The anticonvulsant and proconvulsant effects of adrenoreceptor agonists are mediated by distinct populations of alpha(2A)-adrenoreceptors

The alpha(2)-adrenoreceptor (AR) is the most investigated noradrenergic receptor with regard to modulation of seizure activity. However, because of the complexity of multiple alpha(2)-AR subtypes and their distribution, the exact role of this receptor in modulating seizure activity is not clear. alpha(2A)- and alpha(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 alpha(2)-AR agonist clonidine produced a proconvulsant effect on seizure susceptibility, while the selective alpha(2A)-AR agonist guanfacine was anticonvulsant. The effects of both alpha(2)-AR agonists were absent in alpha(2a)-knockout mice, suggesting that the alpha(2A)-AR mediates the proconvulsant and anticonvulsant effect of alpha(2)-AR agonists on seizure susceptibility. To determine whether the alpha(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 beta-hydroxylase knockout (Dbh -/-) mice that lack NE. The anticonvulsant effect of guanfacine persisted in Dbh -/- mice, suggesting that guanfacine may act preferentially on alpha(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 alpha(2A)-presynaptic autoreceptor is responsible for the proconvulsant effect Of alpha(2)-AR agonists, while the alpha(2A)-Postsynaptic receptor is responsible for the anticonvulsant effect of alpha(2)-AR agonists. These data help to clarify the inconsistent effects of alpha(2)-AR agonists on seizure activity. Published by Elsevier Ltd on behalf of IBRO.