Dystonia is predictive of subsequent altered dopaminergic responsiveness in a chronic 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine 1 3-nitropropionic acid model of striatonigral degeneration in monkeys I. Ghorayeb a , P.O. Fernagut a , N. Stefanova b , G.K. Wenning b , B. Bioulac a , F. Tison a, * a CNRS-UMR 5543, Universite ´ Victor Segalen Bordeaux 2, 146, rue Le ´o-Saignat, 33076 Bordeaux Cedex France b Neurological Research Laboratory, Innsbruck, Austria Received 25 April 2002; received in revised form 16 September 2002; accepted 25 September 2002 Abstract We conducted a new chronic sequential 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3NP) intoxication paradigm in two female monkeys in order to reproduce the striatonigral degeneration type of levodopa-unresponsive parkinsonism. A comparison was made with MPTP-, 3NP-intoxicated and control monkeys. A levodopa-responsive parkinsonism emerged in all MPTP-treated monkeys. During subsequent 3NP intoxication, one of the two MPTP 13NP monkeys exhibited hindlimb dystonia concomitantly with a reduced levodopa response. All MPTP- monkeys had severe cell loss in the substantia nigra pars compacta (.70%), but 3NP-induced discrete lesioned areas and cell loss predominantly in the putamen appeared only in the dystonic and levodopa-unresponsive animal. We propose that the appearance of dystonia after 3NP intoxication following dopaminergic striatal denervation is the key symptom predictive of the loss of dopaminergic response. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Striatonigral degeneration; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3-nitropropionic acid; Parkinsonism; Dystonia; Primate model; Multiple system atrophy Striatonigral degeneration (SND) is the neuropathological hallmark of levodopa- unresponsive parkinsonism associated with multiple system atrophy (SND/MSA-P) [4,13]. We recently initiated the first primate model of levodopa-unre- sponsive parkinsonism associated with SND/MSA-P, by sequential systemic intoxication with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), a nigral dopaminergic toxin, and 3-nitropropionic acid (3NP), a striatal toxin [5]. Levodopa-responsive parkinsonism emerged after MPTP intoxication and subsequent 3NP administration led to a marked reduction of the levodopa response along with the appearance of circumscribed lesioned areas, with severe neuronal loss in the dorsal sensorimotor putamen and ventral caudate. To understand better the relationships between the occurrence of the 3NP-induced motor disorder and the devel- opment of dopaminergic unresponsiveness, we conducted a more chronic sequential intoxication paradigm with MPTP and 3NP compared to monkeys that had received either MPTP or 3NP alone, and one control monkey. Five adult female Cynomolgus Macaca fascicularis monkeys (3–4 kg) were used in accordance with the guide- lines of the French Agriculture and Forestry Ministry. All efforts were made to minimize the number of animals used and their suffering. Monkey #1 received MPTP alone at 0.2 mg/kg i.v. every other day until the emergence of a marked parkinsonism. Monkey #2 received 3NP alone (two i.m. daily injections, 5 days a week) with an intoxication paradigm designed to yield a progressive increase in dose (from 12 mg/kg/day with a weekly increment of 2 mg/kg). Monkeys #3 and #4 received the same intoxication procedure but with sequen- tial MPTP (from day 1 to day 19 for monkey #3 and from day 1 to day 31 for monkey #4), then 3NP (from day 56 to day 184) as described above. At the end of the experiment (day 189), a second series of MPTP injections was performed in monkeys #3 and #4 to compare the levodopa challenge responses in animals displaying the same degree Neuroscience Letters 335 (2002) 34–38 0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(02)01137-0 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 133-5-5757-1551; fax: 133-5- 5690-1421 E-mail address: ftison@neuro.u-bordeaux2.fr (F. Tison).