Summary
The effects of various α-adrenoceptorblocking drugs on the depression of exploratory activity (ambulation and rearing) induced by 0.1 mg/kg i.p. clonidine were investigated in the rat. In parallel experiments, the effects of the same drugs on pre- and postsynaptic α-receptors were determined in vitro (field-stimulated cortex slices and isolated vas deferens of the rat, respectively). Tolazoline, esproquine, yohimbine and piperoxan distinctly antagonized the inhibition of exploration produced by clonidine. All these drugs were found to possess relatively higher selectivity for the presynaptic α-receptors, as judged by the ratios of the concentrations inducing a 50% increase in field-stimulated 3H-noradrenaline-overflow and the concentrations required to shift the EC50 for the antagonism of noradrenaline-induced contractions of the vas deferens to the right by a factor of 2 (pA2, ratio <1): In contrast, phentolamine and phenoxybenzamine which showed preferential postsynaptic α-receptor blocking activity (ratio>1), potentiated rather than antagonized the effects of clonidine. Mianserin, although preferentially blocking the postsynaptic receptors, had no effect on clonidine-induced hypoactivity up to the high dose of 100 mg/kg i.p., probably because of its additional NA-uptake-inhibiting properties. The antagonism of clonidine by the selective presynaptic α-receptor blockers was observed within a limited dose-range. Increasing the doses above an optimal level, which varied from one compound to another, resulted in a decrease in the effect. It is suggested that this phenomenon reflects the counter-balancing postsynaptic α-adrenoceptor blockade occuring at higher concentrations of these drugs. In general, the results show a fairly good correlation between antagonism of clonidine in vivo and preferential blockade of presynaptic α-receptors in vitro. Clonidine-induced suppression of exploration therefore seems to be a valuable model for the investigation of drug interactions with α-adrenergic receptors in the central nervous system.
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Delini-Stula, A., Baumann, P. & Büch, O. Depression of exploratory activity by clonidine in rats as a model for the detection of relative pre- and postsynaptic central noradrenergic receptor selectivity of α-adrenolytic drugs. Naunyn-Schmiedeberg's Arch. Pharmacol. 307, 115–122 (1979). https://doi.org/10.1007/BF00498452
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DOI: https://doi.org/10.1007/BF00498452