Effects of pharmacological manipulation of GABAergic neurotransmission in a new mutant hamster model of paroxysmal dystonia

Fredow, Gabriele; Löscher, Wolfgang

doi:10.1016/0014-2999(91)90045-r

Cited by 71 publications

(23 citation statements)

References 14 publications

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“…The dt sz hamsters were obtained by selective breeding as described in detail elsewhere (Fredow and Löscher, 1991). The control hamsters were obtained from breeding pairs which were provided by a commercial breeder (Central Institute for Laboratory Animal Breeding, Hannover, Germany).…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…Recent pharmacological and neurochemical studies in the dt sz hamster have indicated that an impaired GABAergic function is critically involved in the pathophysiology of generalized dystonia (Fredow and Löscher, 1991;Löscher and Hörstermann, 1992;Nobrega et al, 1995;Pratt et al, 1995;Richter and Löscher, 1993). GABA-potentiating drugs were shown to exert antidystonic effects, while the central stimulant pentylenetetrazole (PTZ), which is thought to reduce GABA A receptor function by an effect on the picrotoxinin site of the GABA A receptor complex (Löscher, 1989;Ramanjaneyulu and Ticku, 1984), aggravated dystonia in mutant hamsters at subconvulsive doses (Fredow and Löscher, 1991;Löscher et al, 1989).…”

Section: Introductionmentioning

confidence: 98%

“…GABA-potentiating drugs were shown to exert antidystonic effects, while the central stimulant pentylenetetrazole (PTZ), which is thought to reduce GABA A receptor function by an effect on the picrotoxinin site of the GABA A receptor complex (Löscher, 1989;Ramanjaneyulu and Ticku, 1984), aggravated dystonia in mutant hamsters at subconvulsive doses (Fredow and Löscher, 1991;Löscher et al, 1989). Quantitative autoradiographic analysis of GABA A receptors revealed increased [ 35 S]TBPS binding density in several brain regions of the mutant dt sz hamster, indicating impaired GABAergic function in dystonic hamsters (Nobrega et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Subconvulsive dose of pentylenetetrazole increases the firing rate of substantia nigra pars reticulata neurons in dystonic but not in nondystonic hamsters

Gernert

Richter

Löscher

1999

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Dystonic attacks, including twisting movements, can be initiated by mild stress in mutant (gene symbol dt(sz)) Syrian golden hamsters, an animal model of idiopathic paroxysmal dystonia. Previous studies suggested that dysfunctions in basal ganglia, which are not restricted to periods of attacks, are involved in the dystonic syndrome in mutant hamsters. Therefore, in the present study in anesthetized animals, we examined whether the spontaneous firing rate of extracellularly recorded neurons of the substantia nigra pars reticulata (SNr) differs between dt(sz) and age-matched nondystonic control hamsters. Furthermore, we investigated the responsiveness of these nondopaminergic, presumably GABAergic neurons to a subconvulsive dose (25mg/kg i.p.) of systemically applied pentylenetetrazole (PTZ), which exerts prodystonic effects in mutant hamsters. The mean basal (spontaneous) firing rate of SNr neurons was not altered in mutant hamsters. However, within 5 min after i.p. injection of PTZ, the mean firing rate of SNr neurons significantly increased to about 160% of predrug control values in dt(sz) but not in control hamsters. Although the present study failed to reveal changes in the basal firing rate of SNr neurons in mutant hamsters, the abnormal response to PTZ is in line with previous pharmacological and biochemical data indicating disturbed function of the GABAergic system.

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Section: Materials and Methods Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Subconvulsive dose of pentylenetetrazole increases the firing rate of substantia nigra pars reticulata neurons in dystonic but not in nondystonic hamsters

Gernert

Richter

Löscher

1999

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“…Systemic administration or intrastriatal injection of agents that increase GABAergic transmission either ameliorate or block dt sz attacks. 10,16,17 In contrast, systemic or local application of GABA receptor antagonists worsens the dystonia. 10,16,17 The improvement observed with drugs that promote GABA release likely occurs by offsetting the significant deficit of GABAergic striatal interneurons, which predicts disinhibition of striatal efferents.…”

