Functional sensitization of striatal dopamine D1 receptors in the 6-hydroxydopamine-lesioned rat.
Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of rats in which the nigrostriatal pathway was lesioned by 6-hydroxydopamine 20-24 months before the experiments. In the intact (contralateral) striatum the potency and the efficacy of dopamine in stimulating adenylyl cyclase was lower in the presence of high NaCl concentrations (120 mM) compared with the effects of dopamine in an NaCl-poor assay medium (20 mM). The same effect of NaCl was observed in the striatum on the side of a weak, behaviourally ineffective 6-hydroxydopamine lesion resulting in a loss of 57% of striatal dopamine. This effect of NaCl was absent in the strongly denervated striatum, i.e. in rats having a 99.8% dopamine loss and rotating when challenged with a low dose of apomorphine. Thus, in denervated vs intact striatum, in the presence of a physiological concentration of NaCl, dopamine-stimulated adenylyl cyclase showed a sensitization which was absent in assays with 20 mM NaCl. The inhibition of adenylyl cyclase by dopamine via D2 receptors, which was seen in the presence of 120 mM NaCl and the D1 antagonist SCH 23390, was not affected by denervation. We suggest that chronic dopaminergic denervation of the striatum results in a stabilized, i.e. NaCl-insensitive, high affinity state of D1 receptors. This may be the basis for a sensitization of the coupling mechanism of the denervated D1 receptors to adenylyl cyclase.
Pifl
C
C
Institute of Biochemical Pharmacology, University of Vienna, Austria.
Reither
H
H
Hornykiewicz
O
O
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology*; D008297:Male; D009043:Motor Activity / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1; D012399:Rotation
D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D016627:Oxidopamine; D000262:Adenylyl Cyclases