Blockade of GABAB receptors facilitates muscarinic agonist-induced epileptiform activity in immature rat piriform cortex in vitro |
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Authors: | V Libri Andrew Constanti Michael Postlethwaite Norman G Bowery |
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Affiliation: | (1) Department of Pharmacology, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK, GB;(2) Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica, I-00173, Rome, Italy, IT;(3) Department of Pharmacology, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK, GB |
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Abstract: | The effects of the selective GABAB receptor antagonist 3-(3,4-dichlorophenyl)methyl]amino]propyl] (diethoxymethyl) phosphinic acid (CGP 52432) on muscarinic
(mAChR) and metabotropic glutamate (mGluR) responsiveness were studied in slices of piriform cortex from both immature (P16–P22)
and adult (≥P40) rats, using a conventional intracellular recording technique. In both adult and immature slices, CGP 52432
(1 μM) had no effect on neuronal membrane properties, whereas it selectively abolished the late inhibitory postsynaptic potential
(IPSP) evoked by local electrical stimulation of association fibre terminals. Age-related changes in mAChR (but not mGluR)
responsiveness were also detected. In adult neurones, bath-application of the mAChR agonist oxotremorine-M (OXO-M; 10 μM),
or the selective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 10 μM) evoked similar membrane depolarization
and inhibition of evoked excitatory postsynaptic potentials (EPSPs). However, while 1S,3R-ACPD and OXO-M produced indistinguishable
slow excitatory effects in immature slices, during superfusion with OXO-M, neurones exhibited spontaneous paroxysmal depolarizing
shifts (PDSs) that were suppressed in the presence of atropine (1 μM) or the selective GABAB receptor agonist β-parachlorophenyl-γ-aminobutyric acid (–)baclofen; 10 μM]. Also, application of OXO-M resulted in a pronounced
prolongation (rather than a decrease) of electrically evoked postsynaptic potentials (PSPs) which now exhibited recurrent
superimposed spike discharges. In adult slices, in the continuous presence of CGP 52432 (1 μM; 20 min pre-incubation), a subsequent
exposure to 10 μM OXO-M or 1S,3R-ACPD failed to induce any spontaneous epileptiform activity, and evoked PSPs were consistently
suppressed. In contrast, in immature slices, after incubation in CGP 52432 (1 μM; 20 min), a subsequent application of a low
dose of OXO-M (2.5 μM), which was inactive per se, was able to produce spontaneous PDSs and a prolongation of evoked PSPs.
We conclude that a reduction in GABAB-mediated synaptic inhibition in immature slices (in co-operation with other factors) may contribute to the facilitation of
excitatory neurotransmission and therefore play a role in the generation of mAChR-induced epileptiform activity.
Received: 16 March 1998 / Accepted: 11 May 1998 |
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Keywords: | Muscarinic agonist-induced epileptiform activity GABAB receptors CGP 52432 Piriform cortex Synaptic transmission Intracellular recording |
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