A single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophrenia symptoms in patients. In conscious rats an equivalent dose of ketamine induces key features of animal models of acute psychosis, including hyperlocomotor activity, deficits in prepulse inhibition and gating of auditory evoked potentials, and concomitantly increases the power of ongoing spontaneously occurring gamma (30-80 Hz) oscillations in the neocortex. This study investigated whether NMDAR antagonist-induced aberrant gamma oscillations could be modulated by acute treatment with typical and atypical antipsychotic drugs. Extradural electrodes were surgically implanted into the skull of adult male Wistar rats. After recovery, rats were subcutaneously administered either clozapine (1-5 mg/kg, n=7), haloperidol (0.05-0.25 mg/kg; n=8), LY379268 (a preclinical agonist at mGluR2/3 receptors: 0.3-3 mg/kg; n=5) or the appropriate vehicles, and 30 min later received ketamine (5 mg/kg s.c.). Quantitative measures of EEG gamma power and locomotor activity were assessed throughout the experiment. All three drugs significantly reduced the power of baseline EEG gamma oscillations by 30-50%, an effect most prominent after LY379268, and all inhibited ketamine-induced hyperlocomotor activity. However, only pretreatment with LY379268 attenuated trough-to-peak ketamine-induced gamma hyperactivity. These results demonstrate that typical and atypical antipsychotic drugs acutely reduce cortical gamma oscillations, an effect that may be related to their clinical efficacy.
Opposite effects of ketamine and deep brain stimulation on rat thalamocortical information processing Sofya P Kulikova (1,2)*, Elena A Tolmacheva (1,2)**, Paul Anderson (1,2,3), Julien Gaudias (1,2)***, Brendan E Adams (1,2)****, Thomas Zheng (1,2,3), and Didier Pinault (1,2)(1) INSERM U666, physiopathologie et psychopathologie cognitive de la schizophrénie, Strasbourg, France. Abstract:Sensory and cognitive deficits are common in schizophrenia. They are associated with abnormal brain rhythms, including disturbances in γ frequency (30-80 Hz) oscillations (GFO) in cortex-related networks. However, the underlying anatomo-functional mechanisms remain elusive. Clinical and experimental evidence suggest that these deficits result from a hyporegulation of glutamate N-Methyl d-Aspartate receptors (NMDAr). Here we modeled these deficits in rats with ketamine, a non-competitive NMDAr antagonist and a translational psychotomimetic substance at subanesthetic doses. We tested the hypothesis that ketamine-induced sensory deficits involve an impairment of the ability of the thalamocortical (TC) system to discriminate the relevant information from the baseline activity. Furthermore we wanted to assess whether ketamine disrupts synaptic plasticity in TC systems. We conducted multisite network recordings in the rat somatosensory TC system, natural stimulation of the vibrissae and high-frequency electrical stimulation (HFS) of the thalamus.A single systemic injection of ketamine increased the amount of baseline GFO, reduced the amplitude of the sensory-evoked TC response and decreased the power of the sensoryevoked GFO. Furthermore, cortical application of ketamine elicited local and distant increases in baseline GFO. The ketamine effects were transient. Unexpectedly, HFS of the TC pathway had opposite actions. In conclusion, ketamine and thalamic HFS have opposite effects on the ability of the somatosensory TC system to discriminate the sensory-evoked response from the baseline GFO during information processing. Investigating the link between the state and function of the TC system may conceptually be a key strategy to design innovative therapies against neuropsychiatric disorders. 3The anatomofunctional mechanisms of sensory and cognitive deficits in schizophrenia are unknown. These deficits are commonly associated with abnormal brain rhythms, including disturbances in γ frequency (30-80 Hz) oscillations (GFO) in corticocortical and thalamocortical (TC) circuits (Bokde et al., 2009;Clinton and Meador-Woodruff, 2004;de Haan W. et al., 2009;Friston, 2002;Herrmann and Demiralp, 2005;Light et al., 2006;Lisman, 2011;Meyer-Lindenberg, 2010;Pinault, 2011;Spencer et al., 2003;Uhlhaas and Singer, 2006). At least four types of GFO should be considered: 1) Spontaneously-occurring (baseline) GFO, which are dominant during desynchronized state of the electroencephalogram (Jasper, 1936;Sheer, 1975); 2) Sensory-evoked GFO, which are phase-locked to the stimulus onset (Pantev et al., 1991;Spencer et al., 2008b); 3) Steadystate GFO during r...
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