Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor

Abstract

Background: Harmaline and harmine are tremorigenic β-carbolines that, on administration to experimental animals, induce an acute postural and kinetic tremor of axial and truncal musculature. This drug-induced action tremor has been proposed as a model of essential tremor. Here we review what is known about harmaline tremor.

Methods: Using the terms harmaline and harmine on PubMed, we searched for papers describing the effects of these β-carbolines on mammalian tissue, animals, or humans.

Results: Investigations over four decades have shown that harmaline induces rhythmic burst-firing activity in the medial and dorsal accessory inferior olivary nuclei that is transmitted via climbing fibers to Purkinje cells and to the deep cerebellar nuclei, then to brainstem and spinal cord motoneurons. The critical structures required for tremor expression are the inferior olive, climbing fibers, and the deep cerebellar nuclei; Purkinje cells are not required. Enhanced synaptic norepinephrine or blockade of ionic glutamate receptors suppresses tremor, whereas enhanced synaptic serotonin exacerbates tremor. Benzodiazepines and muscimol suppress tremor. Alcohol suppresses harmaline tremor but exacerbates harmaline-associated neural damage. Recent investigations on the mechanism of harmaline tremor have focused on the T-type calcium channel.

Discussion: Like essential tremor, harmaline tremor involves the cerebellum, and classic medications for essential tremor have been found to suppress harmaline tremor, leading to utilization of the harmaline model for preclinical testing of antitremor drugs. Limitations are that the model is acute, unlike essential tremor, and only approximately half of the drugs reported to suppress harmaline tremor are subsequently found to suppress tremor in clinical trials.

Keywords: Tremor; animal model; cerebellum; harmaline; harmine; inferior olive.

Figure 1.. β-Carboline Structures.

Harmaline and harmine are used in animal models of tremor. Harmane, found in human tissue, can be converted to harmine.

Figure 2.. Recorded Motion.

Data are shown for example mouse prior to (A), and after intraperitoneal harmaline administration (B). The slow recording speed demonstrates tremor that fluctuates according to general motor activity. The fast recording speed shows that motion is dominated by tremor at 10-16 Hz. Motion between 0 and 34 Hz was detected with a load sensor under a platform and digitized, with filters at 1 and 70 Hz and sampling frequency of 128 Hz.

Figure 3.. The Olivocerebellar Circuit Implicated in the Generation and Expression of Harmaline Tremor.

The Olivocerebellar Circuit Implicated in the Generation and Expression of Harmaline Tremor. Synaptic bar endings connote inhibition, while arrowhead endings connote excitation. Harmaline elicits rhythmic bursting in clusters of inferior olivary neurons, synchronized via dendritic glomeruli. Climbing fibers excite complex spikes in Purkinje cells, which project GABA to both GABAergic and excitatory output deep cerebellar nucleus cells. These cells also receive collaterals from climbing fibers. The deep cerebellar nuclei project GABA to inferior olivary glomeruli, opposing synchrony. Glutamate receptor activation in the inferior olive promotes synchrony. The deep cerebellar nuclei and inferior olive are required for harmaline tremor expression; the absence of Purkinje cells reduces but does not abolish tremor. The deep cerebellar outflow to the brainstem and spinal cord is sufficient for harmaline tremor expression without the need for supratentorial structures.