Pharmacological and neurochemical characterization of the involvement of hippocampal adrenoreceptor subtypes in the modulation of acute limbic seizures.
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 α(2) - and β(2) -antagonist. α(2) -Antagonist administration with maprotiline was associated with a further increase in noradrenaline and dopamine from maprotiline alone; whereas β(2) -antagonist administered with maprotiline inhibited the dopamine increases produced by maprotiline. α(1A) -Antagonism blocked the GABA-ergic but not the anticonvulsive effect of maprotiline. These results were confirmed as combined but not separate α(2) - and β(2) -adrenoreceptor stimulation, using selective agonists, inhibited limbic seizures. Interestingly, α(1A) -receptor stimulation and α(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 α(2) - and β(2) -receptor activation and (ii) α(1A) - and α(1D) -adrenoreceptors mediate opposite effects on hippocampal excitability.
Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium. Ralph.Clinckers@vub.ac.be
Ralph
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Clinckers
Tine
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Zgavc
Katia
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Vermoesen
Alfred
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Meurs
Yvette
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Michotte
Ilse
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Smolders
D000322:Adrenergic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018674:Adrenergic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008032:Limbic System / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D021122:Protein Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism*
D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D021122:Protein Subunits; D011941:Receptors, Adrenergic; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D018343:Receptors, Adrenergic, beta-2