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
Introduction
Functional brain imaging techniques in schizophrenia, including quantitative electroencephalography (qEEG), have yielded to a theory that the disorder can be characterized as a functional brain disconnection syndrome. In schizophrenic patients, qEEG studies consistently show an increase in power in slow waves (delta–theta) over frontal regions (Bourtos et al., 2008, Itil, 1977, Sponheim et al., 1994, Sponheim et al., 2000) in resting conditions and abnormalities in the high frequency range (gamma) in both pre-stimulus and stimulus evoked paradigms (Gandal et al., 2011, Krishnan et al., 2009, Sun et al., 2011). Gamma oscillations are thought to mediate perception processes and cognitive functions which are typically disturbed in schizophrenia. Another qEEG parameter, EEG coherence — a measure of brain functional connectivity — is also frequently affected in patients. However, due to various EEG recording conditions, medication and the heterogeneity of the disease, results obtained from schizophrenic patients are inconsistent, showing an increase as well as decrease in coherence (Bob et al., 2008, Bucci et al., 2007, Nagase et al., 1992). Nevertheless, most authors state that neuroleptic-free schizophrenic patients show a decreased fronto-temporal coherence in resting as well as task-related conditions (Ford et al., 2002, Higashima et al., 2007, Tauscher et al., 1998, Yeragani et al., 2006). An abnormal fronto-temporal connectivity has been described most consistently in other imaging studies (Friston and Frith, 1995, Horacek et al., 2006, Lawrie et al., 2002).
Studies using NMDA antagonists as models of psychosis (Krystal et al., 1994, Lahti et al., 2001) have led to a theory of dysfunctional NMDA receptors in schizophrenia (Bubenikova-Valesova et al., 2008). It was proposed that the blockade of NMDA receptors on gamma-aminobutyric acid (GABA)ergic interneurons results in disinhibition of cortical excitatory pathways producing the hyperglutamatergic state (Bubenikova-Valesova et al., 2008, Olney et al., 1999). According to the recent theory, activated fast-spiking interneurons as well as thalamo-cortical loops and primary sensory cortices both play a fundamental role in gamma oscillation generation. In as much, an increase in baseline gamma oscillations in awakened rats has been observed after the acute administration of NMDA antagonists (Ehrlichman et al., 2009, Hakami et al., 2009, Pinault, 2008). This is also consistent with our previous study (Palenicek et al., 2011b) where ketamine showed an increase in absolute power in delta, beta and gamma bands in EEG traces that comprised segments corresponding to behavioral activity. Since metabotropic glutamate mGlu2/3 receptors play a crucial role in the regulation of glutamate release at the synapse, agonism at these receptors has been proposed to have antipsychotic potential (Chaki, 2010, Marek, 2010, Moghaddam and Adams, 1998, Patil et al., 2007). In line with this hypothesis, agonist activation of these receptors reduces glutamate excitatory postsynaptic potentials (EPSPs) (Anwyl, 1999) and glutamate release (Imre et al., 2006, Imre, 2007). In agreement, mGlu2/3 agonists also showed a unique ability to normalize aberrant gamma oscillations induced by an NMDA antagonist in rats (Jones et al., 2012).
Assuming that the glutamatergic dysfunction might be an underlying mechanism leading to psychosis, gamma abnormalities and disconnection, we examined the effect of the mGlu2/3 agonist LY379268 on EEG power spectra and coherence after acute administration of ketamine in freely moving rats. Before the EEG experiments we also examined the effects of the mGlu2/3 agonist on hyperlocomotion and on disruption of prepulse inhibition (PPI) induced by ketamine (parameters generally used as models of positive symptoms and deficits in sensorimotor processing in psychosis (Bubenikova-Valesova et al., 2008)). The reasons were: 1) to evaluate/confirm the potential antipsychotic activity of the mGlu2/3 agonist in a behavioral study and 2) to determine a behaviorally efficient dose of the drug to be further used in the EEG experiments.
With the intention of obtaining EEG data with translational validity to human findings, the following approaches were combined: 1) a simultaneous recording of EEG from multiple (12 active) cortical electrodes from frontal, parietal and temporal regions was performed and 2) to avoid interference of the EEG signal with the stimulatory activity of ketamine (Palenicek et al., 2011b, Palenicek et al., 2012), the EEG signal was split and analyzed only in epochs corresponding to behavioral inactivity (a model of “resting EEG”). In addition, a comparison of EEG signals from epochs corresponding to behavioral activity versus inactivity was made to elucidate/confirm the direct impact of behavior on EEG.
Section snippets
Animals
All experiments were performed on adult male experimentally naive Wistar rats (specific pathogen free, 250–350 g b.w.) obtained from Biotest Inc. (Konárovice, Czech Republic). Each rat was tested only once. Animals were habituated to the animal facility a minimum of 5 days prior to testing. The rats were housed by pairs in plastic cages and maintained on a 12 h light/dark cycle beginning at 6 a.m., ambient temperature of 21–24 °C and humidity of 40% with standardized diet and water available ad
Locomotor activity
Two way ANOVA of the total trajectory length showed a significant effect of the ketamine treatment (F(2,54) = 12.648, p < 0.001) and LY379268 treatment (F(1,54) = 14.808, p < 0.001), but no interaction between factors (F(2,54) = 1.553, P = 0.221). The total distance was increased by ketamine 30 mg/kg (p < 0.05) (*), on the contrary LY379268 3 mg/kg alone decreased the locomotion of animals (p < 0.05) (*). LY379268 3 mg/kg blocked ketamine 30 mg/kg induced hyperlocomotion (p < 0.01) (++) (Fig. 2a).
Prepulse inhibition of acoustic startle reaction
Startle reaction
Discussion
The main findings of the present study are that the mGlu2/3 agonist was able to reverse the ketamine-induced changes in qEEG and also partially normalize its behavioral effects. Hyperlocomotion induced by ketamine 30 mg/kg and disrupted sensorimotor gating after both doses confirmed the behavioral validity of the model and doses used. LY379268 blocked hyperlocomotion but had no effect on PPI deficits induced by ketamine. Compared to other studies the drug alone produced significant
Conclusion
In conclusion, LY379268 was able to block ketamine-induced hyperlocomotion, normalize changes in high frequency oscillations and restore functional disconnection. These findings indicate that the mGlu2/3 agonism could restore some of the changes in the glutamatergic animal model of psychosis. However, LY379268 was not able to restore ketamine's disrupting effects on sensorimotor gating indicating its potential antipsychotic effects have to be confirmed by further studies.
Acknowledgments
This study was supported by projects IGA MHCR NT/13897, NT/13403, MICR VG20122015080 and VG20122015075, GAUK 674112/2012, ECGA 278006, 260045/SVV/2014, MH CZ — DRO (PCP, 00023752) and PRVOUK P34. We thank Craig Hampson BSc (Hons) for his helpful comments and language correction. No authors have any involvement, financial or otherwise, that might constitute a conflict of interest in the work contained in this manuscript.
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