EXPLORING THE PHARMACOLOGY OF THE PRO-CONVULSANT EFFECTS OF ALPHA-2-ADRENOCEPTOR ANTAGONISTS IN MICE

The effects of selective and specific alpha-2-adrenoceptor antagonists on electroshock seizure threshold in mice were investigated. Idazoxan, at low doses, efaroxan, RX811059 and RX821002 significantly lowered seizure threshold. The alpha-1-agonist St 587 and the beta-agonist isoprenaline were also pro-convulsant. On the other hand the alpha-2-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 alpha-2-adrenoceptors. The pro-convulsant action of alpha-2-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 alpha-2-receptors and/or b) increased activation of alpha-1- and beta-adrenoceptors by elevated synaptic noradrenaline levels following blockade of pre-synaptic alpha-2-adrenoceptors. Of the alpha-2-antagonists tested, idazoxan was unusual in that high doses were not pro-convulsant; this difference may be explained by alpha-1-adrenoceptor mediated actions or be related to its recently described affinity at a non-adrenoceptor site - a function for which is currently unknown.