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

Yu Hsiang Liao, Hsin Jung Lee, Wei Jan Huang, Pi Chuan Fan, Lih Chu Chiou

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Rationale: Hispidulin 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. Objectives: We explored the action mechanism(s) of hispidulin using hyperdopaminergic mouse models induced by methamphetamine and apomorphine, based on the hyperdopaminergic nature of tic disorders. Results: Hispidulin 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. Conclusions: It 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.

Original languageEnglish
Pages (from-to)3187-3199
Number of pages13
JournalPsychopharmacology
Volume233
Issue number17
DOIs
Publication statusPublished - Sep 1 2016

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Methamphetamine
GABA-A Receptors
Cerebellum
Transferases
Benzodiazepines
Tic Disorders
Catecholamines
Apomorphine
Diazepam
Inhibitory Concentration 50
Clerodendrum
Neurotransmitter Receptor
hispidulin
Furosemide
Dopamine Receptors
Microinjections
Flavonoids
Anxiety
Binding Sites
Ligands

Keywords

  • Cerebellum
  • Dopamine
  • Flavonoid
  • GABA receptor
  • Hispidulin
  • Tourrette syndrome

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmacology

Cite this

Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6 subunit-containing GABAA receptors in the cerebellum. / Liao, Yu Hsiang; Lee, Hsin Jung; Huang, Wei Jan; Fan, Pi Chuan; Chiou, Lih Chu.

In: Psychopharmacology, Vol. 233, No. 17, 01.09.2016, p. 3187-3199.

Research output: Contribution to journalArticle

Liao, Yu Hsiang ; Lee, Hsin Jung ; Huang, Wei Jan ; Fan, Pi Chuan ; Chiou, Lih Chu. / Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6 subunit-containing GABAA receptors in the cerebellum. In: Psychopharmacology. 2016 ; Vol. 233, No. 17. pp. 3187-3199.
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AU - Fan, Pi Chuan

AU - Chiou, Lih Chu

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N2 - Rationale: Hispidulin 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. Objectives: We explored the action mechanism(s) of hispidulin using hyperdopaminergic mouse models induced by methamphetamine and apomorphine, based on the hyperdopaminergic nature of tic disorders. Results: Hispidulin 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. Conclusions: It 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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KW - Tourrette syndrome

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