dizocilpine-maleate and Hallucinations

Non-competitive NMDA receptor antagonists, in spite of their neuroprotective effects against neuronal ischemia, brain trauma, etc., cause neuronal damage in the rodent posterior cingulate and retrosplenial cortices (PC/RS), which are thought to be responsible brain regions for their psychotomimetic activity in humans. A number of anesthetics have not only GABAA receptor activating properties but also NMDA receptor antagonist properties. On the other hand, ketamine and nitrous oxide, both of which are potent non-competitive NMDA receptor antagonists and have little GABAA activating properties, are demonstrated to induce neuronal damage in the rat PC/RS. Furthermore, ketamine potentiates the neuronal damage by nitrous oxide. Although many anesthetics, such as halothane, isoflurane, barbiturates and benzodiazepines, inhibit the neuronal damage in the PC/RS by NMDA receptor antagonists, probably through GABAA receptor activation, we anesthesiologists should be aware of the risk of ketamine or nitrous oxide anesthesia, not to speak of the combined use of them, without using GABAA receptor activating agents.

Topics: Anesthetics, Dissociative; Animals; Cerebral Cortex; Dizocilpine Maleate; Drug Synergism; GABA Modulators; Gyrus Cinguli; Hallucinations; Humans; Ketamine; Neurotoxicity Syndromes; Nitrous Oxide; Rats; Receptors, N-Methyl-D-Aspartate

Conceptual and computational models have been advanced that propose that perceptual disturbances in psychosis, such as hallucinations, may arise due to a disruption in the balance between bottom-up (ie sensory) and top-down (ie from higher brain areas) information streams in sensory cortex. However, the neural activity underlying this hypothesized alteration remains largely unexplored. Pharmacological N-methyl-d-aspartate receptor (NMDAR) antagonism presents an attractive model to examine potential changes as it acutely recapitulates many of the symptoms of schizophrenia including hallucinations, and NMDAR hypofunction is strongly implicated in the pathogenesis of schizophrenia as evidenced by large-scale genetic studies. Here we use in vivo 2-photon imaging to measure frontal top-down signals from the anterior cingulate cortex (ACC) and their influence on activity of the primary visual cortex (V1) in mice during pharmacologically induced NMDAR hypofunction. We find that global NMDAR hypofunction causes a significant increase in activation of top-down ACC axons, and that surprisingly this is associated with an ACC-dependent net suppression of spontaneous activity in V1 as well as a reduction in V1 sensory-evoked activity. These findings are consistent with a model in which perceptual disturbances in psychosis are caused in part by aberrant top-down frontal cortex activity that suppresses the transmission of sensory signals through early sensory areas.

Topics: Animals; Axons; Disease Models, Animal; Dizocilpine Maleate; Evoked Potentials, Visual; Excitatory Amino Acid Antagonists; Gyrus Cinguli; Hallucinations; Mice; Neural Inhibition; Neural Pathways; Optical Imaging; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Visual Cortex