Anxiolytic-like effects through a GLUK5 kainate receptor mechanism.
The hypothesis that kainate receptor blockade would be associated with anxiolytic-like effects was tested with a selective ligand, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). LY382884 selectively binds the GLU(K5) kainate receptor subunit (K(b)=0.6 microM) and has 30 microM or greater affinity for cloned human AMPA receptor subtypes. The anxiolytic potential of LY382884 was tested in rats responding under a Vogel conflict procedure, a pharmacologically validated model for the prediction of antianxiety efficacy in humans. Both the benzodiazepine anxiolytic chlordiazepoxide and LY382884 increased suppressed licking without affecting rates of non-suppressed licking. In contrast, an AMPA receptor selective antagonist, 7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-, monohydrochloride (9CI) (GYKI53655), did not increase suppressed responding. The finding that a selective GLU(K5) receptor antagonist produced anxiolytic-like effects in an animal model predictive of efficacy in humans combined with data in the literature on glutamatergic modulation of anxiety suggests that kainate receptor sensitivity to glutamate might be an important mediating event in the pathophysiological expression of anxiety states. The selective targeting of kainate receptors with an antagonist could therefore be a novel pharmacological mechanism to treat anxiety disorders.
Alt
Andrew
A
Neuroscience Discovery Research and Discovery Chemistry, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510, USA.
Weiss
Brianne
B
Ornstein
Paul L
PL
Gleason
Scott D
SD
Bleakman
David
D
Stratford
Robert E
RE
Witkin
Jeffrey M
JM
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D010949:Plasma / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000502:physiology*
D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D007546:Isoquinolines; D021122:Protein Subunits; D018092:Kainic Acid Receptors; C400802:LY382884; C079692:GYKI 53655