Abstracts

Rationale: Noradrenaline acts as endogenous anticonvulsant as it exerts profound inhibitory effects on seizure susceptibility. The identification of a universal anticonvulsant adrenoreceptor was impeded by conflicting results from pharmacological investigations in which non-selective agents were used. We here used subtype selective compounds to delineate the role of hippocampal adrenoreceptor subtypes in seizure susceptibility. Methods: Intracerebral microdialysis was used for intrahippocampal administration of all compounds and as neurotransmitter sampling tool. The modulatory effects on pilocarpine-induced limbic seizures were behaviourally assessed. Concentration response experiments were performed to determine the anticonvulsant and neurochemical properties of maprotiline, a noradrenaline reuptake inhibitor. Co-perfusion experiments of anticonvulsant concentrations (250nM) of maprotiline were conducted with subtype selective antagonists for α_1A (5-methylurapidil), α_1D (BMY-7378), α_2A (BRL-44408), α_2C (MK-912), β₁ (betaxolol), β₂ (ICI-118551) and D₂ (remoxipride) receptors. Finally, selective agonists for α₂ (medetomidine) and β₂ (salmeterol) receptors were tested to confirm our working hypothesis. Results: Maprotiline mediated anticonvulsant effects, associated with increases in extracellular hippocampal noradrenaline, dopamine and GABA levels. The anticonvulsant effect was blocked independently by α₂ and β₂ antagonism. β₂ antagonism inhibited the dopamine increases, while α_1A antagonism blocked the GABA-ergic but not the anticonvulsive effect. Antagonism of hippocampal D₂ receptors, which have been shown to mediate the anticonvulsant effect of dopamine, did not affect the anticonvulsant effect of maprotiline. Combined and not separate α₂ and β₂ agonism inhibited pilocarpine-induced seizures. Conclusions: Hippocampal noradrenaline increases inhibit limbic seizures via combined α₂ and β₂ receptor activation. The concomitant GABA-ergic and dopaminergic effects are not crucially involved in this anticonvulsant effect. These data demonstrate that the noradrenergic system is an interesting target for innovative antiepileptic treatment.