Rapid reversal of denervation supersensitivity of dopamine D1 receptors by l-dopa or a novel dopamine D1 receptor agonist, A68930.
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.
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, IL 60064.
D R
DR
Britton
J W
JW
Kebabian
P
P
Curzon
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D003714:Denervation; D015259:Dopamine Agents / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1
D002839:Chromans; D015259:Dopamine Agents; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; C065380:A 68930