Severe depletion of cocaine recognition sites associated with the dopamine transporter in Parkinson's-diseased striatum.
The cocaine congener [3H]CFT, also designated [3H]WIN 35,428 (2 beta-carbomethoxy-3 beta-(4-fluorophenyltropane), labels cocaine receptors associated with the dopamine transporter in primate striatum. Autoradiographic distribution of [3H]CFT binding (5 nM) in human postmortem control and Parkinson's-diseased striatal tissue sections was compared. In control tissue, high and comparable levels of [3H]CFT binding were observed in the putamen and caudate nucleus. At least 90-99% of total [3H]CFT bound was inhibited by (-)-cocaine (30 microM), suggesting that a high proportion of [3H]CFT is specifically bound. In Parkinson's-diseased tissue, binding sites for [3H]CFT were reduced by 80% in the caudate nucleus and 96% in the putamen. This pattern of depletion parallels the previously reported loss of dopamine in these brain regions (Kish, Shannak, and Hornykiewicz, New Engl. J. Med., 318:876-880, 1988). In the dorsal caudate nucleus of Parkinson's-diseased tissue, a lateral-to-medial gradient of [3H]CFT binding was observed, with the lateral caudate more severely depleted than the medial caudate. The marked decrease of [3H]CFT binding sites in Parkinson's diseased striatum supports the following conclusions: 1) the dopamine transporter is localized primarily on presynaptic nigrostriatal terminals; 2) in the caudate and putamen, cocaine recognition sites are associated primarily with the dopamine transporter; 3) the low level of nonspecific binding of [3H]CFT and the marked depletion of [3H]CFT-labeled sites suggest that radiolabeled derivatives of CFT or its congeners may be suitable imaging probes for presynaptic dopamine nerve terminals.
Kaufman
M J
MJ
Department of Psychiatry, Harvard Medical School, Southborough, Massachusetts.
Madras
B K
BK
D000368:Aged; D001345:Autoradiography; D002352:Carrier Proteins; D002421:Caudate Nucleus / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011699:Putamen / Q000378:metabolism; D011955:Receptors, Drug / Q000032:analysis / Q000378:metabolism*; D012016:Reference Values; D014316:Tritium
D002352:Carrier Proteins; D011955:Receptors, Drug; C061445:cocaine receptor; D014316:Tritium; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine