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.
Table 1.
Comparison of Harmaline Rodent Tremor Model and Essential Tremor
| Feature | Harmaline Tremor | Essential Tremor |
| Clinical | ||
| Action tremor | Yes | Yes |
| Time course | Acute | Chronic |
| Inducing agent | Pharmacologic | Probably neurodegenerative |
| Role of inferior olive | Definite | Uncertain |
| Cerebellar hypermetabolism | Yes | Yes |
| Response to drugs | ||
| Caffeine | Worsens | Worsens in some |
| Citalopram, imipramine | Worsens | Worsens in some |
| Phenoxybenzamine | Does not suppress | Does not suppress |
| Anticholinergics | Do not suppress | Do not suppress |
| Levetiracetam | Does not suppress | Does not suppress |
| Primidone | Suppresses | Suppresses in some |
| Clonazepam, diazepam | Suppresses | Suppresses in some |
| Gabapentin | Suppresses | Suppresses in some |
| Carbamazepine | Suppresses | Does not suppress |
| Valproate | Suppresses | Does not suppress/worsens |
| Zonisamide | Suppresses | Suppresses in some |
| Lacosamide | Suppresses | Does not suppress |
| Carisbamate | Suppresses | Does not suppress |
| Propranolol | Suppresses | Suppresses in some |
| l-dopa, DA agonists | Suppresses | Do not suppress |
| Ethanol | Suppresses | Suppresses in some |
| Gamma-hydroxybutyrate | Suppresses | Suppresses in some |
| Lithium | Suppresses | Does not suppress/worsens |
| 1-Octanol | Suppresses | Suppresses in some |
| Memantine | Weakly suppreses | Weak or no suppression |
| MK-0249 | Suppresses | Does not suppress |