Acute administration of typical and atypical antipsychotics reduces EEG gamma power, but only the preclinical compound LY379268 reduces the ketamine-induced rise in gamma power

Abstract

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.

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications

“…In a similar vein, the positive allosteric modulator TASP0433864 or orthosteric agonist at the metabotropic receptor 2 LY379268 completely reversed the ketamine-induced power increase in high-frequency bands [71,81,82] and partially reversed disrupted coherence [83]. …”

“…Glutamate NMDA receptor antagonists such as PCP, ketamine, and MK-801 have utility in modeling the positive, negative, and cognitive deficits of schizophrenia in healthy man and laboratory animals [68,69,70,71,72]. In preclinical studies, acute administration of PCP elicited aberrant network oscillations in the higher gamma frequency range [73,74,75].…”

“…Acute administration of antipsychotics was shown to reduce the rise of EEG gamma power elicited by ketamine [71]. Pretreatment with antipsychotics abolished abnormal cortical network synchrony in the slow alpha frequency range induced by amphetamine and MK801 and in the higher gamma frequency range induced by NMDA antagonists.…”

Gamma Power and Cognition in Patients with Schizophrenia and Their First-Degree Relatives

“…It has been suggested that this association may reflect a cortical hyperexcitability that possibly disturbs the conscious experience [11]. Consistently, administration of typical and atypical antipsychotics reduced gamma power in patients with schizophrenia [17]. …”

Neurophysiologic and Antipsychotic Profiles of TASP0433864, a Novel Positive Allosteric Modulator of Metabotropic Glutamate 2 Receptor

“…In support of the aforementioned mechanisms, mGlu2/3 receptor agonists have been reported to inhibit excitatory neurotransmission in electrophysiologic studies (Kilbride et al, 1998;Kew et al, 2001;Benneyworth et al, 2007), to normalize excessive glutamate levels in the prefrontal cortex (PFC) in schizophrenia animal models (Moghaddam and Adams, 1998;Lorrain et al, 2003), and to reduce the aberrant PFC activity caused by N-methyl-D-aspartic acid (NMDA) receptor antagonists (Homayoun et al, 2005;Gozzi et al, 2008;Chin et al, 2011;Dedeurwaerdere et al, 2011;Jones et al, 2012). The relative contributions of mGlu2 and -3 to the mechanisms of action of mGlu2/3 receptor agonists remain unknown.…”