Jiří Horáček

Models of schizophrenia in humans and animals based on inhibition of NMDA receptors.

The research of the glutamatergic system in schizophrenia has advanced with the use of non-competitive antagonists of glutamate NMDA receptors (phencyclidine, ketamine, and dizocilpine), which change both human and animal behaviour and induce schizophrenia-like manifestations. Models based on both acute and chronic administration of these substances in humans and rats show phenomenological validity and are suitable for searching for new substances with antipsychotic effects. Nevertheless, pathophysiology of schizophrenia remains unexplained. In the light of the neurodevelopmental model of schizophrenia based on early administration of NMDA receptor antagonists it seems that increased cellular destruction by apoptosis or changes in function of glutamatergic NMDA receptors in the early development of central nervous system are decisive for subsequent development of psychosis, which often does not manifest itself until adulthood. Chronic administration of antagonists initializes a number of adaptation mechanisms, which correlate with findings obtained in patients with schizophrenia; therefore, this model is also suitable for research into pathophysiology of this disease.

The relationship between central serotonergic activity and insulin sensitivity in healthy volunteers

In order to determine whether central serotonin (5-HT) activity is related to sensitivity of insulin receptors, 19 healthy volunteers with normal basal glycemia and HbAlc were studied. The relationship between prolactin response to D-fenfluramine (delta PRL) in a challenge test and metabolic clearance rates (MCR) of glucose during the hyperinsulinemic-euglycemic clamp technique was evaluated. delta PRL had been chosen as a correlate of central 5-HT activity. Two levels of insulin concentration of approximately 70 mU/l (MCRsubmax) and 2000 mU/l (MCRmax) were used in a clamp, each for a duration of 120 min. A negative correlation was found between delta PRL and MCRsubmax (r = -0.55, P < 0.02) and between delta PRL and MCRmax (r = -0.51, P < 0.03). We did not find any correlation between the prolactin response to D-fenfluramine and body weight, body mass index (BMI) or waist and hip circumference (WHR). The data support the hypothesis of a close connection between 5-HT activity in the brain and peripheral sensitivity to insulin. The possible physiological mechanisms of this connection are discussed.

Medial frontal and dorsal cortical morphometric abnormalities are related to obsessive-compulsive disorder

Whole-brain voxel-based morphometry (VBM) studies provide support for orbitofrontal, medial frontal as well as for dorsal cortical volumetric alteration in obsessive-compulsive disorder (OCD). However, there is still a need to replicate a priori unpredicted findings and to elucidate white matter volumetric abnormalities and relationships between grey (GM) and white (WM) matter volume and clinical characteristics of OCD. We compared GM and WM volume in a group of 14 patients with OCD and 15 healthy controls using a 3T MRI scanner and an optimized VBM protocol. Regression analysis was used to examine relationships between GM and WM volume and clinical variables. In OCD we have found total WM volume reduction and marked mediofrontal, right temporo-parieto-occipital, right precentral, left middle temporal, left cerebellar and bilateral pons and mesencephalon GM volume reduction in the voxel-based analysis (p<or=0.05, FDR corrected, extent threshold 100 voxels). Regression analysis indicated a positive relationship between left orbitofrontal GM volume and severity of obsessive-compulsive symptoms and a negative relationship between symptom severity and GM volume in supramarginal gyri. Earlier age of OCD onset and longer illness duration were associated with smaller left occipital GM and right parietal WM and with greater left medial frontal GM and left frontal WM (p <or=0.001, uncorrected, extent threshold 50 voxels). Our results confirm volumetric abnormalities in the medial frontal and dorsal cortical areas in OCD. The relationships between OCD and clinical variables provide further evidence that frontal, parietal and occipital structures play a role in the disorder.

Differences in onset of disease and severity of psychopathology between toxoplasmosis-related and toxoplasmosis-unrelated schizophrenia.

Toxoplasmosis is a lifelong parasitic disease that appears to be associated to schizophrenia. However, no distinguishing attributes in Toxoplasma‐infected schizophrenia patients have been described as yet.

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.

Psilocybin – Summary of knowledge and new perspectives

Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.

