Complete characterisation of the involvement of hippocampal noradrenergic receptor subtypes in the modulation of acute seizures.

Affective disorders and the epilepsies appear to share partially similar pathogenic mechanisms. A component of the shared predisposition arises from innate monoaminergic deficits. In the past, we characterised the anticonvulsant properties of the hippocampal dopamine and serotonin system. The present in vivo microdialysis study was undertaken to evaluate the anticonvulsant properties of the hippocampal noradrenergic system. More precisely, this study aimed at characterising the involvement of all adrenoreceptor subtypes expressed in the rat hippocampus in seizure suppression. In vivo microdialysis experiments were performed on freely moving rats. Limbic seizures were induced by intrahippocampale perfusion of pilocarpine, a muscarinergic agonist. Neurochemical changes were monitored and correlated with seizure-related behavioural changes. Intrahippocampal perfusion of the antidepressant maprotiline, a noradrenaline reuptake blocker, was tested for its anticonvulsant properties against limbic seizures. Different subtype selective adrenoreceptor antagonists (5-methylurapidil (a1A), BMY-7378 (a1D), SKF86466 (a2), BRL-44408 (a2A) and MK-912 (a2C), betaxolol (b1), and ICI-118551 (b2)) were administered both separately and in co-perfusion with maprotiline. Intrahippocampal maprotiline perfusion completely prevented pilocarpine-induced seizure activity. This effect was associated with significant increases in extracellular hippocampal noradrenaline, dopamine and GABA levels. a2 antagonism completely blocked this anticonvulsant effect, while selective a2A and a2C antagonism only partially blocked the anticonvulsant effect. Both the anticonvulsant and dopaminergic effect of maprotiline were abolished by b2 antagonism, while b1 antagonism was ineffective. Finally, a1A and a1D antagonism independently prevented development of limbic seizure activity. Additionally, the maprotiline-induced GABA-ergic effect was blocked by a1A and a1D antagonism without influence on the anticonvulsant effect. To conclude, the antidepressant maprotiline mediates potent anticonvulsant effects following intrahippocampal administration via a2 and b2-adrenoreceptor stimulation. Noradrenergic modulation of hippocampal dopamine and GABA release is mediated by b2 and a1 receptors respectively. The current results suggest that hippocampal dopaminergic and GABA-ergc modulation do not significantly contribute to the anticonvulsant effect of maprotiline. In view of the important co-morbidity of epilepsy and depression, maprotiline may be useful not only for the treatment of depression, but also for the treatment of concomitant epilepsy. Finally, highly selective a1A and a1D antagonists are potent anticonvulsant agents.