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 alpha 1- and alpha 2-adrenoceptor subtype binding, central alpha 2-adrenoceptor antagonist potency, as well as effects on brain neurochemistry and behavioural pharmacology of two alpha 2-adrenoceptor antagonists, atipamezole and yohimbine. Atipamezole had higher selectivity for alpha 2- vs. alpha 1-adrenoceptors than yohimbine regardless of the subtypes studied. Both compounds had comparable affinity for the alpha 2A-, alpha 2C- and alpha 2B-adrenoceptors, but yohimbine had significantly lower affinity for the alpha 2D-subtype. This may account for the fact that significantly higher doses of yohimbine than atipamezole were needed for reversal of alpha 2-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 alpha 2-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 (> or = 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 (> or = 3 mg/kg) decreased exploratory behaviour. The dissimilar effects of the antagonists on neurochemistry and behaviour are thought to be caused by non alpha 2-adrenoceptor properties of yohimbine. In conclusion, the alpha 2-antagonist atipamezole blocked all alpha 2-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 alpha 2D-adrenoceptor combined with its unspecific effects complicates the use of yohimbine as pharmacological tool to study alpha 2-adrenoceptor physiology and pharmacology.

Genetic alteration of the α2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels

“…Furthermore, binding of many purportedly selective ␣ 2 -AR antagonists to other receptors, such as 5-HT 1A -receptors, may be an additional confounding factor. 43 We speculate that subtype non-selective ␣ 2 -AR antagonists could induce excessive arousal via the LC, perhaps leading to feelings of anxiety. The current results suggest that a selective ␣ 2C -AR antagonist might have antidepressant-like actions without prominent NE-releasing and anxiogenic properties.…”

Comparison of the effects of acute and subchronic administration of atipamezole on reaction to novelty and active avoidance learning in rats

“…Atipamezole is an α 2 -adrenoceptor antagonist that has a high α 2 /α 1 -selectivity ratio and does not display differential affinity for α 2 -adrenoceptor subtypes (Virtanen et al 1989;Haapalinna et al 1997). It has negligible affinity for the non-adrenoceptor [ 3 H]idazoxan binding sites (imidazoline I 2 -sites; Savontaus et al 1997).…”

“…In contrast to other α 2 -adrenoceptor antagonists, atipamezole does not have affinity for 5-HT 1A receptors (Llado et al 1996;Meana et al 1996;Newman et al 1998). This receptor specificity is reflected throughout its pharmacology (Virtanen et al 1989;Yavich et al 1994;Haapalinna et al 1997), evidencing that atipamezole has no marked effects on systems other than α 2 -adrenoceptors and is well tolerated over a wide dosage range. Thus it can be viewed as a specific pharmacological tool with which to evaluate the effects of α 2 -adrenoceptor blockade in vivo.…”

“…Therefore, we studied the effects of continuous subchronic treatments with atipamezole on exploratory behaviour in a staircase test (Haapalinna et al 1997) and active avoidance learning (Haapalinna et al 1998) of male rats. The effects of selected acute doses were confirmed, because there were some modifications in the protocols in comparison with our previous studies and even minor modifications to behavioural protocols can have major consequences.…”

Infusion of Alpha-2-Adrenergic Agents into the Paraventricular and Arcuate Nuclei of the Hypothalamus in the Siberian Hamster: Opposing Effects on Basal Prolactin

“…Medetomidine has an α 2 /α 1 ratio of 1,620 – compared to clonidine (220) and detomidine (260). Atipamezole has an α 2 /α 1 ratio 200–300 times that of idazoxan and yohimbine [26, 27, 28, 29, 30]. …”