Effect of adding the D1 agonist CY 208-243 to chronic bromocriptine treatment. I: Evaluation of motor parameters in relation to striatal catecholamine content and dopamine receptors.
A group of four cynomolgus monkeys previously rendered parkinsonian by the toxin 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP) were observed in locomotion cages equipped with photocells during four periods of 7 days during which they received saline or two doses of the D1 agonist CY 208-243. The larger dose of 0.5 mg/kg produced a significant increase in locomotion in three of four animals. A second group of eight monkeys also previously rendered parkinsonian by MPTP and having received no other treatment were given a daily treatment of bromocriptine 1.66 mg/kg orally daily during 4 weeks. In four of the animals, after a week on bromocriptine alone, the D1 agonist CY 208-243 was added in increasing doses of 0.05, 0.1, and 0.5 mg/kg. The motor response as measured by locomotion, hand dexterity, and a disability score improved progressively at least in some of the animals on bromocriptine alone. The addition of CY 208-243 produced a more striking improvement of all three parameters, which appeared to be dose dependent. Biochemical analysis of the brain of these animals plus one control and one MPTP untreated monkey showed a > 90% loss of dopamine in the striatum in six of the eight treated monkeys. Both D2 and D1 dopamine receptors were increased in density by denervation, but both treatments abolished this increase for the D2 receptors while increasing the affinity of the D1 receptors.
Gomez-Mancilla
B
B
School of Pharmacy, Laval University Medical Center, Sainte-Foy, Québec, Canada.
Boucher
R
R
Gagnon
C
C
Di Paolo
T
T
Markstein
R
R
Bédard
P J
PJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D001971:Bromocriptine / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006719:Homovanillic Acid / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage*; D008124:Locomotion / Q000187:drug effects; D008252:Macaca fascicularis; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009460:Neurologic Examination; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D010617:Phenanthridines / Q000008:administration & dosage*; D011597:Psychomotor Performance / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000648:ultrastructure; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000648:ultrastructure
D000978:Antiparkinson Agents; D007211:Indoles; D010617:Phenanthridines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; C054531:CY 208-243; D015102:3,4-Dihydroxyphenylacetic Acid; D001971:Bromocriptine; D004298:Dopamine; D006719:Homovanillic Acid