L-DOPA produces strong induction of c-fos messenger RNA in dopamine-denervated cortical and striatal areas of the common marmoset.
Common marmosets (Callithrix jacchus) with near-complete unilateral 6-hydroxydopamine denervation of the dopaminergic input received a single injection of saline or L-DOPA (15mg/kg plus 6.25mg/kg benserazide). Using in situ hybridization, the effects of these treatments on c-fos messenger RNA expression in the cerebral cortex, the striatal complex and the external layer of the pallidum were studied. Moreover, receptor autoradiography was used to determine the levels of dopamine D(1) and D(2) receptors in these areas. In the cerebral cortex, animals treated with L-DOPA displayed a high expression of c-fos messenger RNA restricted to the dopamine-denervated hemisphere. No changes in the levels of cortical D(1) and D(2) receptors were found in the dopamine-denervated hemisphere. L-DOPA treatment also induced a strong expression of c-fos messenger RNA in the striatal complex in the dopamine-denervated hemisphere. The levels of striatal D(2), but not D(1), receptors were increased in the dopamine-denervated hemisphere. In the external pallidum, the major terminal region for D(2) dopamine receptor-containing striatal projection neurons, L-DOPA treatment induced c-fos messenger RNA expression in both the intact and the dopamine-denervated hemispheres.Thus, using c-fos messenger RNA as a biochemical marker of postsynaptic neuronal activation, these results provide evidence that near-complete dopamine depletion causes a profound supersensitization to L-DOPA treatment in the cerebral cortex and in the striatal complex, but not in the external layer of the pallidum, of the primate brain. The cortical response may be unique to the primate brain, but c-fos messenger RNA activation within the striatum has also been reported in the rodent. The effects of L-DOPA probably depend both on a direct activation of supersensitized dopamine receptors by dopamine produced in the few remaining, but hyperactive, dopaminergic nerve terminals and in serotonergic nerve terminals, as well as on indirect actions of L-DOPA related to activation of circuitries connecting cerebral cortex and basal ganglia structures. These results provide novel information on the mechanisms underlying L-DOPA's action in the cerebral cortex, striatum and external pallidum in a primate model of Parkinson's disease.
Svenningsson
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Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden. svennip@rockvax.rockefeller.edu
Gunne
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Andren
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D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western; D002144:Callithrix; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D003714:Denervation; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004745:Enkephalins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology; D011498:Protein Precursors / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020891:Raclopride / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000032:analysis / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000235:genetics; D013373:Substance P / Q000235:genetics; D013378:Substantia Nigra / Q000737:chemistry / Q000502:physiology; D013565:Sympatholytics; D014316:Tritium
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004745:Enkephalins; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; D014316:Tritium; D013373:Substance P; D020891:Raclopride; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin; D004298:Dopamine