Essential tremor (ET) is among the most prevalent
neurological disorders and the most common cause of abnormal
tremors. It is characterized by postural and
action tremors ranging from 4 to 12 Hz. The treatments of choice for ET are
propranolol and
primidone, but their use is associated with adverse effects like
hypotension, depression, and
cognitive impairments.
Benzodiazepines, which nonselectively enhances the effect of
GABA at the GABAA α1/2/3/5 receptors, have been shown to be effective in treating ET. Their use, however, is limited due to sedation,
ataxia, tolerance development and memory impairment. Sedation and
ataxia are attributed to the activity at the α1 subunit while
cognitive impairment is ascribed to the action on the α5 subunit of the GABAA receptors. It can be hypothesized that subtype selective GABAA receptor modulators only acting via the α2, and α3 subunits may have an improved side effect profile while retaining the beneficial effects. Here, we have evaluated the effect of subtype selective GABAA α2/3/5 receptor modulators on
harmaline-induced
tremors in rats. The
tremors were automatically quantified in
tremor boxes. We show that the GABAA α2/3 subtype selective modulator
NS16085 significantly and dose-dependently inhibits
harmaline-induced
tremors in rats, indicating that potentiation of α2- and α3-containing GABAA receptors is sufficient to ameliorate
harmaline-induced
tremors. These results provide the first support for a therapeutic role of a subtype selective GABAA α2/3 modulator in the treatment of ET.