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Analysis of the changes induced in top-down systems of the motivational control underlying the effects of the dissociative anesthetic ketamine


Ketamine is a non-competitive NMDA-glutamate antagonist that shares the ability to modulate GABA and glutamate neurotransmission. That is the reason for its stimulant, hypnotic and analgesic properties, and for its influence on the mental state. These unusual and disturbing effects, which limit the clinical use, poses ketamine as a recreational drug. Chronic ketamine administration changes normal encephalic activity and induces psychotic states. Ketamine also disrupts field evoked potentials, including the auditory ones. The dissociative effects of ketamine are supposed to be due to the sensory overload resulted from a reduction exerted by the inhibitory top-down control on the mesencephalic bottom-up processes resulting in the induction of psychotic-like symptoms where cognitive impairment, emotional blunting, and auditory hallucinations are the core signs. An auditory hallucination is related to functional and structural abnormalities in several regions of this system, including the inferior colliculus, thalamus, primary auditory and somatosensory cortices, with a significant contribution of NMDA and GABA receptors. In fact, the effects of ketamine on the sensory systems are powerful involving changes at the electrophysiological and cognitive domains, as revealed by studies using unconditioned or selective attention. The present study sought to determine the influence of ketamine on the processing of auditory stimuli, from the mesencephalic sensory gating to cortical modulatory areas. Changes in this system, contributing to the expression of anomalous symptoms and stressing the impairment of psychic functions. Besides, similarities among species enable to infer data got from translational models to the clinical domain. Although studies aimed to understand the pharmacological action of long-term use of ketamine have been more focused on complex cognitive functions, such as those related to working memory and executive processing, this project is mainly directed to the study of the modulatory role of GABA and glutamate receptors of the inferior colliculus, the brainstem relay of auditory ascending information, on the auditory evoked-potentials elicited in the primary auditory and the somatosensory cortex. (AU)

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