title: EEG-β/γ spectral power elevation in rat: a translatable biomarker elicited by GABA(Aα2/3)-positive allosteric modulators at nonsedating anxiolytic doses.
abstract: Benzodiazepine drugs, through interaction with GABA(Aα1), GABA(Aα2,3), and GABA(Aα5) subunits, modulate cortical network oscillations, as reflected by a complex signature in the EEG power spectrum. Recent drug discovery efforts have developed GABA(Aα2,3)-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 GABA(Aα2,3)-mediated vs. GABA(Aα1) or GABA(Aα5) currents in voltage clamped oocytes transfected with those GABA(A) subunits. These compounds were shown with in vivo receptor occupancy techniques to competitively displace [(3)H]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 γ-band power increases showed a significant positive correlation to in vitro GABA(Aα2,3) modulatory intrinsic activity across the compound set, further supporting a hypothesis that this EEG signature was linked specifically to pharmacological modulation of GABA(Aα2,3) signaling. These findings encourage further evaluation of this EEG signature as a noninvasive clinical translational biomarker that could ultimately facilitate development of GABA(Aα2,3)-subtype-selective drugs for anxiety and potentially other indications.
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware; edchristian3@gmail.com.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Christian
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Dean H
authors.initials: DH
authors.lastname: Snyder
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: David A
authors.initials: DA
authors.lastname: Gurley
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Joanne
authors.initials: J
authors.lastname: Smolka
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Donna L
authors.initials: DL
authors.lastname: Maier
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Farzin
authors.initials: F
authors.lastname: Gharahdaghi
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Xiaodong F
authors.initials: XF
authors.lastname: Liu
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Maninder
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Department of Disposition, Metabolism and Pharmacokinetics, AstraZeneca Pharmaceuticals, Wilmington, Delaware; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Ribadeneira
authors.affiliation: Department of Chemistry, AstraZeneca Pharmaceuticals, Wilmington, Delaware.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Chapdelaine
authors.affiliation: Department of Disposition, Metabolism and Pharmacokinetics, AstraZeneca Pharmaceuticals, Wilmington, Delaware; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Dudley
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Arriza
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Carla
authors.initials: C
authors.lastname: Maciag
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: Michael C
authors.initials: MC
authors.lastname: Quirk
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, Delaware;
authors.forename: James J
authors.initials: JJ
authors.lastname: Doherty
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001307:Auditory Perception / Q000187:drug effects / Q000502:physiology; D001611:Beta Rhythm / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003220:Conflict, Psychological; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D004569:Electroencephalography; D018682:GABA Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D065818:Gamma Rhythm / Q000187:drug effects* / Q000502:physiology; D016014:Linear Models; D008297:Male; D018408:Patch-Clamp Techniques; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D018682:GABA Agents; C520011:Gabra2 protein, rat; C546259:Gabra3 protein, rat; D011963:Receptors, GABA-A
keywords: GABAA subtypes; anxiolysis; benzodiazepine; electroencehalography; gamma network oscillation; pharmaco-EEG