The dystonic rat is a model of inherited movement disorders discovered in Sprague-Dawley rats. The dt rat displays sustained, twisting movements in the waking state, starting on postnatal days 9-10 following a period of apparently normal development. The movements seen in the dt rat are analogous to those that characterize the disease torsion dystonia in man. Inheritance in the rat model follows an autosomal recessive pattern. As in the human disease, routine histopathological study reveals no evidence of morphological lesions or degenerative processes in the central or peripheral nervous system of rats displaying advanced clinical signs. However, in the rat model application of neurochemical, morphological and psychopharmacological techniques to study noradrenergic, dopaminergic, cholinergic, and GABAergic systems in brain has revealed specific abnormalities including increased GAD activity in the deep cerebellar nuclei, increased steady state levels of cerebellar norepinephrine and decreased cerebellar cGMP. These are not generalized abnormalities in noradrenergic or GABAergic systems. Other evidence of pathology in the cerebellum includes the presence of tubular, honeycombed inclusions of axons seen in electron micrographs. The dt rats are also less sensitive to the tremorogenic effects of harmaline, a drug that acts on one of the major cerebellar afferent systems. The proposed studies are designed to continue a systematic interdisciplinary investigation of the dt rat. Emphasis is given to studies that are designed to provide explanations for previously documented neurochemical and psychopharmacological abnormalities. Specifically, studies are proposed to assess the function to major components of cerebellar circuitry and to determine their relationship to dystonia. Neurochemical, electrophysiological and anatomical techniques will be used. The proposed studies are expected to lead to increased understanding of human torsion dystonia and normal development of motor systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS018062-04A1
Application #
3398115
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1981-12-01
Project End
1988-08-31
Budget Start
1985-09-09
Budget End
1986-08-31
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Stratton, S E; Lorden, J F (1991) Effect of harmaline on cells of the inferior olive in the absence of tremor: differential response of genetically dystonic and harmaline-tolerant rats. Neuroscience 41:543-9
Beales, M; Lorden, J F; Walz, E et al. (1990) Quantitative autoradiography reveals selective changes in cerebellar GABA receptors of the rat mutant dystonic. J Neurosci 10:1874-85
Brown, L L; Lorden, J F (1989) Regional cerebral glucose utilization reveals widespread abnormalities in the motor system of the rat mutant dystonic. J Neurosci 9:4033-41
Lutes, J; Lorden, J F; Beales, M et al. (1988) Tolerance to the tremorogenic effects of harmaline: evidence for altered olivo-cerebellar function. Neuropharmacology 27:849-55
Bowen, W D; Walker, J M; Yashar, A G et al. (1988) Altered haloperidol-sensitive sigma receptors in the genetically dystonic (dt) rat. Eur J Pharmacol 147:153-4
Lorden, J F; Oltmans, G A; Stratton, S et al. (1988) Neuropharmacological correlates of the motor syndrome of the genetically dystonic (dt) rat. Adv Neurol 50:277-97
Lorden, J F; Stratton, S E; Mays, L E et al. (1988) Purkinje cell activity in rats following chronic treatment with harmaline. Neuroscience 27:465-72
Stratton, S E; Lorden, J F; Mays, L E et al. (1988) Spontaneous and harmaline-stimulated Purkinje cell activity in rats with a genetic movement disorder. J Neurosci 8:3327-36
Sukin, D; Skedros, D G; Beales, M et al. (1987) Temporal sequence of motor disturbances and increased cerebellar glutamic acid decarboxylase activity following 3-acetylpyridine lesions in adult rats. Brain Res 426:82-92
Oltmans, G A; Moss, L E; Lorden, J F et al. (1987) Acute and chronic effects of climbing fiber lesions on cerebellar cyclic guanosine monophosphate. Brain Res 437:183-8

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