Rapid development of dopaminergic supersensitivity in reserpine-treated rats demonstrated with 14C-2-deoxyglucose autoradiography.
Dopaminergic denervation supersensitivity has been implicated in the pathogenesis of levodopa-induced dyskinesias, the most common and limiting side effect in the drug treatment of Parkinson's disease, yet the mechanisms that mediate altered drug sensitivity remain poorly understood. In animals models, one key component of denervation supersensitivity is the enhanced efficacy of selective D1 agonists to stimulate locomotion. In rats with chronic dopamine depletion induced by 6-hydroxydopamine nigral lesion, the increased ability of D1 agonists to stimulate regional cerebral glucose utilization (RCGU) in the substantia nigra pars reticulata (SNr) has provided a metabolic correlate to the heightened motor response. In this study, we used the stimulation of RCGU in the SNr as a sensitive in vivo assay of D1 agonist effect to examine the time course of development of supersensitivity in rats following acute dopamine depletion with single doses of reserpine (5.0 mg/kg, i.p.) and alpha-methyl-p-tyrosine (AMPT; 100 mg/kg, i.p.). The stimulatory effect of the D1 agonist SKF 38393 (30 mg/kg) on RCGU in the SNr was first enhanced 6 hr after reserpine/AMPT injection and was maximally enhanced at 12-24 hr (relative 2-deoxyglucose uptake increased 32-51%; P less than 0.05). The response to SKF 38393 returned to control values 5 d after reserpine/AMPT injection. The single reserpine/AMPT injections depleted striatal dopamine to 1-2% of control values from 3-48 hr postinjection, whereas D1 and D2 dopamine receptor densities were unchanged at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Trugman
J M
JM
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville 22908.
James
C L
CL
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D008781:Methyltyrosines / Q000494:pharmacology; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology*; D013997:Time Factors; D019805:alpha-Methyltyrosine
D002250:Carbon Radioisotopes; D008781:Methyltyrosines; D019805:alpha-Methyltyrosine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D012110:Reserpine; D003847:Deoxyglucose; D004298:Dopamine