Behavioural effects of (+)-4-propyl-9-hydroxynaphthoxazine in primates rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Three monkeys received a chronic intravenous course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) so as to produce a permanent parkinsonian syndrome. One primate was electively commenced on chronic levodopa therapy 6 weeks after the cessation of MPTP treatment. Four months following the termination of MPTP administration, the response to oral doses of the novel D-2 dopamine agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was assessed in all animals using a clinical rating scale and automatic activity counters. PHNO was found to be a highly potent antiparkinsonian agent, completely reversing the symptoms of parkinsonism in a dose-dependent manner. Peak-dose dyskinesia was noted in 2 MPTP-treated animals during trials with PHNO, but was more severe in the animal receiving chronic levodopa therapy. Response fluctuations such as 'end-of-dose' deterioration and the 'on-off' phenomenon were common to all 3 parkinsonian animals following PHNO. The anti-parkinsonian effect and frequency of treatment-induced side-effects appeared to be similar with PHNO and levodopa. These results confirm the efficacy of PHNO as an anti-parkinsonian drug and link the production of dyskinesia with the D-2 dopamine receptor.
Clarke
C E
CE
Department of Cell and Structural Biology, Medical School, University of Manchester, United Kingdom.
Boyce
S
S
Sambrook
M A
MA
Stahl
S M
SM
Crossman
A R
AR
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004298:Dopamine; D015259:Dopamine Agents / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D007980:Levodopa / Q000627:therapeutic use; D008252:Macaca fascicularis; D008297:Male; D010078:Oxazines / Q000494:pharmacology*; D010302:Parkinson Disease, Secondary / Q000188:drug therapy / Q000503:physiopathology*; D011725:Pyridines / Q000633:toxicity*
D015259:Dopamine Agents; D010078:Oxazines; D011725:Pyridines; C042631:naxagolide; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine