Cerebellar α6GABA Receptors as a Therapeutic Target for Essential Tremor: Proof-of-Concept Study with Ethanol and Pyrazoloquinolinones
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
Journal Volume
20
Journal Issue
2
Start Page
399
End Page
418
ISSN
1933-7213
Date Issued
2023-03
Author(s)
Huang, Ya-Hsien
Lee, Ming Tatt
Hsueh, Han-Yun
Knutson, Daniel E
Cook, James
Mihovilovic, Marko D
Sieghart, Werner
Abstract
Ethanol has been shown to suppress essential tremor (ET) in patients at low-to-moderate doses, but its mechanism(s) of action remain unknown. One of the ET hypotheses attributes the ET tremorgenesis to the over-activated firing of inferior olivary neurons, causing synchronic rhythmic firings of cerebellar Purkinje cells. Purkinje cells, however, also receive excitatory inputs from granule cells where the α6 subunit-containing GABA receptors (α6GABARs) are abundantly expressed. Since ethanol is a positive allosteric modulator (PAM) of α6GABARs, such action may mediate its anti-tremor effect. Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of ethanol and α6GABAR-selective pyrazoloquinolinone PAMs. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Ethanol significantly and dose-dependently attenuated action tremor at non-sedative doses (0.4-2.4 g/kg, i.p.). Propranolol and α6GABAR-selective pyrazoloquinolinones also significantly suppressed tremor activity. Neither ethanol nor propranolol, but only pyrazoloquinolinones, restored burrowing activity in harmaline-treated mice. Importantly, intra-cerebellar micro-injection of furosemide (an α6GABAR antagonist) had a trend of blocking the effect of pyrazoloquinolinone Compound 6 or ethanol on harmaline-induced tremor. In addition, the anti-tremor effects of Compound 6 and ethanol were synergistic. These results suggest that low doses of ethanol and α6GABAR-selective PAMs can attenuate action tremor, at least partially by modulating cerebellar α6GABARs. Thus, α6GABARs are potential therapeutic targets for ET, and α6GABAR-selective PAMs may be a potential mono- or add-on therapy.
Subjects
Cerebellum
Essential tremor
Ethanol
GABAA receptor α6 subunit
GABRA6
Harmaline
Type
journal article