Michaela Fujáková

Electroencephalographic Spectral and Coherence Analysis of Ketamine in Rats: Correlation with Behavioral Effects and Pharmacokinetics

Aims: This study was designed to evaluate the changes in EEG power spectra and EEG coherence in a ketamine model of psychosis in rats. Analyses of behavioral measurements – locomotion and sensorimotor gating – and the pharmacokinetics of ketamine and norketamine were also conducted. Methods: Ketamine and norketamine levels in rat sera and brains were analyzed by gas chromatography-mass spectrometry after ketamine 30 mg/kg (i.p.). Ketamine 9 and 30 mg/kg (i.p.) were used in the behavioral and EEG experiments. Locomotor effects in an open field test and deficits in prepulse inhibition of acoustic startle reaction (PPI ASR) were evaluated in the behavioral experiments. EEG signals were simultaneously recorded from 12 implanted active electrodes; subsequently, an EEG power spectral and coherence analysis was performed. Results: Ketamine had a rapid penetration into the brain; the peak concentrations of the drug were reached within 15 min after administration. Ketamine induced marked hyperlocomotion and deficits in the PPI ASR. EEG spectral analysis mainly showed increases in EEG power as well as coherence. These were most robust at 10–15 min after the administration and influenced all parts of the spectrum with ketamine 30 mg/kg. Conclusions: Ketamine at behaviorally active doses induces a robust increase in EEG power spectra and coherence. The maximum levels of change correlated with the kinetics of ketamine.

Behavioral, hyperthermic and pharmacokinetic profile of para-methoxymethamphetamine (PMMA) in rats

Despite poisoning with the ecstasy substitute para-methoxymethamphetamine (PMMA) being typically associated with severe hyperthermia and death, behavioral and toxicological data on this drug are missing. Herein we present the behavioral profile of PMMA, its hyperthermic potency and pharmacokinetic profile in rats. The effects of PMMA 5 and 20 mg/kg on locomotion, on prepulse inhibition (PPI) of acoustic startle reaction (ASR), on body temperature under isolated and crowded conditions and on the pharmacokinetics analyzed with gas chromatography mass spectrometry (GC-MS) were evaluated. PMMA increased overall locomotion with the higher dose showing a biphasic effect. PPI was decreased dose-dependently. The hyperthermic response was present only with PMMA 20 mg/kg and was accompanied by extensive perspiration under crowded conditions. Serum levels of PMMA peaked at approximately 30 min after both treatments; on the contrary the maximum brain concentrations of PMMA at 20 mg/kg peaked approximately 1h after the administration, which was rather delayed compared to maximum after 5mg/kg dose. These data indicate that PMMA has a similar behavioral profile to stimulants and hallucinogens and that the toxicity might be increased in a crowded environment. High doses of PMMA have a gradual penetration to the brain which might lead to the delayed peak concentrations and prolonged effects of the drug.

Biochemical, histopathological and morphological profiling of a rat model of early immune stimulation: relation to psychopathology.

Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson’s disease and Alzheimer’s disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases - glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders.

The effect of ((−)-2-oxa-4-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY379268), an mGlu2/3 receptor agonist, on EEG power spectra and coherence in ketamine model of psychosis

In the present study we investigated the potential antipsychotic effects of the mGlu2/3 agonist LY379268 on changes in EEG power spectra and coherence in the ketamine model of psychosis. In order to use behaviorally active drug doses, experiments detecting changes in locomotor activity and sensorimotor gating were also conducted. In EEG experiments, adult male Wistar rats were injected with ketamine 30 mg/kg i.p. and LY379268 3 mg/kg i.p. Cortical EEG was recorded from twelve (2 × 6) electrodes placed homolaterally on each hemisphere. To avoid interference with the behavioral hyperactivity of ketamine challenge, the behavioral activity of animals was simultaneously registered at the time of recording. Subsequent power spectral and coherence analyses were assessed in epochs corresponding to behavioral inactivity. Analysis of segments with behavioral activity compared to inactivity was also performed. The effects of LY379268 3 mg/kg i.p. on the deficits in sensorimotor processing and on hyperlocomotion induced by ketamine were evaluated in the test of prepulse inhibition of acoustic startle reaction (PPI ASR) and in the open field. LY379268 reversed the ketamine-induced hyperlocomotion but had no effect on ketamine-induced PPI deficits. In EEG epochs corresponding to behavioral inactivity ketamine decreased the power in the delta band, induced a power increase in the high frequency bands and globally decreased EEG coherence. Pretreatment with the LY379268 completely reversed the ketamine-induced power increase in high frequency bands and had a partial effect on EEG coherence. LY379268 alone induced a decrease of beta, high beta and low-gamma power, and an increase in coherence in high frequency bands. Additional analysis revealed that behavioral activity increases power as well as coherence in most frequency bands. In conclusion, agonism of mGlu2/3 receptors was effective in reversing most of the changes induced by ketamine, however due to the lack of effectiveness on PPI deficits its potential antipsychotic properties remain disputable.

