Loss of D3 receptors in the zitter mutant rat is not reversed by L-dopa treatment.
In Parkinson's disease (PD) and animal models of parkinsonism the destruction of nigrostriatal (NSB) system results in a marked loss of the dopamine D(3) receptor and mRNA in the islands of Calleja (ICj) and the nucleus accumbens shell (NAS). In animal models, it has been reported that both measures are elevated by repeated intermittent administration of L-dopa. However, a large proportion of PD cases are resistant to L-dopa-induced elevation of D(3) receptor number. The zitter mutant (Zi/Zi) rat replicates the slow progressive degeneration of the NSB observed in PD and also exhibits a loss of D(3) receptor number in the NAS or ICj. To test if this could be reversed with subchronic L-dopa treatment, injections of carbidopa (10 mg/kg i.p.) were followed an hour later with injection of L-dopa (100 mg/kg i.p.) twice a day for 10 days. In control Sprague-Dawley (SD) and zitter heterozygote (Zi/-) rats that do not show a loss of D(3) receptors with vehicle treatment, L-dopa produced no change in D(3) receptor number or in DA terminal density as measured by dopamine transporter (DAT) binding and tyrosine hydroxylase immunoautoradiography (TH-IR). There was a marked loss of DAT and TH-IR in caudate-putamen (CPu) and NA, as well as D(3) receptors in NAS and ICj in Zi/Zi rats but no further change with L-dopa treatment. To determine if the resistance to L-dopa-induced increase in D(3) receptor was due to a deficiency in expression of cortical BDNF or its receptor, TrkB, in CPu and NAS, we examined BDNF mRNA by ISHH in frontal cortex and TrkB mRNA in frontal cortex, CPu, and NA. The loss of the NSB in the Zi/Zi did not alter levels of BDNF or TrkB mRNA, nor did L-dopa administration alter levels BDNF or TrkB mRNA. Thus, unlike in 6-hydroxydopamine-treated rats, in Zi/Zi rats administered L-dopa does not reverse the loss of BDNF mRNA or lead to an elevation of D(3) receptor number.
Joyce
Jeffrey N
JN
Thomas H. Christopher Center for Parkinson's Disease Research, Sun Health Research Institute, Sun City, AZ 85351, USA. Jeff.Joyce@sunhealth.org
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Renish
Lynn
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Osredkar
Tracy
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Hagner
Diane
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Reploge
Maria
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Sakakibara
Shinichi
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Ueda
Shuichi
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D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D050483:Dopamine Plasma Membrane Transport Proteins; D006579:Heterozygote; D006720:Homozygote; D020670:Islands of Calleja / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009833:Olfactory Pathways / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000978:Antiparkinson Agents; D019208:Brain-Derived Neurotrophic Factor; D050483:Dopamine Plasma Membrane Transport Proteins; C493595:Drd3 protein, rat; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C493216:Slc6a3 protein, rat; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D020813:Receptor, trkB