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Effects of pharmacological entopeduncular manipulations on idiopathic dystonia in the dt sz mutant hamster

Journal of Neural Transmission volume 117, pages 747–757 (2010)Cite this article

Abstract

The pathophysiology of idiopathic dystonias is still unknown, but it is regarded as a basal ganglia disorder. Previous experiments in the dt sz hamster, a model of primary paroxysmal dystonia, demonstrated reduced discharge rates and an abnormal pattern within the entopeduncular nucleus (EPN), a basal ganglia output structure. To clarify if this is based on abnormal γ-aminobutyric acid(GABA)ergic or glutamatergic input, microinjections into the EPN were done in mutant hamsters in the present study. The GABAA receptor antagonists pentylenetetrazole and bicuculline exerted moderate antidystonic effects, while previous systemic administrations worsened dystonia in the dt sz mutant. GABA-potentiating drugs, i.e., the GABAA receptor agonist muscimol and the GABA transporter inhibitor 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxy-lic acid (NNC-711), which are known to improve dystonia after systemic treatment in mutant hamsters, did not exert significant effects after EPN injections, but NNC-711 tended to increase the severity at the highest dose (2.5 ng bilateral). The NMDA receptor antagonist d(−)-2-amino-5-phosphopentanoic acid (AP-5) retarded the onset of a dystonic attack. However, this effect was not dose dependent and the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol(f)quinoxaline (NBQX) alone or in combination with AP-5 and NNC-711, also failed to show any effects on dystonia. The present data do not provide clear evidence for an enhanced striatal GABAergic input or a reduced glutamatergic activation of the EPN via the subthalamic nucleus, i.e., more pronounced antidystonic effects of GABAA receptor antagonists and stronger prodystonic effects of GABAmimetics and glutamate receptor antagonists were expected. Nevertheless, previously found changes in entopeduncular activity probably play a critical pathophysiological role in dystonic hamsters.

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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid

AP-5:

d(−)-2-amino-5-phosphopentanoic acid

EPN:

Entopeduncular nucleus

GABA:

γ-aminobutyric acid

GAT-1:

GABA transporter type 1

GPe:

Globus pallidus pars externus

GPi:

Globus pallidus pars internus

NBQX:

2, 3-dihydroxy-6-nitro-7-sulfamoylbenzol(f)quinoxaline

NMDA:

N-methyl-d-aspartate

NNC-711:

1, 2, 5, 6-Tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid

PNKC:

Paroxysmal non-kinesiogenic dyskinesia

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (Ri 845/1-2 and Ri 845/1-3). We thank A. Russ for his excellent technical assistance.

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Affiliations

  1. Department of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, Koserstr. 20, 14195, Berlin, Germany

    Melanie Hamann, Svenja E. Sander, Annette Kreil & Angelika Richter

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  1. Melanie Hamann
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  2. Svenja E. Sander
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  3. Annette Kreil
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  4. Angelika Richter
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Correspondence to Melanie Hamann.

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Hamann, M., Sander, S.E., Kreil, A. et al. Effects of pharmacological entopeduncular manipulations on idiopathic dystonia in the dt sz mutant hamster. J Neural Transm 117, 747–757 (2010). https://doi.org/10.1007/s00702-010-0410-y

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Keywords

  • Basal ganglia
  • Animal model
  • Movement disorder
  • Dyskinesia