+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Harmaline Tremor: Underlying Mechanisms in a Potential Animal Model of Essential Tremor

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.



          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.


          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.


          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.


          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.

          Related collections

          Most cited references 147

          • Record: found
          • Abstract: found
          • Article: not found

          Oscillatory properties of guinea-pig inferior olivary neurones and their pharmacological modulation: an in vitro study.

          The oscillatory properties of the membrane potential in inferior olivary neurones were studied in guinea-pig brain-stem slices maintained in vitro. Intracellular double-ramp current injection at frequencies of 1-20 Hz revealed that inferior olivary neurones tend to fire at two preferred frequencies: 3-6 Hz when the cells were actively depolarized (resting potential less than -50 mV), and 9-12 Hz when they were actively hyperpolarized (resting potential more than -75 mV). In 10% of the experiments spontaneous subthreshold oscillations of the membrane potential were observed. These oscillations, which resembled sinusoidal wave forms and had a frequency of 4-6 Hz and an amplitude of 5-10 mV, occurred synchronously in all cells tested within the slice. These oscillations persisted in the presence of 10(-4) M-tetrodotoxin and were blocked by Ca2+ conductance blockers or by the removal of Ca2+ from the bathing solution. The oscillations were affected by gross extracellular stimulation of the slice but not by intracellular activation of any given neurone. The data indicate that these oscillations reflect the properties of neuronal ensembles comprised of a large number of coupled elements. Similar ensemble oscillation could be induced, in most experiments, by adding harmaline (0.1 mg/ml) and serotonin (10(-4) M) to the bath and could be blocked by bath addition of noradrenaline. Harmaline was found to increase cell excitability by hyperpolarizing the neurones and shifting the inactivation curve for the somatic Ca2+ spike to a more positive membrane potential level. The role inferior olivary oscillations play in the organization of motor coordination is discussed.
            • Record: found
            • Abstract: found
            • Article: not found

            Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances.

            The electrophysiological properties of guinea-pig inferior olivary (I.O.) cells have been studied in an in vitro brain stem slice preparation. 1. Intracellular recordings from 185 neurones in this nucleus reveal that antidromic, orthodromic or direct stimulation generates action potentials consisting of a fast spike followed by an after-depolarizing potential (ADP). The ADP had an amplitude of 49 +/- 8 mV (mean +/- S.D.) and a duration which varied over a wide range with the level of depolarization. This ADP is followed by an after-hyperpolarizing potential (AHP) having an amplitude of 12 +/- 3 mV (mean +/- S.D.) from rest and lasting up to 250 msec. The AHP shows a rebound depolarization wave. 2. Synaptic activation may be obtained by peri-olivary stimulation with a bipolar electrode located in the immediate vicinity of the I.O. nucleus. These potentials are a mixture of depolarizing and hyperpolarizing synaptic events which can be reversed by direct membrane polarization. 3. Addition of tetrodotoxin (TTX) to the bath, or removal of extracellular Na, abolishes the fast initial action potential but does not modify the ADP or the AHP. Blockage of Ca conductance by Co, Mn, Cd or D600, or replacement of Ca by Mg, abolishes the ADP--AHP sequence. 4. Hyperpolarization of the neurone uncovers a low-threshold Ca conductance which is inactivated at rest and has similar pharmacological properties to the ADP. This low-threshold spike plays a central role in the rebound potential following the AHP. 5. Simultaneous impalement of I.O. neurone pairs demonstrated the presence of electrotonic coupling between neurones, which is especially prominent in the medial accessory olive.
              • Record: found
              • Abstract: found
              • Article: not found

              Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro.

              The electrophysiological properties of the high- and low-threshold Ca spikes described in inferior olivary neurones were analysed in detail. 1. During hyperpolarization the low- and high-threshold Ca action potentials can coexist as two distinct spikes, demonstrating non-mutual exclusion. 2. The high-threshold Ca spike shows a lack of refractoriness, is generated remotely from the site of recording and is composed of several all-or-none components, the last two properties suggesting a dendritic origin. 3. Hyperpolarization of the neurones allows the activation of the low-threshold Ca spike, which has activation properties resembling those of the early K conductance described in invertebrates. This low-threshold Ca spike shows refractoriness. 4. The relation between membrane polarization and low-threshold Ca spike is S-shaped. Low-threshold Ca spikes become apparent at -70 mV and have a maximum rate of rise (saturation) at polarization levels more negative than -85 mV. Thus, hyperpolarization removes a voltage-dependent Ca inactivation which is present at normal resting membrane potential (-65 mV). 5. Replacement of extracellular Ca by Ba or addition of tetraethylammonium to the bath corroborates the lack of fast inactivation for the high-threshold Ca spike and the inactivation properties of the low-threshold Ca conductance. It also demonstrates that the duration of the after-depolarization is determined by an interplay between inward Ca current and both voltage-dependent and Ca-dependent K currents. 6. Extracellular recordings from single cells indicate that the Na-dependent spike and the low-threshold Ca action potential are somatic in origin, while the high-threshold Ca spike (after-depolarization) and the hyperpolarization that follows are apparently located in the dendrites. 7. The ionic conductances comprise the main components of the oscillatory behaviour of these cells. The sequence of events leading to oscillation entails initially a low-threshold Ca spike or Na spike, followed by an after-depolarization/after-hyperpolarization sequence and then a post-anodal exaltation product by a rebound low-threshold Ca spike.

                Author and article information

                Tremor Other Hyperkinet Mov (N Y)
                Tremor Other Hyperkinet Mov (N Y)
                Tremor and Other Hyperkinetic Movements
                Columbia University Libraries/Information Services
                12 September 2012
                : 2
                [1 ]Neurology Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
                Columbia University, United States of America
                Author notes
                *To whom correspondence should be addressed. E-mail: charles.handforth@ 123456va.gov

                This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.


                tremor, harmaline, harmine, inferior olive, cerebellum, animal model


                Comment on this article