Exploring the pharmacology of the pro-convulsant effects of α2-adrenoceptor antagonists in mice
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.
Key wordsElectroshock seizure threshold Selective α2- adrenoceptor antagonists Noradrenaline α1-adrenoceptors α2-adrenoceptors β-adrenoceptors Mice
Unable to display preview. Download preview PDF.
- Crunelli V, Cervo L, Samanin R (1981) Evidence for a preferential role of central noradrenergic neurons in electrically induced convulsions and activity of various anticonvulsants in the rat. In: Morselli PL, Lloyd KG, Loscher W, Meldrum B, Reynolds EH (eds) Neurotransmitters, seizures and epilepsy. Raven Press, New York, pp 195–202Google Scholar
- Doxey JC, Lane AC, Roach AG, Smith CFC, Walter DS (1985) Selective α2-adrenoceptor agonists and antagonists. In: Szabadi E, Bradshaw CM, Nahorski SR (eds) Pharmacology of adrenoceptors. MacMillan, New York, pp 13–22Google Scholar
- Finney, DJ (1971) Probit analysis. Cambridge University Press, CambridgeGoogle Scholar
- Fletcher A, Forster EA (1984) Proconvulsant actions of selective α2-adrenoceptor antagonists. Br J Pharmacol 81:39PGoogle Scholar
- Fuxe K, Ungerstedt U (1968) Histochemical studies on the effect of (+)-amphetamine, drugs of the imipramine group and trypamine on central catecholamine and 5-hydroxytryptamine neurons after intraventricular injection of catecholamine and 5-hydroxytryptamine. Eur J Pharmacol 4:135–144PubMedGoogle Scholar
- Gadie B, Tulloch IF (1985) Proconvulsant action of α2-adrenoceptor antagonists in mice: possible involvement of α1-adrenoceptors. Br J Pharmacol 84:192PGoogle Scholar
- Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113Google Scholar
- Lloyd KG, Worms P (1982) Differential effect of yohimbine in several chemical models of convulsions in mice. Br J Pharmacol 77:340PGoogle Scholar
- Mallard N, Tyacke R, Hudson AL, Nutt DJ (1991) Comparative binding studies of [3H]-idazoxan and [3H]-RX821002 in the rat brain. Br J Pharmacol 102:221PGoogle Scholar
- Stern MB, Wood JH (1984) Norepinephrine in epilepsy. In: Ziegler MG, Lake CR (eds) Norepinephrine. Williams & Wilkins, Baltimore, pp 142–159Google Scholar
- Swinyard EA (1972) Electrically induced convulsions. In: Purpura DP, Penry JK, Tower DB, Woodbury DM, Walter RD (eds) Experimental models of epilepsy-a manual for the laboratory worker. Raven Press, New York, pp 433–458Google Scholar