The anticonvulsant and proconvulsant effects of α 2-adrenoreceptor agonists are mediated by distinct populations of α 2a-adrenoreceptors

Abstract

The α 2-adrenoreceptor (AR) is the most investigated noradrenergic receptor with regard to modulation of seizure activity. However, because of the complexity of multiple α 2-AR subtypes and their distribution, the exact role of this receptor in modulating seizure activity is not clear. α 2A- and α 2C-ARs function as both autoreceptors (presynaptic) on noradrenergic neurons, where they regulate norepinephrine (NE) release, and as postsynaptic receptors on neurons that receive noradrenergic innervation, where they regulate the release of other neurotransmitters (heteroreceptor). The nonselective α 2-AR agonist clonidine produced a proconvulsant effect on seizure susceptibility, while the selective α 2A-AR agonist guanfacine was anticonvulsant. The effects of both α 2-AR agonists were absent in α 2a-knockout mice, suggesting that the α 2A-AR mediates the proconvulsant and anticonvulsant effect of α 2-AR agonists on seizure susceptibility. To determine whether the α 2-AR agonists were acting on inhibitory presynaptic autoreceptors to decrease NE release or on postsynaptic receptors on NE target neurons, the effects of clonidine and guanfacine were determined in dopamine β-hydroxylase knockout ( Dbh −/−) mice that lack NE. The anticonvulsant effect of guanfacine persisted in Dbh −/− mice, suggesting that guanfacine may act preferentially on α 2A-postsynaptic receptors that regulate the action of NE on target neurons. In contrast, the proconvulsant effect of clonidine was lost in Dbh −/− mice, suggesting that clonidine may act on presynaptic autoreceptors to decrease NE release. We hypothesize that the α 2A-presynaptic autoreceptor is responsible for the proconvulsant effect of α 2-AR agonists, while the α 2A-postsynaptic receptor is responsible for the anticonvulsant effect of α 2-AR agonists. These data help to clarify the inconsistent effects of α 2-AR agonists on seizure activity.