Sodium dependent [3H]cocaine binding associated with dopamine uptake sites in the rat striatum and human putamen decrease after dopaminergic denervation and in Parkinsons disease

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Abstract
The binding of radiolabelled cocaine, an inhibitor of dopamine uptake, to the post-mortem human putamen was studied and compared to that in the rat striatum. Saturation analysis of [3H]cocaine binding to the human putamen revealed the presence of a high affinity component of binding with a K d of 0.21 μmol/l and a B max of 1.47 pmol/mg protein. In addition a low affinity component (K d=26.4 μmol/l) was demonstrated, having a B max of 42.2 pmol/mg protein. Also in the rat striatum [3H]cocaine binding was both of high affinity (K d=0.36 μmol/l, B max=5.56 pmol/mg protein) and low affinity (K d=25.9 μmol/l, B max=35.6 pmol/mg protein). A pharmacological characterisation of high affinity [3H]cocaine binding to rat striatal membranes clearly indicates an association with the neuronal dopamine transporter. The IC50 values of 8 selected drugs for inhibition of [3H]cocaine binding in the rat striatum were highly significantly correlated with their potency to inhibit [3H]dopamine uptake into slices of the rat striatum. [3H]Cocaine binding was stereospecifically inhibited by (+)nomifensine and (+)diclofensine which were 50–80-fold more active than their respective (-)isomers. Drugs with dopamine releasing activity were more potent at inhibiting [3H]dopamine uptake than at competing for the high affinity site of [3H]cocaine binding. A highly significant correlation was found between IC50 values for [3H]cocaine binding in the rat striatum and the human putamen. Further evidence in support of an association of [3H]cocaine binding in the rat striatum with the dopamine transporter was obtained from lesion studies. Thus, intranigral 6-hydroxydopamine administration produced a marked (67%) decrease in striatal [3H]cocaine binding. Also in the human putamen high affinity [3H]cocaine binding sites appear localized on dopaminergic nerve terminals as evidenced by a prominent decrease in binding in the putamen obtained from subjects with Parkinsons disease. It is concluded that [3H]cocaine may be a useful ligand to examine the dopamine transporter in the rat striatum and the human putamen. Therefore it offers a new and valuable approach in the study of drug effects and neuropsychiatric diseases.

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