title: 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.
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 Kd of 0.21 mumol/l and a Bmax of 1.47 pmol/mg protein. In addition a low affinity component (Kd = 26.4 mumol/l) was demonstrated, having a Bmax of 42.2 pmol/mg protein. Also in the rat striatum [3H]cocaine binding was both of high affinity (Kd = 0.36 mumol/l, Bmax = 5.56 pmol/mg protein) and low affinity (Kd = 25.9 mumol/l, Bmax = 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.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000818:Animals; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D003042:Cocaine / Q000378:metabolism* / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D006892:Hydroxydopamines / Q000494:pharmacology; D066298:In Vitro Techniques; D026901:Membrane Transport Proteins / Q000378:metabolism; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism*; D011699:Putamen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism
chemical_list: D006892:Hydroxydopamines; D026901:Membrane Transport Proteins; D016627:Oxidopamine; D012964:Sodium; D003042:Cocaine; D004298:Dopamine