Chronic CY 208-243 treatment of MPTP-monkeys causes regional changes of dopamine and GABAA receptors.
Four monkeys were rendered parkinsonian by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) i.v. administration and then treated chronically with increasing doses of the D1 agonist CY 208-243 (0.05, 0.1 and 0.5 mg/kg). All animals showed a dose-dependent improvement of their parkinsonian signs after the chronic CY 208-243 treatment; however, half of them developed peak-dose dyskinesias. Dopamine levels were more decreased in the striatum of MPTP-monkeys with dyskinesias compared to those without dyskinesias. [3H]SCH 23390 and [3H]SKF 38393 binding to D1 receptors were in general similar in the striatum of both groups of MPTP-monkeys except [3H]SKF 38393 binding which was lower in the posterior putamen of dyskinetic compared to non-dyskinetic monkeys reflecting decreased coupling of this receptor to G proteins. [3H]spiperone and [3H]N-n-propylnorapomorphine binding to D2 receptors in the striatum tended in general to be higher in dyskinetic compared to non-dyskinetic monkeys, and this reached statistical significance in the posterior caudate labelled with [3H]n-propylnorapomorphine. [3H]muscimol binding to GABAA receptors was significantly higher in the posterior caudate of dyskinetic compared to non-dyskinetic monkeys. The extent of striatal DA denervation, decreased D1, elevated D2 and GABAA receptors, as well as the decrease of the D1/D2 receptor ratio in the posterior striatum may be involved in the appearance of dyskinesias after chronic CY 208-243 treatment.
Gagnon
C
C
School of Pharmacy, Laval University, Que., Canada.
Gomez-Mancilla
B
B
Bédard
P J
PJ
Di Paolo
T
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008252:Macaca fascicularis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects*
D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; C054531:CY 208-243; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019204:GTP-Binding Proteins; D004298:Dopamine