Anxiolytic-like effects through a GLUK5 kainate receptor mechanism

Andrew Alt, Brianne Weiss, Paul L. Ornstein, Scott D. Gleason, David Bleakman, Robert E. Stratford, Jeffrey M. Witkin

Research output: Contribution to journalArticle

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Abstract

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 GLUK5 kainate receptor subunit (Kb = 0.6 μM) and has 30 μM 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 GLUK5 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.

Original languageEnglish (US)
Pages (from-to)1482-1487
Number of pages6
JournalNeuropharmacology
Volume52
Issue number7
DOIs
StatePublished - Jun 1 2007

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Keywords

  • AMPA receptors
  • Anxiolytic drugs
  • Chlordiazepoxide
  • GYKI53655
  • Kainate receptors
  • LY382884
  • Rats

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Alt, A., Weiss, B., Ornstein, P. L., Gleason, S. D., Bleakman, D., Stratford, R. E., & Witkin, J. M. (2007). Anxiolytic-like effects through a GLUK5 kainate receptor mechanism. Neuropharmacology, 52(7), 1482-1487. https://doi.org/10.1016/j.neuropharm.2007.02.005