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Exploring the pharmacology of the pro-convulsant effects of α2-adrenoceptor antagonists in mice

Abstract

The effects of selective and specific α2-adrenoceptor antagonists on electroshock seizure threshold in mice were investigated. Idazoxan, at low doses, efaroxan, RX811059 and RX821002 significantly lowered seizure threshold. The α1-agonist St 587 and the β-agonist isoprenaline were also pro-convulsant. On the other hand the α2-agonists clonidine and UK 14,304 produced small increases in seizure threshold. Anticonvulsant effects were also produced by low doses of the noradrenaline uptake inhibitor desipramine. This compound increases levels of noradrenaline in the synaptic cleft which could subsequently act at post-synaptic α2-adrenoceptors. The pro-convulsant action of α2-adrenoceptor antagonists could be explained in terms of two mechanisms: a) blockade of endogenous noradrenaline which may normally exert a tonic anti-convulsant influence on seizure threshold, through post-synaptic α2-receptors and/or b) increased activation of α1- and β-adrenoceptors by elevated synaptic noradrenaline levels following blockade of pre-synaptic α2-adrenoceptors. Of the α2-antagonists tested, idazoxan was unusual in that high doses were not pro-convulsant; this difference may be explained by α1-adrenoceptor mediated actions or be related to its recently described affinity at a non-adrenoceptor site — a function for which is currently unknown.

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Jackson, H.C., Dickinson, S.L. & Nutt, D.J. Exploring the pharmacology of the pro-convulsant effects of α2-adrenoceptor antagonists in mice. Psychopharmacology 105, 558–562 (1991). https://doi.org/10.1007/BF02244380

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Key words

  • Electroshock seizure threshold
  • Selective α2- adrenoceptor antagonists
  • Noradrenaline
  • α1-adrenoceptors
  • α2-adrenoceptors
  • β-adrenoceptors
  • Mice