Considerations Using Harmaline for a Primate Model of Tremor

Background: While harmaline has been used as a pharmacological model of essential tremor (ET) in rodents and pigs, less is known about the effects of this pharmacological treatment in awake-behaving non-human primates. In this study, we investigated the time-course, amplitude, frequency, and consistency of harmaline tremor in primates. Methods: Three rhesus macaques were administered doses of harmaline ranging from 2-12 mg/kg (i.m.), and tremorous movements were quantified with accelerometers. One subject was also trained to perform a self-paced cued reaching task, with task engagement assessed under harmaline doses ranging from 2-8 mg/kg (i.m.). Results: Whole-body tremors manifested within 30 minutes of threshold-dose administration, and peak oscillatory frequency ranged between 10-14 Hz. However, large differences in tremor intensity and intermittency were observed across individual subjects under similar dosing levels. Additionally, engagement with the reaching task was dependent on harmaline dose, with performance mostly unaffected at 2 mg/kg and with little task-engagement at 8 mg/kg. Discussion: We provide a detailed assessment of factors that may underlie the heterogeneous responses to harmaline, and lay out important caveats towards the applicability of the behaving harmaline-tremoring non-human primate as a preclinical model for ET. Highlights The harmaline-primate is revisited for its potential as a preclinical model of tremor. Spontaneous tremor was heterogenous in amplitude across subjects despite similar harmaline doses, action tremors were not consistently observed, and performance on a behavioral task degraded with higher dosages.