In vivo and in vitro evidence of dopaminergic system down regulation induced by chronic L-DOPA.
The biochemical modifications which occur in the dopaminergic system after chronic administration of L-DOPA are investigated. Levels of DA and of its metabolite 3-methoxytyramine (3-MT), an expression of the amount of DA released, were raised to the same extent in controls given a single dose of 1-DOPA and in chronically treated rats given 100 mg/kg of 1-DOPA plus 25 mg/kg of benserazide twice a day for 24 days. However, the reduction in neuronal function expressed by the decrease in 3-MT which follows treatment with DA agonists such as piribedil and apomorphine was less pronounced in the chronically L-DOPA treated rats. This suggests that such treatment causes a down regulation of DA receptors. These in vivo results were confirmed by in vitro analysis of DA receptor activity after chronic L-DOPA. Under these conditions there was a significant reduction in the number of [3H]-spiperone and [3H]-ADTN binding sites with no changes in their affinity. The in vivo and in vitro findings both suggest the involvement of a subsensitive compensatory mechanism or down regulation of dopaminergic neurons after chronic treatment with L-DOPA.
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001545:Benserazide / Q000494:pharmacology*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D006834:Hydrazines; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C031611:spiroperidol receptor; D007980:Levodopa; D013134:Spiperone; C011639:ADTN; D001545:Benserazide; D014446:Tyrosine 3-Monooxygenase; C001746:3-methoxytyramine; D001058:Apomorphine; D004298:Dopamine