The effect of nigral implantation on sensitization to dopamine agonists in 6-hydroxydopamine-lesioned rats.
The implantation of fetal nigral tissue into the striatum of patients with Parkinson's disease is a promising approach to treatment which may produce clinical benefit partly by influencing drug responsiveness. The purpose of the present study was to determine the pharmacological mechanisms which drug response changes by measuring to what extent sensitization produced by repeated apomorphine treatment was attenuated by tissue implantation in rats with nigrostriatal lesions. Prior to implantation of nigral cell suspensions, the daily administration of apomorphine to rats with unilateral 6-hydroxydopamine lesions produced a progressive increase in the magnitude and duration of rotational behaviour. After implantation, apomorphine-induced rotational effects were reduced to levels observed upon the initial exposure to drug and did not increase following repeated treatment. Attenuated responses to selective D1 and D2 agonists were also observed after implantation. In vehicle-implanted rats, the initial response to apomorphine was attenuated but then increased following repeated apomorphine administration. No attenuation in responses to selective D1 and D2 agonists was observed in this group. Cell suspensions prepared from fresh and cyropreserved tissue produced similar behavioural effects, even though the volume of transplanted striatum exhibiting tyrosine hydroxylase activity was greater with fresh tissue. The duration of rotational behaviour induced by apomorphine was not affected by cell implantation. These findings suggest that the expression of sensitization in an animal model of parkinsonism may disappear after a period without drug treatment. Implantation of nigral tissue may produce beneficial results in parkinsonism by limiting the development of dopamine agonist-induced sensitization.
Gancher
S
S
Department of Neurology, L226 Oregon Health Sciences University, Portland 97201, USA.
Mayer
A
A
Youngman
S
S
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000637:transplantation*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008124:Locomotion / Q000187:drug effects; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000637:transplantation*
D018491:Dopamine Agonists; D016627:Oxidopamine; D001058:Apomorphine