Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein.
Overexpression of alpha-synuclein causes familial Parkinson's disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. Male Thy1-aSyn and wild-type mice received vehicle, benserazide/L-DOPA (25 mg/kg, i.p.), high (2 mg/kg, s.c.) and low doses (0.125, 0.25, 0.5 mg/kg, s.c.) of apomorphine, and amphetamine (5 mg/kg, i.p.), beginning at 3 months of age, and were tested on the challenging beam, spontaneous activity, pole test, and gait. l-DOPA had a paradoxical effect and worsened the deficits in Thy1-aSyn mice compared with controls, whereas the high dose of apomorphine only produced few deficits above those already present in Thy1-aSyn. In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of alpha-synuclein led to abnormal pharmacological responses in mice.
Fleming
S M
SM
Department of Neurology and Neurobiology, The David Geffen School of Medicine at the University of California Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA.
Salcedo
J
J
Hutson
C B
CB
Rockenstein
E
E
Masliah
E
E
Levine
M S
MS
Chesselet
M-F
MF
D000661:Amphetamine / Q000009:adverse effects; D000818:Animals; D001058:Apomorphine / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001545:Benserazide / Q000009:adverse effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019956:Stereotypic Movement Disorder / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D018491:Dopamine Agonists; D051844:alpha-Synuclein; D001545:Benserazide; D000661:Amphetamine; D001058:Apomorphine