Anti-Tremor Action of Subtype Selective Positive Allosteric Modulators of GABAA Receptors in a Rat Model of Essential Tremors

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 GABA(A) alpha 1/2/3/5 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 alpha 1 subunit while cognitive impairment is ascribed to the action on the alpha 5 subunit of the GABA(A) receptors. It can be hypothesized that subtype selective GABA(A) receptor modulators only acting via the alpha 2, and alpha 3 subunits may have an improved side effect profile while retaining the beneficial effects. Here, we have evaluated the effect of subtype selective GABA(A) alpha 2/3/5 receptor modulators on harmaline-induced tremors in rats. The tremors were automatically quantified in tremor boxes. We show that the GABA(A) alpha 2/3 subtype selective modulator NS16085 significantly and dose-dependently inhibits harmaline-induced tremors in rats, indicating that potentiation of alpha 2- and alpha 3-containing GABA(A) receptors is sufficient to ameliorate harmaline-induced tremors. These results provide the first support for a therapeutic role of a subtype selective GABA(A) alpha 2/3 modulator in the treatment of ET.