Pramipexole Reduces zif-268 mRNA Expression in Brain Structures involved in the Generation of Harmaline-Induced Tremor

Abstract

Essential tremor is one of the most common neurological disorders, however, it is not sufficiently controlled with currently available pharmacotherapy. Our recent study has shown that pramipexole, a drug efficient in inhibiting parkinsonian tremor, reduced the harmaline-induced tremor in rats, generally accepted to be a model of essential tremor. The aim of the present study was to investigate brain targets for the tremorolytic effect of pramipexole by determination of the early activitydependent gene zif-268 mRNA expression. Tremor in rats was induced by harmaline administered at a dose of 15 mg/kg ip. Pramipexole was administered at a low dose of 0.1 mg/kg sc. Tremor was measured by Force Plate Actimeters where four force transducers located below the corners of the plate tracked the animal's position on a Cartesian plane. The zif-268 mRNA expression was analyzed by in situ hybridization in brain slices. Harmaline induced tremor and increased zif-268 mRNA levels in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei and motor cortex. Pramipexole reversed both the harmaline-induced tremor and the increase in zif-268 mRNA expression in the inferior olive, cerebellar cortex and motor cortex. Moreover, the tremor intensity correlated positively with zif-268 mRNA expression in the above structures. The present results seem to suggest that the tremorolytic effect of pramipexole is related to the modulation of the harmaline-increased neuronal activity in the tremor network which includes the inferior olive, cerebellar cortex and motor cortex. Potential mechanisms underlying the above pramipexole action are discussed.

The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models

“…Pramipexole also reduced the level of harmaline-increased expression of zif-268 mRNA in the ION, cerebellar cortex, and motor cortex. These results obtained by the authors [ 140 , 177 ] confirmed the beneficial effects of pramipexole, a registered anti-parkinsonian drug, in the harmaline model of ET and its potential role in ET therapy. In addition, the attenuation of the harmaline-induced activity of the ION, cerebellar cortex, and motor cortex may be important in the tremorolytic effect of pramipexole, although the exact neuronal mechanisms underlying the drug action are unfortunately still unclear.…”

“…In the following study, Kosmowska et al [ 140 ] searched for brain structures involved in the tremorolytic effect of pramipexole and determined the expression of the early activity-dependent gene, zif-268 mRNA, by in situ hybridization. They found that harmaline increased both the tremor and expression of zif-268 mRNA in the IO, cerebellar cortex, ventral nuclei of the thalamus, and motor cortex [ 140 ]. Pramipexole reversed the harmaline-induced tremor and there was an increase in zif-268 mRNA expression in all the structures examined except for the ventral thalamic nuclei [ 140 ].…”

“…They found that harmaline increased both the tremor and expression of zif-268 mRNA in the IO, cerebellar cortex, ventral nuclei of the thalamus, and motor cortex [ 140 ]. Pramipexole reversed the harmaline-induced tremor and there was an increase in zif-268 mRNA expression in all the structures examined except for the ventral thalamic nuclei [ 140 ]. Moreover, the tremor intensity was positively correlated with the expression of this early gene in all the structures mentioned above, suggesting that the tremorolytic effect of pramipexole is related to the modulation of the enhanced harmaline-induced neuronal activity in the well-known structures of the tremor network, including the ION, cerebellar cortex, and motor cortex [ 140 ] ( Figure 2 B).…”

“… A scheme showing the process of dopamine synthesis within a dopaminergic neuron terminal ( A ), and brain structures potentially involved in the tremorolytic effect of pramipexole ( B ) (according to research [ 140 ]). AADC: aromatic L-amino acid decarboxylase (DOPA decarboxylase), DA: dopamine, DAT: dopamine transporter, DCN: deep cerebellar nuclei, GC: granular cell, ION: inferior olive nuclei, L-DOPA:L-3,4-dihydroxyphenylalanine (levodopa), M.Ctx: motor cortex, PC: Purkinje cell, TH: tyrosine hydroxylase, VA/VL: ventroanterior/ventrolateral thalamic nuclei, VMAT: vesicular monoamine transporter.…”

GABA-A Alpha 2/3 but Not Alpha 1 Receptor Subunit Ligand Inhibits Harmaline and Pimozide-Induced Tremor in Rats

“…As summarized above, convergent input from anatomical, pharmacological, and neurochemical studies have strongly implicated the enhancement of GABAergic neurotransmission through GABA-A receptors as an important anti-tremor mechanism both in ET and PD [35,38,46,[51][52][53][54][55]. Although enhanced inhibition by GABA-A receptor PAMs that non-selectively interact with α1, α2, α3, and α5 subunits produces anti-tremorogenic effects, such PAMs are also associated with sedation, ataxia, tolerance development, memory impairment, and abuse liability [56].…”