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 activity-dependent 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.
Highlights
Essential tremor (ET) is one of the most common neurological disorders and the most frequently occurring, apart from the restless leg syndrome, movement disorder in adults [1]
Pramipexole given alone did not influence the zif-268 mRNA expression in any of the above structures in naive rats, but when administered 30 min before harmaline, it inhibited the harmaline-induced effect by decreasing the zif268 mRNA expression in inferior olive (IO), motor cortex and selected lobules of cerebellar cortex but did not affect the gene expression in VA/VL (Fig. 1)
Peripheral harmaline administration induces a rapid increase in the expression level of early response genes, such as c-fos or zif-268, in the IO and cerebellar cortex [6, 15, 16, 27] as well as in the VA/VL thalamic nuclei and motor cortex [6, 18], indicating the involvement of olivo-cerebellothalamo-cortical pathway in the generation and spread of tremor induced by this compound
Summary
Essential tremor (ET) is one of the most common neurological disorders and the most frequently occurring, apart from the restless leg syndrome, movement disorder in adults [1]. ET treatment is based mainly on pharmacotherapy and the first-line drugs include propranolol and primidone, which have good efficacy, but in more than 50% of patients produce serious side effects, such as hypotension, dizziness, bradycardia, cognitive impairment, fatigue or erectile dysfunction [2]. Paterson et al [4] observed that apomorphine (a non-selective dopamine receptors’ agonist) and quinpirole (D2/D3 receptor agonist) decreased harmaline tremor, while SKF 82,958 (D1 receptor agonist) and raclopride (D2 receptor antagonist) had no effect on it. What is more, they showed that GBR 12,909 [dopamine transporter (DAT) inhibitor] diminished the tremor, but only at the middle dose (the lower and higher doses were ineffective). Our own results indicate that apomorphine increases tremor induced by harmaline [8], while pramipexole and 7-OH-DPAT, which are preferential D3 receptor agonists, visibly inhibit this behavior at low doses [5]
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