Selective Antagonism of mGluR5 Alters Sleep-Wake and Quantitative EEG and Ameliorates Behavioral Abnormalities in a Rodent Model of Traumatic Stress

Abstract

Post-Traumatic Stress Disorder (PTSD) is characterized by persistent stress responses after experiencing a traumatic event. Hyperarousal and accompanying sleep disruptions, such as insomnia and nightmares, are among the most debilitating symptoms. Traumatic stress has been shown to induce state-dependent alterations in cortical network activity as measured by sleep-wake and quantitative electroencephalography (qEEG) that may predict the onset or severity of chronic symptoms. The single prolonged stress (SPS) rodent model of traumatic stress recapitulates many physiological and behavioral correlates of the human disorder, but its effect on sleep-wake and qEEG spectral power has not been examined. We demonstrated the long-term effects of SPS on sleep-wake architecture and state-dependent qEEG power spectra. We also discovered ameliorative effects of VU0409106, a novel, selective negative allosteric modulator (NAM) of the metabotropic glutamate receptor subtype 5 (mGluR5). Specifically, VU0409106 administered immediately after SPS acutely reduced time spent in REM sleep, possibly impairing the consolidation of traumatic memory, and prevented the subsequent development of augmented threat responding. Thus, selective antagonism of mGlu5 represents a novel, potentially therapeutic intervention for symptoms related to PTSD.