Paul Ornstein - Anxiolytic-like effects through a GLUK5 kainate receptor mechanism

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  Alt, Andrew, Weiss, Brianne, Ornstein, Paul L., Gleason, Scott   D., Bleakman, David, Stratford, Robert E., Witkin, Jeffrey M.   Neuropharmacology 2007 52 (7)   1482-1487

  Abstract: 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-decahydroisoqui noline-3-carboxylic   acid (LY382884). LY382884 selectively binds the GLUK5 kainate   receptor subunit (K b =0.6μM) and has 30μM 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.   [Copyright &y& Elsevier]

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