Differential effect of chronic dopaminergic treatment on dopamine D1 and D2 receptors in the monkey brain in MPTP-induced parkinsonism.
Dopamine D1 and D2 receptors located within the striatum (caudate nucleus and putamen) were studied autoradiographically, using [3H]SCH 23390 and [3H]sulpiride respectively, in (i) seven monkeys rendered parkinsonian by the systemic administration of MPTP, four of which were chronically exposed to anti-parkinsonian drugs (levodopa or apomorphine), (ii) two hemi-parkinsonian monkeys (induced by intra-carotid infusion of MPTP), one of which received chronic exposure to apomorphine, and (iii) three control monkeys which received neither MPTP nor dopaminergic drugs. Anti-parkinsonian drug exposure resulted in a reversal of symptoms and was accompanied by the development of limb dyskinesias. In parkinsonian monkeys not chronically exposed to drugs. [3H]SCH 23390 binding was slightly but not significantly elevated above control values, whilst in the same animals [3H]sulpiride binding was significantly increased above that found in the control group. Rostrally [3H]SCH 23390 binding was similar in the control and drug-exposed parkinsonian groups but more caudally there was a small consistent, although not significant, increase in [3H]SCH 23390 binding in the drug-exposed animals as compared to the parkinsonian monkeys not exposed to drugs. In contrast at all rostro-caudal levels [3H]sulpiride binding in the drug-exposed parkinsonian group was lower than the corresponding values from the non-drug exposed animals. [3H]SCH 23390 binding showed no major side-to-side difference in the hemi-parkinsonian animal which was not exposed to levodopa/apomorphine, whilst in the hemi-parkinsonian monkey which received apomorphine there was again an increase in binding on the MPTP-treated side of the brain. In both drug- and non-drug exposed hemi-parkinsonian animals there was a greater density of [3H]sulpiride binding in the parkinsonian side of the brain; the general level of binding in the drug-exposed monkey was less than that seen in the other animal. These results would support the idea that in MPTP-induced parkinsonism, dopaminergic denervation results in a greater change in the D2 receptors, but furthermore would indicate a differential effect of levodopa/apomorphine exposure on the D1 and D2 receptor populations. Drug exposure apparently encourages the reversal of the MPTP-induced increase in the D2 receptor binding, whilst the D1 receptor binding appears to proliferate in response to these drugs. These results may have important implications in relation to the development of dyskinesias, subsequent to the chronic use of some anti-parkinsonian drug treatments.
Graham
W C
WC
Department of Cell and Structural Biology, University of Manchester Medical School, UK.
Sambrook
M A
MA
Crossman
A R
AR
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography; D001552:Benzazepines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D005260:Female; D007262:Infusions, Intravenous; D007980:Levodopa / Q000494:pharmacology; D020267:MPTP Poisoning; D008252:Macaca fascicularis; D008297:Male; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D013469:Sulpiride / Q000378:metabolism
D001552:Benzazepines; D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D013469:Sulpiride; D001058:Apomorphine