Sigma 1 receptor-mediated increase in hippocampal extracellular dopamine contributes to the mechanism of the anticonvulsant action of neuropeptide Y.

Alfred Meurs, Ralph Clinckers, Guy Ebinger, Yvette Michotte, Ilse Julia Smolders

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

The potent anticonvulsant properties of neuropeptide Y (NPY) are generally to a Y2 receptor-mediated inhibition of glutamatergic synaptic transmission. Independent studies have shown that NPY increases brain dopamine content, possibly via interaction with sigma 1 receptors. Recently, we showed that increased extracellular hippocampal dopamine attenuates pilocarpine-induced limbic seizures via activation of hippocampal D2 receptors. Our aim in this study was to elucidate the role of increased hippocampal dopamine in the mechanism of the anticonvulsant action of NPY and to investigate the involvement of Y2 and sigma 1 receptors in this process. Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. NPY was administered intracerebroventricularly, intrahippocampally via the microdialysis probe, or coadministered intrahippocampally with the D2 receptor antagonist remoxipride, the Y2 receptor antagonist BIIE0246 or the sigma 1 receptor antagonist BD1047. Changes in hippocampal extracellular dopamine were monitored, and behavioural changes indicative of seizure activity were scored. Intracerebroventricular (10 nmol/3 µL) and intrahippocampal (20-50 µM) NPY administration increased hippocampal dopamine and attenuated pilocarpine-induced seizures. Hippocampal D2 receptor blockade (4 µM remoxipride) reversed the anticonvulsant effect of NPY. Y2 receptor blockade (1 µM BIIE0246) reversed the anticonvulsant effect of NPY but did not prevent NPY-induced increases in hippocampal dopamine. Sigma 1 receptor blockade (10 µM BD1047) abolished NPY-induced increases in hippocampal dopamine are mediated via sigma 1 receptors and contribute to the anticonvulsant effect of NPY via increased activation of hippocampal D2 receptors. This novel mechanism of anticonvulsant action of NPY is separate from, and may be complementary to, the well established Y2 receptor-mediated inhibition of hippocampal excitability.
Original languageEnglish
Pages (from-to)3079-3092
Number of pages14
JournalEuropean Journal of Neuroscience
Volume26
Publication statusPublished - 2007

Keywords

  • hippocampus, microdialysis, rat, seizure
  • epilepsy
  • neuropeptide

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