Section: Animal Models Implicating Basal Ganglia Dysfunctionmentioning

confidence: 99%

“…10,16,17 In contrast, systemic or local application of GABA receptor antagonists worsens the dystonia. 10,16,17 The improvement observed with drugs that promote GABA release likely occurs by offsetting the significant deficit of GABAergic striatal interneurons, which predicts disinhibition of striatal efferents. 15 These defects in GABAergic regulation within the striatum suggest the dt sz disorder may be pathogenically related to some forms of idiopathic paroxysmal dyskinesia in humans because dystonia in mutant hamsters and patients responds to similar pharmacological treatments, such as systemic administration of benzodiazepines.…”

Section: Animal Models Implicating Basal Ganglia Dysfunctionmentioning

confidence: 99%

Animal models of generalized dystonia

2005

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Summary: Dystonia is a prevalent neurological disorder characterized by abnormal co-contractions of antagonistic muscle groups that produce twisting movements and abnormal postures. The disorder may be inherited, arise sporadically, or result from brain insult. Dystonia is a heterogeneous disorder because patients may exhibit focal or generalized symptoms associated with abnormalities in many brain regions including basal ganglia and cerebellum. Elucidating the pathogenic mechanisms underlying dystonia has therefore been challenging. Animal models of dystonia exhibit similar heterogeneity and are useful for understanding pathogenesis. The neurochemical and neurophysiological abnormalities in rodents with idiopathic generalized dystonia suggest that dysfunctional output from basal ganglia, cerebellum, or from multiple systems is the cause of motor dysfunction. Findings from drug-or toxininduced dystonia in rodents and nonhuman primates mirror the genetic models. The parallels between dystonia in humans and animals suggest that the models will continue to prove useful in determining pathogenesis. Furthermore, detailed characterization of the existing models of dystonia and the development of new models hold promise for the identification of novel therapeutics.

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In vivo extracellular electrophysiology of pallidal neurons in dystonic and nondystonic hamsters

1999

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In the dt(sz) hamster, a model of idiopathic paroxysmal dystonia, recent findings indicated a decreased neuronal activity within the globus pallidus (GP) and an impaired gamma aminobutyric acid (GABA)ergic function when compared to nondystonic controls. Therefore, in the present study, extracellular single-unit recordings combined with systemical application of a subconvulsant prodystonic dose of pentylenetetrazole (PTZ) were used to compare the electrophysiological properties of GP neurons in anesthetized dt(sz) hamsters and nondystonic controls. The spontaneous discharge rate of GP neurons was not decreased but a trend towards a wide-ranged distribution was found in mutants compared to controls. Since the single-unit activity of striatal neurons was recently shown to be significantly increased in dt(sz) hamsters, the lack of significant changes in GP discharge rates was unpredicted. We suggest that this is due to antagonistic convergent striatal and subthalamic inputs and to lateral monosynaptic inhibition known for striatum and GP. While no significant changes of the discharge rate of GP neurons could be detected, the spike morphology was significantly altered in dt(sz) hamsters, suggesting subtle impaired information processing in the GP. The lack of marked changes in basal firing pattern may be related to the anesthesia. Administration of PTZ (25 mg/kg i.p.) at a subconvulsant dose, which aggravates dystonia in awake dt(sz) hamsters, seemed to induce more marked changes in spike morphology and firing pattern in mutants than in controls, although the discharge rate did not differ significantly between both animal groups in response to PTZ. In view of recent findings, we assume that GABAergic dysfunctions in dystonic hamsters are of regionally different extent.

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Effects of pharmacological manipulation of GABAergic neurotransmission in a new mutant hamster model of paroxysmal dystonia

Cited by 71 publications

References 14 publications

Subconvulsive dose of pentylenetetrazole increases the firing rate of substantia nigra pars reticulata neurons in dystonic but not in nondystonic hamsters

Subconvulsive dose of pentylenetetrazole increases the firing rate of substantia nigra pars reticulata neurons in dystonic but not in nondystonic hamsters

Animal models of generalized dystonia

In vivo extracellular electrophysiology of pallidal neurons in dystonic and nondystonic hamsters

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