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Locomotor activity detects subunit-selective effects of agonists and decahydroisoquinoline antagonists at AMPA/kainic acid ionotropic glutamate receptors in adult rats

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Abstract

Rationale

In vitro studies have identified a series of decahydroisoquinoline compounds with differential selectivity for the subunits that comprise AMPA/kainic acid receptors. Compounds have been identified that have preferential activity at AMPA receptors (LY302679), whereas others (LY377770) have affinity for GluR5-kainic acid preferring subunit, which is activated by ATPA and kainic acid.

Objectives

These studies set out to determine if locomotor activity could differentiate these profiles in vivo.

Methods

Locomotor activity was assessed in photocell drums in male Lister Hooded rats.

Results

AMPA, kainic acid and the GluR5 selective agonist ATPA, all suppressed spontaneous locomotor activity (SLA) in rats at doses of 1.0, 5.0 and 20 mg/kg resp. All three agonists achieve micromolar concentrations measured in whole brain after dosing with 10 mg/kg SC. The decahydroisoquinoline antagonist compounds, LY302679 (GluR2), LY293558 (GluR2, 5) and LY377770 (GluR5) all decreased SLA in rats (EDmin 2.5, 5.0 and 20 mg/kg respectively). The rank order of potency at GluR2 subunits (LY302679>LY293558>LY377770) was reflected in the same rank order of activity for suppression of SLA. LY293558 reversed the suppression of SLA induced by all three agonists (0.62–2.5 mg/kg). LY377770 reversed the effects of ATPA only (EDmin 1.0 mg/kg), LY302679 (EDmin 2.5 mg/kg) attenuated the effect of kainic acid but was ineffective against AMPA and ATPA.

Conclusions

Both agonist and antagonist suppression of SLA is associated with greater affinity for the GluR2 subunit, while compounds with affinity for the GluR5 subunit were less potent in suppressing SLA.

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Authors and Affiliations

  1. Lilly Research Centre, Erl Wood Manor, Sunninghill Rd, Windlesham, Surrey, GU20 6PH, UK

    Michael F. O’Neill, Graham Sanger, David J. Osborne & Sandra M. Woodhouse

  2. Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Ind., USA

    Paul L. Ornstein

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  1. Michael F. O’Neill
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  2. Graham Sanger
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  3. Paul L. Ornstein
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  4. David J. Osborne
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  5. Sandra M. Woodhouse
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Correspondence to Michael F. O’Neill.

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O’Neill, M.F., Sanger, G., Ornstein, P.L. et al. Locomotor activity detects subunit-selective effects of agonists and decahydroisoquinoline antagonists at AMPA/kainic acid ionotropic glutamate receptors in adult rats. Psychopharmacology 179, 181–188 (2005). https://doi.org/10.1007/s00213-004-2055-8

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  • DOI: https://doi.org/10.1007/s00213-004-2055-8

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