory-gating paradigm: an attempt for modelling some symptoms of psychosis in man

FORENAP – FRP – Institute for Research in Neuroscience, Neuropharmacology and Psychiatry, Rouffach, France, Peter.Boeijinga{at}forenap.asso.fr

L. Soufflet

FORENAP – FRP – Institute for Research in Neuroscience, Neuropharmacology and Psychiatry, Rouffach, France.

F. Santoro

FORENAP Pharma, Rouffach, France.

R. Luthringer

FORENAP Pharma, Rouffach, France.

Disturbances in integrative function have been consistentLy described in psychotic disorder; for instance, prepulse inhibition of the startLe reflex (startle-PPI) which is a marker of sensory gating, is deficient in persons with schizophrenia. The N-methyl-D-aspartate antagonist ketamine produces in control subjects a spectrum of neurobehaviouraL symptoms like encountered in schizophrenia, and disrupts startle-PPI in animals. In the present study, we investigated in 12 healthy subjects whether ketamine would reduce sensory-gating in auditory responses at doses which produce psychotic symptoms. In a double-blind, crossover design loading doses of 0.024, 0.081 and 0.27 mg/kg or saline were employed, followed by maintenance infusion for 120 min. A passive paradigm has been developed which consisted in tone bursts, preceded or not by a (near-threshold) click at intervals of 100 ms or 500 ms. Brain electromagnetic activity imaging of the responses to sound stimuli has been carried out by way of a 148-channel magnetoencephalography-system. Actual evoked response amplitudes and underlying equivalent current dipole strengths have been compared to multieLectrode evoked potentials from the scalp. A click stimulus is capable to inhibit test responses under placebo at the 100 ms interval. During maintenance infusion of ketamine at steady-state (for >30 min) after 0.27 mg/kg, no such amplitude changes were observed anymore (p <0.05) and under these circumstances significant increases in Brief Psychiatric Rating scale and Scale for the Assessment of Negative Symptoms scores were evidenced (p < 0.001). Intermediate effects have been observed when the dose was lowered to 0.081 mg/kg. The present results have shown that ketamine may induce a psychotic-like clinical state associated with gating deficits in healthy subjects.

Key Words: sensory gating • NMDA receptors • ketamine • human auditory responses • magnetoencephalography • schizophrenia

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