title: FG7142, yohimbine, and βCCE produce anxiogenic-like effects in the elevated plus-maze but do not affect brainstem activated hippocampal theta.
abstract: The neurobiological underpinnings of anxiety are of paramount importance to selective and efficacious pharmaceutical intervention. Hippocampal theta frequency in urethane anaesthetized rats is suppressed by all known (and some previously unknown) anti-anxiety (anxiolytic) drugs. Although these findings support the predictive validity of this assay, its construct validity (i.e., whether theta frequency actually indexes anxiety per se) has not been a subject of systematic investigation. We reasoned that if anxiolytic drugs suppress hippocampal theta frequency, then drugs that increase anxiety (i.e., anxiogenic agents) should increase theta frequency, thus providing evidence of construct validity. We used three proven anxiogenic drugs--two benzodiazepine receptor inverse agonists, N-methyl-β-carboline-3-carboxamide (FG7142) and β-carboline-3-carboxylate ethyl ester (βCCE), and one α2 noradrenergic receptor antagonist, 17α-hydroxy-yohimban-16α-carboxylic acid methyl ester (yohimbine) as pharmacological probes to assess the construct validity of the theta model. Although all three anxiogenic drugs significantly increased behavioural measures of anxiety in the elevated plus-maze, none of the three increased the frequency of hippocampal theta oscillations in the neurophysiological model. As a positive control, we demonstrated that diazepam, a proven anxiolytic drug, decreased the frequency of hippocampal theta, as in all other studies using this model. Given this discrepancy between the significant effects of anxiogenic drugs in the behavioural model and the null effects of these drugs in the neurophysiological model, we conclude that the construct validity of the hippocampal theta model of anxiety is questionable.
authors.affiliation: Department of Psychology, University of Alberta, P-449 Biological Sciences Building, Edmonton, AB, Canada T6G 2E9.
authors.forename: Michelle
authors.initials: M
authors.lastname: Yeung
authors.affiliation: Department of Psychology, University of Alberta, P-449 Biological Sciences Building, Edmonton, AB, Canada T6G 2E9.
authors.forename: Lily
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Psychology, University of Alberta, P-449 Biological Sciences Building, Edmonton, AB, Canada T6G 2E9.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Hughes
authors.affiliation: Department of Psychology, University of Alberta, P-449 Biological Sciences Building, Edmonton, AB, Canada T6G 2E9; Centre for Neuroscience, 513 Heritage Medical Research Center, University of Alberta, Edmonton, AB, Canada T6G 2R3. Electronic address: dtreit@ualberta.ca.
authors.forename: Dallas
authors.initials: D
authors.lastname: Treit
authors.affiliation: Department of Psychology, University of Alberta, P-449 Biological Sciences Building, Edmonton, AB, Canada T6G 2E9; Centre for Neuroscience, 513 Heritage Medical Research Center, University of Alberta, Edmonton, AB, Canada T6G 2R3; Department of Physiology, 7-55 Medical Sciences Building, University of Alberta, Edmonton, AB, Canada T6G 2H7.
authors.forename: Clayton T
authors.initials: CT
authors.lastname: Dickson
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D001703:Biophysics; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology*; D002243:Carbolines / Q000633:toxicity*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D018756:GABA Antagonists / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013826:Theta Rhythm / Q000187:drug effects; D015016:Yohimbine / Q000633:toxicity
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D002243:Carbolines; D018756:GABA Antagonists; D015016:Yohimbine; C035874:FG 7142; C024915:beta-carboline-3-carboxylic acid ethyl ester
keywords: Anxiety; Anxiogenesis; Benzodiazepine receptor; Elevated plus-maze; Hippocampus; Inverse agonist; Oscillation; Theta suppression model; α2 Adrenergic