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      Lesion of the Cerebellar Noradrenergic Innervation Enhances the Harmaline-Induced Tremor in Rats

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          Abstract

          Abnormal synchronous activation of the glutamatergic olivo-cerebellar pathway has been suggested to be crucial for the harmaline-induced tremor. The cerebellum receives two catecholaminergic pathways: the dopaminergic pathway arising from the ventral tegmental area/substantia nigra pars compacta, and the noradrenergic one from the locus coeruleus. The aim of the present study was to examine a contribution of the cerebellar catecholaminergic innervations to the harmaline-induced tremor in rats. Rats were injected bilaterally into the cerebellar vermis with 6-hydroxydopamine (6-OHDA; 8 μg/0.5 μl) either alone or this treatment was preceded (30 min earlier) by desipramine (15 mg/kg ip). Harmaline was administered to animals in doses of 7.5 or 15 mg/kg ip. Tremor of forelimbs was measured as a number of episodes during a 90-min observation. Rats were killed by decapitation 30 or 120 min after harmaline treatment. The levels of dopamine, noradrenaline, serotonin, and their metabolites were measured by HPLC in the cerebellum, substantia nigra, caudate–putamen, and frontal cortex. 6-OHDA injected alone enhanced the harmaline-induced tremor. Furthermore, it decreased the noradrenaline level by ca. 40–80% in the cerebellum and increased the levels of serotonin and 5-HIAA in the caudate–putamen and frontal cortex in untreated and/or harmaline-treated animals. When 6-OHDA treatment was preceded by desipramine, it decreased dopaminergic transmission in some regions of the cerebellum while inducing its compensatory activation in others. The latter lesion did not markedly influence the tremor induced by harmaline. The present study indicates that noradrenergic innervation of the cerebellum interacts with cerebral serotonergic systems and plays an inhibitory role in the harmaline-induced tremor.

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          Most cited references 56

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          The cerebellum communicates with the basal ganglia.

          The cerebral cortex is interconnected with two major subcortical structures: the basal ganglia and the cerebellum. How and where cerebellar circuits interact with basal ganglia circuits has been a longstanding question. Using transneuronal transport of rabies virus in macaques, we found that a disynaptic pathway links an output stage of cerebellar processing, the dentate nucleus, with an input stage of basal ganglia processing, the striatum.
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            Role of hyperactive cerebellum and motor cortex in Parkinson's disease.

            Previous neuroimaging studies have found hyperactivation in the cerebellum and motor cortex and hypoactivation in the basal ganglia in patients with Parkinson's disease (PD) but the relationship between the two has not been established. This study examined whether cerebellar and motor cortex hyperactivation is a compensatory mechanism for hypoactivation in the basal ganglia or is a pathophysiological response that is related to the signs of the disease. Using a BOLD contrast fMRI paradigm PD patients and healthy controls performed automatic and cognitively controlled thumb pressing movements. Regions of interest analysis quantified the BOLD activation in motor areas, and correlations between the hyperactive and hypoactive regions were performed, along with correlations between the severity of upper limb rigidity and BOLD activation. There were three main findings. First, the putamen, supplementary motor area (SMA) and pre-SMA were hypoactive in PD patients. The left and right cerebellum and the contralateral motor cortex were hyperactive in PD patients. Second, PD patients had a significant negative correlation between the BOLD activation in the ipsilateral cerebellum and the contralateral putamen. The correlation between the putamen and motor cortex was not significant. Third, the BOLD activation in the motor cortex was positively correlated with the severity of upper limb rigidity, but the BOLD activation in the cerebellum was not correlated with rigidity. Further, the activation in the motor cortex was not correlated with upper extremity bradykinesia. These findings provide new evidence supporting the hypothesis that hyperactivation in the ipsilateral cerebellum is a compensatory mechanism for the defective basal ganglia. Our findings also provide the first evidence from neuroimaging that hyperactivation in the contralateral primary motor cortex is not a compensatory response but is directly related to upper limb rigidity.
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              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.
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                Author and article information

                Contributors
                +48-12-6623321 , +48-12-6374500 , ossowska@if-pan.krakow.pl
                Journal
                Cerebellum
                Cerebellum (London, England)
                Springer-Verlag (New York )
                1473-4222
                1473-4230
                29 January 2011
                29 January 2011
                June 2011
                : 10
                : 2
                : 267-280
                Affiliations
                [1 ]Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343 Kraków, Poland
                [2 ]Department of Pharmacology, Medical University of Silesia, 19 H. Jordana St, 41-808 Zabrze, Poland
                [3 ]Department of Descriptive and Topographic Anatomy, Medical University of Silesia, 19 H. Jordana St, 41-808 Zabrze, Poland
                Article
                250
                10.1007/s12311-011-0250-9
                3114101
                21279489
                © The Author(s) 2011
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC 2011

                Neurology

                dopamine, rat, cerebellum, serotonin, tremor, noradrenaline, harmaline

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