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Rapid reversal of denervation supersensitivity of dopamine D1 receptors by l-dopa or a novel dopamine D1 receptor agonist, A68930. 1991

D R Britton, and J W Kebabian, and P Curzon
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, IL 60064.

The present report describes the effects of sub-chronic treatment with l-dopa or with a recently characterized, selective dopamine D1 receptor agonist (A68930) on the denervation-induced behavioral supersensitivity of the dopamine D1 receptor. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway, when treated for four successive days with l-dopa + carbidopa show robust contralateral rotation on each day. However, after three days of l-dopa + carbidopa treatment lesioned animals show a significant loss of behavioral supersensitivity to the dopamine D1-selective agonists, A68930 and SKF38393. When lesioned animals were treated daily with A68930, by the second day they showed a virtually complete loss of responsiveness to a dose of the dopamine D1 agonist which previously produced near maximal rotation. In contrast, locomotor hyperactivity to A68930 by intact rats was undiminished over five successive treatment days. These data demonstrate rapid and substantial diminution of the supersensitivity of the denervated dopamine D1 receptor following treatment with l-dopa + carbidopa or with a selective dopamine D1 agonist, while normosensitive dopamine D1 receptor-mediated locomotion in non-lesioned rats is unaltered.

UI MeSH Term Description Entries
D007980 Levodopa The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. L-Dopa,3-Hydroxy-L-tyrosine,Dopaflex,Dopar,L-3,4-Dihydroxyphenylalanine,Larodopa,Levopa,3 Hydroxy L tyrosine,L 3,4 Dihydroxyphenylalanine,L Dopa
D008297 Male Males
D009043 Motor Activity Body movements of a human or an animal as a behavioral phenomenon. Activities, Motor,Activity, Motor,Motor Activities
D011919 Rats, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding. August Rats,Inbred Rat Strains,Inbred Strain of Rat,Inbred Strain of Rats,Inbred Strains of Rats,Rat, Inbred Strain,August Rat,Inbred Rat Strain,Inbred Strain Rat,Inbred Strain Rats,Inbred Strains Rat,Inbred Strains Rats,Rat Inbred Strain,Rat Inbred Strains,Rat Strain, Inbred,Rat Strains, Inbred,Rat, August,Rat, Inbred Strains,Rats Inbred Strain,Rats Inbred Strains,Rats, August,Rats, Inbred Strain,Strain Rat, Inbred,Strain Rats, Inbred,Strain, Inbred Rat,Strains, Inbred Rat
D011954 Receptors, Dopamine Cell-surface proteins that bind dopamine with high affinity and trigger intracellular changes influencing the behavior of cells. Dopamine Receptors,Dopamine Receptor,Receptor, Dopamine
D002839 Chromans Benzopyrans saturated in the 2 and 3 positions. Dihydrobenzopyrans
D003714 Denervation The resection or removal of the nerve to an organ or part. Laser Neurectomy,Neurectomy,Peripheral Neurectomy,Radiofrequency Neurotomy,Denervations,Laser Neurectomies,Neurectomies,Neurectomies, Laser,Neurectomies, Peripheral,Neurectomy, Laser,Neurectomy, Peripheral,Neurotomies, Radiofrequency,Neurotomy, Radiofrequency,Peripheral Neurectomies,Radiofrequency Neurotomies
D000704 Analysis of Variance A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable. ANOVA,Analysis, Variance,Variance Analysis,Analyses, Variance,Variance Analyses
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015259 Dopamine Agents Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons. Dopamine Drugs,Dopamine Effect,Dopamine Effects,Dopaminergic Agents,Dopaminergic Drugs,Dopaminergic Effect,Dopaminergic Effects,Agents, Dopamine,Agents, Dopaminergic,Drugs, Dopamine,Drugs, Dopaminergic,Effect, Dopamine,Effect, Dopaminergic,Effects, Dopamine,Effects, Dopaminergic

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