Rats bred for enhanced apomorphine susceptibility have elevated tyrosine hydroxylase mRNA and dopamine D2-receptor binding sites in nigrostriatal and tuberoinfundibular dopamine systems.
From a Wistar population two rat lines were generated using as criterion the behavioral response to the dopamine agonist apomorphine. Rats of the apomorphine-susceptible (apo-sus) line revealed a vigorous gnawing response to apomorphine administration while the other rat line, the apomorphine-unsusceptible (apo-unsus) line, was selected for lack of response to the drug. In the present study using the 12th and 13th generation of these genetically selected lines, we have investigated whether this difference in apomorphine responsiveness was correlated with changes in dopamine neurochemistry. Therefore, we measured tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, as well as dopamine D1 and D2 receptor mRNA levels in discrete brain regions by in situ hybridization. Dopamine (D2/D3) receptor binding was assessed with [125I]iodosulpride in a membrane binding assay and by quantitative autoradiography on tissue sections. [3H]SCH 23390 was used to analyze D1 receptor binding. Apo-sus rats displayed significantly higher TH mRNA levels in the A9 cell group of the substantia nigra pars compacta and in the A12 cell group of the arcuate nucleus. No difference was found in the A10 cell group of the VTA and the A6 cell group of the locus coeruleus. The density of D2/3 binding sites as well as D1 receptor mRNA levels in the striatal projection area of the A9 substantia nigra neurons, were significantly elevated in apo-sus rats. Dopamine D2 receptor mRNA and D1 receptor binding levels in caudate putamen and nucleus accumbens, however, were similar in rats of both lines. In conclusion, high apomorphine susceptibility is related to a potentially enhanced dopamine responsiveness selective for the nigrostriatal and tuberoinfundibular pathways.
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Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, University of Leiden, The Netherlands.
Cools
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Bérod
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Voorn
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Rostène
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de Kloet
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D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D001345:Autoradiography; D001665:Binding Sites; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000502:physiology*; D004351:Drug Resistance / Q000235:genetics; D017403:In Situ Hybridization; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D013378:Substantia Nigra / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
C493595:Drd3 protein, rat; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine