The effect of intracerebroventricular infusion of (+)-4-propyl-9-hydroxynapthoxacine (PHNO) through a totally implanted drug delivery system in rats with dopamine deficiency.
Rats with experimentally induced DA deficiency were treated with intracerebroventricular administration of (+)-4-propyl-9-hydroxynaphthoxacine (PHNO) through a totally implanted chronic delivery system which delivered PHNO, 0.9 microgram/h, continuously for up to 2 weeks. Rats with 6-OH-DA induced unilateral nigrostriatal lesion showed, after PHNO infusion, a potent and persistent contralateral turning behavior (8-11 turns/min) which was not present in vehicle-infused animals. The intensity of spontaneous and apomorphine-induced rotation did not decrease after 2 weeks of continuous infusion, suggesting that tolerance to PHNO or to other dopamine agonists did not develop. The magnitude of the spontaneous turning behavior in PHNO-infused animals correlated well with the baseline response to apomorphine (r = 0.505, p less than 0.025). Rats implanted with pumps delivering PHNO or vehicle were treated with reserpine, 0.5 mg/kg/day for 14 days. Vehicle-infused, reserpinized animals had a severe akinesia and weight loss during the experimental period (motor activity, measured in counts per minute was reduced to 5-10% of baseline levels, and body weight to 50% of baseline levels). PHNO-infusion partially restored activity to 60% of baseline counts and reduced the severity of weight loss. PHNO effects were observed for as long as the infusion was maintained. No side effects were observed. Intracerebroventricular infusion of PHNO may be an alternative experimental approach to untreatable motor fluctuations in Parkinson's disease.
de Yebenes
J G
JG
Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Fahn
S
S
Jackson-Lewis
V
V
Mena
M A
MA
D000818:Animals; D001921:Brain / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency*; D015259:Dopamine Agents / Q000008:administration & dosage*; D007260:Infusion Pumps; D007276:Injections, Intraventricular / Q000295:instrumentation*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009434:Neural Pathways / Q000187:drug effects; D010078:Oxazines / Q000008:administration & dosage*; D010302:Parkinson Disease, Secondary / Q000188:drug therapy; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects
D015259:Dopamine Agents; D010078:Oxazines; D011954:Receptors, Dopamine; C042631:naxagolide; D004298:Dopamine