Selective M1 muscarinic acetylcholine receptor (mAChR) agonists are being developed for possible therapeutic application in a number of disease states. However, activation of mAChRs using broad-spectrum agonists has also been shown to produce hyper-excitability within the brain which, at the behavioural level, is manifest as seizure activity. The aim of the current study was to assess whether selective M1 receptor agonists promote pathological patterns of activity within the hippocampus in vitro. Extracellular recordings were used to monitor spontaneous field potentials in 450μm coronal rat hippocampal slices [1]. Application of the M1 selective agonist 77LH281 (10μM) resulted in a gamma frequency oscillatory activity (n=10, mean dominant frequency = 32 ± 3.6 Hz) that was sensitive to AMPA receptor blockade (2μM NBQX). In contrast, application of the broad spectrum mAChR agonist oxotremorine-M (10μM) induced inter-ictal-like epileptiform bursts which, in many instances (n=11 of 22), transformed into more prolonged ictal-like discharges. We also assessed whether mAChRs modulated established epileptiform activities. Specifically, convulsant regimes including potassium channel blockade (4AP, 20μM), blockade of GABAA receptor-mediated inhibition (bicuculline, 20μM) or enhanced NMDA receptor activation (0mM Mg2+ perfusion medium) were used to induce epileptiform activity[1]. Subsequent co-application of 10μM 77LH281 did not produce any significant changes in epileptiform burst frequency in any of the three models examined (120 ± 30 %, 144 ± 74 % and 114 ± 35 %; all p>0.05; n=10-17). Conversely, co-application of 10μM oxotremorine-M significantly increased epileptiform burst frequency in all models investigated (180 ± 34 %, 401 ± 108 % and 148 ± 21 %; all p<0.05; n = 8-10). Moreover, in the majority of slices tested, 10μM oxotremorine-M converted the network from inter-ictal-like bursting behaviour to prolonged ictal-like patterns of activity (n=15 of 24, 9 of 13 and 11 of 16 slices for 4AP, bicuculline and 0mM Mg2+ models respectively). These results suggest that, in contrast to the broad spectrum mAChR agonist oxotremorine-M, the selective M1 receptor agonist 77LH281 does not display a propensity to induce, or enhance, epileptiform activity.
Life Sciences 2007 (2007) Proc Life Sciences, PC44
Poster Communications: A study comparing the pro-epileptogenic actions of a non-selective muscarinic acetylcholine receptor agonist and a specific M1 receptor agonist in vitro
J. R. Broad1, C. H. Davies1, 2, S. R. Cobb1
1. Div. of Neuroscience and Biomedical Systems, IBLS, Glasgow University, Glasgow, United Kingdom. 2. Psychiatry CEDD , GlaxoSmithKline, Harlow, United Kingdom.
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Where applicable, experiments conform with Society ethical requirements.