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Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6 subunit-containing GABAA receptors in the cerebellum

Authors
  • Liao, Yu-Hsiang1
  • Lee, Hsin-Jung2
  • Huang, Wei-Jan3
  • Fan, Pi-Chuan4
  • Chiou, Lih-Chu1, 2, 5, 6
  • 1 National Taiwan University, Graduate Institute of Pharmacology, College of Medicine, Taipei, Taiwan , Taipei (Taiwan)
  • 2 National Taiwan University, Department of Pharmacology, College of Medicine, No. 1, Jen-Ai Rd., Section 1, Taipei, 100, Taiwan , Taipei (Taiwan)
  • 3 Taipei Medical University, Graduate Institute of Pharmacognosy, Taipei, Taiwan , Taipei (Taiwan)
  • 4 National Taiwan University Hospital, Department of Pediatrics, Taipei, Taiwan , Taipei (Taiwan)
  • 5 National Taiwan University, Graduate Institute of Brain and Mind Sciences, College of Medicine, Taipei, Taiwan , Taipei (Taiwan)
  • 6 China Medical University, Research Center for Chinese Medicine and Acupuncture, Taichung, Taiwan , Taichung (Taiwan)
Type
Published Article
Journal
Psychopharmacology
Publication Date
Jul 06, 2016
Volume
233
Issue
17
Pages
3187–3199
Identifiers
DOI: 10.1007/s00213-016-4365-z
Source
Springer Nature
Keywords
License
Yellow

Abstract

RationaleHispidulin is a flavonoid we isolated from Clerodendrum inerme, an herb that effectively remitted a case of intractable motor tic disorders. Hispidulin was shown to be a positive allosteric modulator (PAM) of GABAA receptors, including the α6 subunit-containing subtype (α6GABAAR) that is predominantly expressed in cerebellar granule cells and insensitive to diazepam.ObjectivesWe explored the action mechanism(s) of hispidulin using hyperdopaminergic mouse models induced by methamphetamine and apomorphine, based on the hyperdopaminergic nature of tic disorders.ResultsHispidulin significantly inhibited methamphetamine-induced hyperlocomotion (MIH) at i.p. doses without affecting apomorphine-induced hyperlocomotion and stereotypy behaviors or having significant benzodiazepine-like effects (BZLE), including sedation, anxiety, and motor impairment. When given by intracerebellar (i.c.b.) microinjection, hispidulin also alleviated MIH and this effect was prevented by i.c.b. coadministration of furosemide, an α6GABAAR antagonist, and mimicked by i.c.b. Ro 15-4513, an α6GABAAR PAM. Conversely, i.c.b. diazepam did not affect MIH while it reduced MIH at i.p. doses having significant BZLE. In a screening assay for 92 neurotransmitter receptors/degradation enzymes/transporters, hispidulin displayed significant (>50 % inhibition of radiolabeled ligand binding at 10 μM) binding affinity only at the benzodiazepine binding site of GABAARs (IC50 0.73∼1.78 μM) and catecholamine-o-methyl-transferase (COMT) (IC50 1.32 μM). OR-486, a more potent COMT inhibitor than hispidulin, did not affect MIH.ConclusionsIt is suggested that hispidulin alleviates MIH via acting as a PAM of cerebellar α6GABAARs, but not through COMT inhibition or affecting dopamine receptor responsiveness. Thus, selective α6GABAAR PAMs may have the potential to be a novel treatment for hyperdopaminergic disorders.

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