Evaluation of the effects of a specific α2-adrenoceptor antagonist, atipamezole, on α1- and α2-adrenoceptor subtype binding, brain neurochemistry and behaviour in comparison with yohimbine

Abstract

In the present study we evaluated the α₁- and α₂-adrenoceptor subtype binding, central α₂-adrenoceptor antagonist potency, as well as effects on brain neurochemistry and behavioural pharmacology of two α₂-adrenoceptor antagonists, atipamezole and yohimbine. Atipamezole had higher selectivity for α₂- vs. α₁-adrenoceptors than yohimbine regardless of the subtypes studied. Both compounds had comparable affinity for the α_2A-, α_2C- and α_2B-adrenoceptors, but yohimbine had significantly lower affinity for the α_2D-subtype. This may account for the fact that significantly higher doses of yohimbine than atipamezole were needed for reversal of α₂-agonist (medetomidine) -induced effects in rats (mydriasis) and mice (sedation and hypothermia). The effect on central monoaminergic activity was estimated by measuring the concentrations of transmitters and their main metabolites in whole brain homogenate. At equally effective α₂-antagonising doses in the rat mydriasis model, both drugs stimulated central noradrenaline turnover (as reflected by increase in metabolite levels) to the same extent. Atipamezole increased dopaminergic activity only slightly, whereas yohimbine elevated central dopamine but decreased central 5-hydroxytryptamine turnover rates. In behavioural tests, atipamezole (0.1–10 mg/kg) did not affect motor activity but stimulated food rewarded operant (FR-10) responding (0.03–3 mg/kg) whereas yohimbine both stimulated (1 mg/kg) and decreased (≥ 3 mg/kg) behaviour in a narrow dose range in these tests. In the staircase test, both antagonists increased neophobia, but in the two compartment test only yohimbine (≥ 3 mg/kg) decreased exploratory behaviour. The dissimilar effects of the antagonists on neurochemistry and behaviour are thought to be caused by non α₂-adrenoceptor properties of yohimbine. In conclusion, the α₂-antagonist atipamezole blocked all α₂-adrenoceptor subtypes at low doses, stimulated central noradrenergic activity and had only slight effects on behaviour under familiar conditions, but increased neophobia. The low affinity for the α_2D-adrenoceptor combined with its unspecific effects complicates the use of yohimbine as pharmacological tool to study α₂-adrenoceptor physiology and pharmacology.