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

• Published in: Psychopharmacology Vol. 233; no. 17; pp. 3187 - 3199
• Main Authors: Liao, Yu-Hsiang, Lee, Hsin-Jung, Huang, Wei-Jan, Fan, Pi-Chuan, Chiou, Lih-Chu
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2016
• Subjects: Allosteric Regulation; Animals; Apomorphine - pharmacology; Azides - pharmacology; Behavior, Animal - drug effects; Benzodiazepines - pharmacology; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - metabolism; Central Nervous System Stimulants - pharmacology; Cerebellum - drug effects; Cerebellum - metabolism; Diazepam - pharmacology; Dopamine Agonists - pharmacology; Flavones - pharmacology; GABA Modulators - pharmacology; Humans; Locomotion - drug effects; Methamphetamine - pharmacology; Mice; Neurons - drug effects; Neurons - metabolism; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Synaptic Transmission - drug effects; Cerebellum; Tourrette syndrome; receptor; Dopamine; GABA; Hispidulin; Flavonoid; GABAA receptor
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4365-z

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 GABA A receptors, including the α 6 subunit-containing subtype (α 6 GABA A R) 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 α 6 GABA A R antagonist, and mimicked by i.c.b. Ro 15-4513, an α 6 GABA A R 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 GABA A Rs (IC 50 0.73∼1.78 μM) and catecholamine-o-methyl-transferase (COMT) (IC 50 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 α 6 GABA A Rs, but not through COMT inhibition or affecting dopamine receptor responsiveness. Thus, selective α 6 GABA A R PAMs may have the potential to be a novel treatment for hyperdopaminergic disorders.