Biochemical alterations of dopamine receptor responses following chronic L-dopa therapy.
The effects of chronic l-dopa treatment on rat striatal adenylate cyclase and dopaminereceptor binding activities were studied using an oral dose of Sinemet (250 mg l-dopa/25 mg carbidopa). The calculated average daily oral intake of l-dopa was 150 mg/rat. A 4-fold increase in the ec(50) for dopamine on adenylate cyclase activity in homogenstes of the caudate nucleus was observed in the oral drug-treated group with no change in the maximal level of enzyme activity. Binding studies using [(3)H]spiroperidol, a dopamine-receptor antagonist, revealed a decrease in the dissociation constant from 0.26 nM in the control group to 0.069 nM in the oral drug-treated group. In addition, the B(max) for [(3)H]spiroperidol specific binding in the animals receiving oral l-dopa increased by 300 fmoles/mg over that observed in the control group. Dopamine-sensitive adenylate cyclase and binding activities in animals receiving a lower dose of l-dopa alone, given intraperitoneally (50 mg/kg) twice daily, were determined to be similar to control values. Analysis of the cerebrospinal fluid biogenic amine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), by gas chromatography/mass spectrometry revealed a 13-fold increase in HVA following oral l-dopa and a 44 per cent increase in MHPG levels. These data, which demonstrate an increased number of dopamine binding sites following long-term l-dopa therapy, are consistent with demonstrations of behavioral hypersensitivity in animals undergoing this particular drug treatment. The results also suggest that the subsensitivity of the adenylate cyclase system may reflect a side effect of this drug, due to prolonged administration.
Wilner
K D
KD
Departments of Pharmacology, Neurobiology, Neurology and Biochemistry, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Butler
I J
IJ
Seifert
W E
WE
Clement-Cormier
Y C
YC
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002230:Carbidopa / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013134:Spiperone / Q000494:pharmacology
D011954:Receptors, Dopamine; D007980:Levodopa; D013134:Spiperone; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; D000262:Adenylyl Cyclases; D002230:Carbidopa; D004298:Dopamine; D006719:Homovanillic Acid