| Autor: |
Christian, Edward P., Snyder, Dean H., Wei Song, Gurley, David A., Smolka, Joanne, Maier, Donna L., Min Ding, Gharahdaghi, Farzin, Xiaodong F. Liu, Chopra, Maninder, Ribadeneira, Maria, Chapdelaine, Marc J., Dudley, Adam, Arriza, Jeffrey L., Maciag, Carla, Quirk, Michael C., Doherty, James J. |
| Předmět: |
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| Zdroj: |
Journal of Neurophysiology; 1/1/2015, Vol. 113 Issue 1, p116-131, 16p |
| Abstrakt: |
Benzodiazepine drugs, through interaction with GABAAα1, GABAAα2,3, and GABAAα5 subunits, modulate cortical network oscillations, as reflected by a complex signature in the EEG power spectrum. Recent drug discovery efforts have developed GABAAα2,3-subunit-selective partial modulators in an effort to dissociate the side effect liabilities from the efficacy imparted by benzodiazepines. Here, we evaluated rat EEG and behavioral end points during dosing of nine chemically distinct compounds that we confirmed statistically to selectively to enhance GABAAα2,3-mediated vs. GABAAα1 or GABAAα5 currents in voltage clamped oocytes transfected with those GABAA subunits. These compounds were shown with in vivo receptor occupancy techniques to competitively displace [³H]flumazenil in multiple brain regions following peripheral administration at increasing doses. Over the same dose range, the compounds all produced dose-dependent EEG spectral power increases in the β- and and γ-bands. Finally, the dose range that increased γ-power coincided with that eliciting punished over unpunished responding in a behavioral conflict model of anxiety, indicative of anxiolysis without sedation. EEG y-band power increases showed a significant positive correlation to in vitro GABAAα2,3 modulatory intrinsic activity across the compound set, further supporting a hypothesis that this EEG signature was linked specifically to pharmacological modulation of GABAAα,3 signaling. These findings encourage further evaluation of this EEG signature as a noninvasive clinical translational biomarker that could ultimately facilitate development of GABAAα,3-subtype-selective drugs for anxiety and potentially other indications. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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