Dopamine receptor agonists reverse behavioral abnormalities of alpha-synuclein transgenic mouse, a new model of Parkinson's disease.
Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is alpha-synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residues 1-130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L-DOPA and DA receptor agonists. Administration of L-DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D(2) agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non-Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D(2)-like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease.
Wakamatsu
Masaki
M
Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Iwata
Shingo
S
Funakoshi
Takeo
T
Yoshimoto
Makoto
M
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000523:psychology*; D010446:Peptide Fragments / Q000235:genetics; D010479:Pergolide / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics*
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018491:Dopamine Agonists; D010446:Peptide Fragments; D017448:Receptors, Dopamine D2; D051844:alpha-Synuclein; D010479:Pergolide; D007980:Levodopa