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In vitro and in vivo studies in rats with LY293558 suggest AMPA/kainate receptor blockade as a novel potential mechanism for the therapeutic treatment of anxiety disorders

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Abstract

Rationale

Although convergent evidence exists for a role of glutamate in the regulation of anxiety, the involvement of specific glutamate receptor subtypes has yet to be defined.

Objective

To evaluate the potential for blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors to produce anxioltyic-like effects with the AMPA/GLUK5 (kainate) antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5yl)ethyl]decahydroisoquinoline-3carboxylic acid (LY293558)

Materials and methods

Punished responding of rats was used to determine the efficacy of LY293558. Other in vivo and in vitro studies further characterized the specificity of LY293558 for AMPA/kainate receptors.

Results

LY293558 had a rank order of potency of GLUK5 ≥ GLUK5/6 ≈ GLUA2i ≈ GLUK2/5 ≈ GLUA1i ≈ GLUA2o ≈ GLUA3i ≈ GLUA1o ≥ GLUA3o ≥ GLUA4i ≈ GLUA4o and >100 μM affinity for rat cortical GABAA receptors. Comparison of the blockade of AMPA- vs N-methyl-d-aspartate (NMDA)-induced inward currents demonstrated that LY293558 was five-fold more potent as an antagonist at AMPA vs NMDA receptors in vitro. In keeping with the low affinity of LY293558 for NMDA receptors, LY293558 was not effective in preventing NMDA-induced seizures in mice. LY293558 increased punished responding, a preclinical predictor of anxiolytic efficacy, at a dose that decreased unpunished responding (10 mg/kg, i.p.). Chlordiazepoxide produced comparable increases in both punished and unpunished responding. The NMDA antagonist dizocilpine [(+)-MK-801] also increased both punished and unpunished responding.

Conclusions

These data along with those in the literature suggest that AMPA and/or kainate receptor blockade may be an important component to producing anxiolytic-like effects and may therefore be a target for compounds with efficacy in the therapeutic treatment of anxiety disorders.

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Acknowledgements

We thank Dr. Paul Ornstein for synthesizing LY292558. We thank Dr. Darryle Schoepp, Mark Benvenga, and Dr. Smriti Iyengar for valuable discussions. We also thank Denise Morrow for expert technical assistance.

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Authors and Affiliations

  1. Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Andrew Alt, Brianne Weiss, Ann Marie Ogden, Xia Li, Scott D. Gleason, David O. Calligaro, David Bleakman & Jeffrey M. Witkin

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  1. Andrew Alt
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  2. Brianne Weiss
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  3. Ann Marie Ogden
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  4. Xia Li
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Correspondence to Jeffrey M. Witkin.

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Alt, A., Weiss, B., Ogden, A.M. et al. In vitro and in vivo studies in rats with LY293558 suggest AMPA/kainate receptor blockade as a novel potential mechanism for the therapeutic treatment of anxiety disorders. Psychopharmacology 185, 240–247 (2006). https://doi.org/10.1007/s00213-005-0292-0

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