Characterisation of the effects of ATPA, a GLU(K5) kainate receptor agonist, on GABAergic synaptic transmission in the CA1 region of rat hippocampal slices.
Kainate receptors are implicated in a variety of physiological and pathological processes in the CNS. Previously we demonstrated that (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA), a selective agonist for the GLU(K5) subtype of kainate receptor, depresses monosynaptically evoked inhibitory postsynaptic potentials (IPSPs) in the CA1 region of the rat hippocampus. In the current study, we provide a more detailed characterisation of this effect. Firstly, our data demonstrate a rank order of potency of domoate>kainate>ATPA>alpha-amino-3-(3-hydroxy-5-methyl-4-isoxalolyl)propionic acid Secondly, we confirm that the effects of ATPA are not mediated indirectly via the activation of gamma-aminobutyric acid receptors (i.e. either GABA(A) or GABA(B)). Thirdly, we show that the small increase in conductance induced by ATPA is insufficient to account for the depression of monosynaptic inhibition. Fourthly, we show that the effects of ATPA on IPSPs are antagonised by the GLU(K5)-selective antagonist (3S, 4aR, 6S, 8aR)-6-(4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). However, LY382884 is less potent as an antagonist of the effects of ATPA on IPSPs compared to its depressant effect on EPSPs.
MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, University Walk, Bristol BS8 1TD, UK. v.r.clarke@bris.ac.uk
V R J
VR
Clarke
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GL
Collingridge
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017097:Electric Impedance; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018682:GABA Agents / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000819:agonists* / Q000037:antagonists & inhibitors; D009435:Synaptic Transmission / Q000187:drug effects*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001569:Benzodiazepines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; D018698:Glutamic Acid; D007555:Isoxazoles; D007608:Kainic Acid; D011422:Propionates; D018092:Kainic Acid Receptors; D014633:Valine; D005680:gamma-Aminobutyric Acid; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate; C079692:GYKI 53655; C056639:2-amino-5-phosphopentanoic acid; C012301:domoic acid