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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 manFORENAP – FRP – Institute for Research in Neuroscience, Neuropharmacology and Psychiatry, Rouffach, France, Peter.Boeijinga{at}forenap.asso.fr
FORENAP – FRP – Institute for Research in Neuroscience, Neuropharmacology and Psychiatry, Rouffach, France.
FORENAP Pharma, Rouffach, France.
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
Journal of Psychopharmacology, Vol. 21, No. 3,
321-337 (2007) |
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