The mechanism of action of α2 adrenoceptor blockers as revealed by effects on open field locomotion and escape reactions in the shuttle-box

Abstract

The precise mechanism of action of α₂ adrenoceptor blockers is not known, although in principle they have two main effects: (i) they stimulate the norepinephrinergic system by inhibiting the negative feed back of norepinephrine release (presynaptic effect) and (ii) they inhibit the effects of norepinephrine on postsynaptic α₂ adrenoceptors. We postulate that if the presynaptic actions of the antagonists prevail, the enhanced norepinephrine release leads to an activation of postsynaptic α₁ or β adrenoceptors. In this case the effects of α₂ adrenoceptor blockers can be reversed by antagonists acting on the latter two adrenoceptors, since postsynaptic α₂ adrenoceptors are also blocked. If the postsynaptic blockade of α₂ adrenoceptors is the main cause of effects, than the blockade of α₁ or β adrenoceptors should not reverse the action of α₂ blockers. The α₂ blocker idazoxan (dose 0.5–5 mg/kg) increased locomotor activity in an open field, an effect that was abolished by both α₁ and β receptor blockers (prazosin and propranolol, respectively). Escape responses in a shuttle box were strongly suppressed by idazoxan (0.5–2 mg/kg). However, this effect was not changed by concomitant α₁ or β receptor blockade. These results suggest that the mechanism of action of α₂ adrenoceptor blockers depends on which effects are studied. Exploration seems to be affected by a presynaptic mechanism as neurons bearing postsynaptic α₁ or β adrenoceptors are involved in the control of this behavior, while escape reactions appear to be affected by the postsynaptic blockade of α₂ adrenoceptors (i.e. neurons bearing postsynaptic α₂ adrenoceptors are involved in its control). Thus, there is no generalized mechanism of action for α₂ adrenoceptor blockers; their precise mode of action should be investigated in each particular case.