Pharmacological and neurochemical characterization of the involvement of hippocampal adrenoreceptor subtypes in the modulation of acute limbic seizures

Abstract

Noradrenaline exerts inhibitory effects on seizure susceptibility. Subtype selective agonists and antagonists were used to identify the anticonvulsant hippocampal adrenoreceptors. Intrahippocampal dialysis was used for administration of all compounds, including pilocarpine for limbic seizure induction, and as the neurotransmitter sampling tool. The noradrenaline reuptake inhibitor maprotiline mediated anticonvulsant effects, associated with dose-dependent increases in extracellular hippocampal noradrenaline, dopamine and GABA levels. At high concentrations, maprotiline produced proconvulsant effects associated with high levels of noradrenaline, dopamine and glutamate. Maprotiline's anticonvulsant effect was blocked by administration of either a selective alpha(2)- and beta(2)-antagonist. alpha(2)-Antagonist administration with maprotiline was associated with a further increase in noradrenaline and dopamine from maprotiline alone; whereas beta(2)-antagonist administered with maprotiline inhibited the dopamine increases produced by maprotiline. alpha(1A)-Antagonism blocked the GABA-ergic but not the anticonvulsive effect of maprotiline. These results were confirmed as combined but not separate alpha(2)- and beta(2)-adrenoreceptor stimulation, using selective agonists, inhibited limbic seizures. Interestingly, alpha(1A)-receptor stimulation and alpha(1D)-antagonism alone also inhibited seizures associated with respectively significant hippocampal GABA increases and glutamate decreases. The main findings of this study are that (i) increased hippocampal noradrenergic neurotransmission inhibits limbic seizures via combined alpha(2)- and beta(2)-receptor activation and (ii) alpha(1A)- and alpha(1D)-adrenoreceptors mediate opposite effects on hippocampal excitability

Additional Antiepileptic Mechanisms of Levetiracetam in Lithium-Pilocarpine Treated Rats

“…The enhancement of noradrenaline by the anticonvulsant could be attributed to increased synthesis and/or reduction in its metabolism as previously elucidated in a PIL seizure model [52], a fact that may entail the effect of LEV on dopamine. Notably, β 2 adrenergic receptor activation increases hippocampal dopamine level that stimulates D 2 receptor to prevent epileptogenesis [53,54]. Meanwhile, the activation of α 1A adrenergic receptor increases hippocampal GABA to inhibit limbic seizures [54].…”

“…Notably, β 2 adrenergic receptor activation increases hippocampal dopamine level that stimulates D 2 receptor to prevent epileptogenesis [53,54]. Meanwhile, the activation of α 1A adrenergic receptor increases hippocampal GABA to inhibit limbic seizures [54]. The latter event aggregates additively to halt excitotoxicity [55] giving a further insight to the anticonvulsant effect of LEV.…”

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Interestingly, combined but not separate α 2 - and β 2 -AR stimulation inhibited limbic seizures induced by pilocarpine infusion in the hippocampus of rats. On the other hand, α 1A -AR stimulation and α 1D -AR antagonism alone also inhibited seizures associated with respectively significant hippocampal GABA increases and GLU decreases (Clinckers et al, 2010). …”

The antidepressants citalopram and reboxetine reduce seizure frequency in rats with chronic epilepsy

“…Under these conditions overactivation of monoaminergic signaling is likely to result in the activation of additional biologic pathways that may be proconvulsant. Indeed, we demonstrated previously that high hippocampal levels of monoaminergic neurotransmitters nonspecifically promote glutamate release leading to increased excitability and proconvulsant effects (Clinckers et al., 2004, 2005, 2010). In contrast, in the same studies, we showed that moderate monoamine increases, as attained during treatment with therapeutic concentrations of monoaminergic antidepressants, have an anticonvulsant effect.…”