Dopaminergic functional supersensitivity: effects of chronic L-dopa and carbidopa treatment in an animal model of Parkinson's disease.
We have evaluated the effects of L-Dopa and carbidopa treatment (30 days) on dopamine (DA) turnover, intracellular cyclic AMP (cAMP) accumulation and tetrahydrobiopterin levels in the nigrostriatal pathway of rats with a unilateral 6-OHDA lesions (greater than 90% lesions). We observed significant increase in the 3,4-dihydroxy-phenylacetic acid/DA and homovanillic acid/DA ratios, and in basal cAMP levels (92%) in the ipsilateral striatum, but not in the substantia nigra when compared to the contralateral intact hemisphere. After L-dopa/carbidopa treatment, the increased 3,4-dihydroxy-phenylacetic acid/DA, homovanillic acid/DA ratios and the elevated levels of cAMP in the ipsilateral striatum were reduced significantly and returned to the control levels of contralateral non-lesioned side. Tetrahydrobiopterin levels obtained on both sides remained unaffected after treatment. The D1 agonist SKF 38393 (10 microM) increased cAMP accumulation significantly in striatal slices from the lesioned and intact hemispheres in both vehicle and treatment group, which were completely inhibited by the D1 antagonist SCH 23390 (10 microM). In contrast, the ability of SKF 38393 to enhance the cAMP accumulation was blocked by the D2 agonist quinpirole (10 microM) in striatal slices from the intact hemisphere, but not from the lesioned side. In substantia nigra, no significant differences in cAMP accumulation were observed. Our data suggests that chronic L-dopa/carbidopa treatment reverses the increased dopaminergic activity and D1 receptor functional supersensitivity seen after 6-hydroxydopamine lesions, and indicates a D1 receptor-mediated action of L-dopa.(ABSTRACT TRUNCATED AT 250 WORDS)
Hossain
M A
MA
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
Weiner
N
N
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism; D002230:Carbidopa / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D065127:Dopamine D2 Receptor Antagonists; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D012680:Sensitivity and Specificity; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D001708:Biopterins; D007980:Levodopa; D016627:Oxidopamine; D000242:Cyclic AMP; C003402:sapropterin; D002230:Carbidopa; D004298:Dopamine; D006719:Homovanillic Acid