EEG source analysis in obsessive–compulsive disorder

OBJECTIVE The goal of this study was to assess the activity of intracortical EEG sources in patients with OCD. METHODS We compared resting state EEG from 50 OCD patients and 50 matched controls using standardized low-resolution electromagnetic tomography (sLORETA) and normative independent component analysis (NICA). Data were analyzed with 1 Hz frequency resolution. Group ICA was used to separate seven independent components from the control group data. The resulting weights and norms served to derive the same components from the OCD group and to compare their power with controls. RESULTS In OCD, sLORETA indicated low-frequency power excess (2-6 Hz) in the medial frontal cortex, whereas group ICA showed increased low-frequency power in a component reflecting the activity of subgenual anterior cingulate, adjacent limbic structures and to a lesser extent also of lateral frontal cortex. CONCLUSIONS Both methods provided evidence for medial frontal hyperactivation in OCD. SIGNIFICANCE Our study is the first to use normative ICA in a clinical sample and indicates its potential utility as a diagnostic tool. The findings provide consistent results based on EEG source localization in OCD and are of practical interest for therapeutic interventions.

Expression of the hippocampal NMDA receptor GluN1 subunit and its splicing isoforms in schizophrenia: postmortem study.

There is accumulating evidence that disturbances in N-methyl-d-aspartate receptor (NMDA-R) functioning are associated with the pathogenesis of schizophrenia. To assess actual changes in the expression of the GluN1 subunit and its isoforms, we measured absolute differences in the levels of mRNA/protein for panGluN1 (eight isoforms altogether) as well as the mRNA individual isoforms in the postmortem left/right hippocampus of patients with schizophrenia in comparison with non-psychiatric subjects. There were no significant differences in the panGluN1 subunit mRNA expression, but the absolute left/right differences were much more pronounced in the patients with schizophrenia. Protein levels of the GluN1 subunit in the left hippocampus in male schizophrenic patients were lower than controls. The expression of the NR1-4b isoform was attenuated in the left, whereas the NR1-2b was reduced in the right hippocampus of schizophrenic patients. Isoforms associated with the efficiency of NMDA-induced gene expression and with phosphorylation occurred more commonly in schizophrenic hippocampi. In summary, our study suggests that NMDA-R hypofunction in schizophrenia might be selectively dependent on the dysregulation of GluN1 subunit expression, which exhibits a somewhat different expression in the left/right hippocampus of psychotic patients.

Relation of sex and estrous phase to deficits in prepulse inhibition of the startle response induced by ecstasy (MDMA)

Sensorimotor gating is the ability of a weak sensory event to inhibit the motor response to an intense stimulus. Drugs that act as serotonin releasers, such as MDMA (3,4-methylenedioxymethamphetamine), impair sensorimotor gating, which is measured as a prepulse inhibition (PPI) of the acoustic startle response. The first objective of the present study was to compare the effect of different doses of MDMA on PPI and the acoustic startle response (ASR) in male and female Wistar rats. The second objective was to examine the effect of MDMA on PPI across the estrous cycle in female rats. MDMA was administered in doses of 2.5, 5 and 10 mg/kg s.c. 15 min before the start of the experiment. The controls received saline in equivalent volumes. MDMA dose-dependently decreased PPI in both the male and female rats and produced higher levels of ASR in the male rats compared to the females. In addition, we found that female rats in the diestrous and metestrous phases are more sensitive to MDMA and showed higher deficits in PPI than female rats in the proestrous and estrous phases. Our result showed that female rats in the proestrous and estrous phases were less sensitive to the disruption of PPI by MDMA.

Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect

BACKGROUND Theta cordance is a novel quantitative electroencephalography (QEEG) measure that correlates with cerebral perfusion. A series of clinical studies has demonstrated that the prefrontal theta cordance value decreases after 1 week of treatment in responders to antidepressants and that this effect precedes clinical improvement. Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, has a unique rapid antidepressant effect but its influence on theta cordance is unknown. METHOD In a double-blind, cross-over, placebo-controlled experiment we studied the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a group of 20 healthy volunteers. RESULTS Ketamine infusion induced a decrease in prefrontal theta cordance and an increase in the central region theta cordance after 10 and 30 min. The change in prefrontal theta cordance correlated with ketamine and norketamine blood levels after 10 min of ketamine infusion. CONCLUSIONS Our data indicate that ketamine infusion immediately induces changes similar to those that monoamineric-based antidepressants induce gradually. The reduction in theta cordance could be a marker and a predictor of the fast-acting antidepressant effect of ketamine, a hypothesis that could be tested in depressive patients treated with ketamine.