EPA-0137 – EEG power spectra and connectivity changes in animal serotonergic and glutamatergic models of psychosis – implications for treatment

Pharmacological models of psychosis bring a unique tool for studying brain disconnection in humans as well as in animals. Even though several electrophysiological biomarkers have been already described in schizophrenia, little is known about EEG biomarkers in pharmacological models of psychosis and about the translational validity of these data. Studies on EEG brain connectivity in rodents under these circumstances are extremely rare. To elucidate the characteristic patterns of EEG connectivity in freely moving rats we have conducted a series of experiments in serotonergic and glutamatergic models of psychosis. Using multiple cortical electrodes, EEG spectral and connectivity analysis was performed on selected episodes of behavioral inactivity – a model of resting EEG. The analyses showed consistent changes that were specific for each of the models used. Glutamatergic models with ketamine and dizocilpin (MK-801) induced typical global increase in high frequency oscillations. On the contrary, in serotonergic models (psilocin, mescaline, LSD, DOB, 2C-B) a global power decrease was observed. A common denominator in both models was a global decrease in connectivity expressed as decreased coherence in most of the frequency bands. A translational validity of these findings is supported by findings in schizophrenia patients and by recent human studies with ketamine and psilocybin. Recently obtained results with drugs modulating serotonergic, dopaminergic and glutamatergic neurotransmission will be also discussed in the light of potential therapeutic implications. This work was supported by projects IGA MH CZ NT/13897 and DRO (PCP, 00023752), MI CZ VG20122015080 and VG20122015075, ECGA 278006.

P-1234 - The effect of 5-HT2A, D2 and AMPA antagonists and an mGlu2/3 agonist on quantitative EEG in animal models of psychosis

Introduction Schizophrenia has been associated with disrupted neural networks, which can be documented by the changes in EEG. NMDA antagonists as well as 5-HT2 agonists induce psychosis-like symptoms in animals and humans. Objectives Spectral analyses of NMDA antagonists/5-HT2 agonists have been performed by many authors, however no EEG coherence and spectra was analyzed with a higher number of cortical electrodes. Aims The aim of this study was to compare the effect of mGlu2/3 agonist, 5-HT2A/D2 antagonist, D2 antagonist and AMPA antagonist on quantitative EEG changes in glutamatergic and serotoninergic animal models of psychosis. Methods Male Wistar rats were treated with either NMDA antagonist or 5-HT2A agonist. Subsequently mGlu2/3 agonist, 5-HT2A/D2 antagonist, D2 antagonist or AMPA antagonist were applied. Stereotactical implantation of 14 electrodes was performed before EEG recording. During EEG recording, the signal was recorded simultaneously from 12 implanted electrodes located bilaterally in frontal, parietal and temporal regions while the animals behavior was continuously observed. Subsequent power spectral analysis and the EEG coherences were assessed with the observed passive behaviour. Results Agonist of mGlu2/3 receptor normalized power spectral changes induced by ketamine. AMPA antagonist had an only partial effect on power after administration of MK801 without any effect on 2C-B. Both D2 antagonists partially normalized power spectral changes. In EEG coherences, intra- and interhemispheral changes in both animal models of psychosis were not completely normalized by applied treatments. Conclusion The presented data will be discussed in relation to data already identified, as well as data found in schizophrenic patients.

Contents Vol. 63, 2011

A. Drago, Naples G. Erdmann, Berlin A. Fischer, Göttingen J.M. Ford, San Francisco, Calif. S. Galderisi, Naples M. Hatzinger, Solothurn U. Hegerl, Leipzig K. Hirata, Mibu M. Kato, Osaka J. Kornhuber, Erlangen D. Lehmann, Zürich P. Monteleone, Naples G. Okugawa, Osaka G.N. Papadimitriou, Athens M. Popoli, Milano M. Reuter, Bonn F. Rösler, Marburg G. Ruigt, Oss J.K. Rybakowski, Poznan F. Schneider, Aachen R. Schwarting, Marburg M. Shigeta, Tokyo D. Souery, Brussels A. Steiger, Munich P. Willner, Swansea Associate Editors