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Striatal Dopaminergic Abnormalities in Human Cocaine Users

OBJECTIVE: Previous human postmortem experiments have shown an abnormally high number of dopamine uptake sites in the striatum of chronic cocaine users, which might contribute to cocaine withdrawal symptoms such as depression and suicidality. Previous inconsistencies in results were perhaps related to selective radioligand affinity changes or a coexisting loss of dopamine neurons. METHOD: In the present study, binding of the cocaine analog [³H]WIN 35428 to the dopamine transporter was assayed in postmortem striatal samples from 15 cocaine-using subjects and 15 matched comparison subjects to determine whether there were differences in number of binding sites or in affinity. Binding to the vesicular monoamine transporter, a measure of total dopaminergic terminals, was also assessed by using the radioligand (+)-[³H]dihydrotetrabenazine (DTBZ). RESULTS: Striatal [³H]WIN 35428 binding sites were significantly more numerous in the cocaine users: the mean B_max value was 9.0 fmol bound/µg protein (SD=2.8) for the cocaine users but only 6.0 (SD=1.7) for the comparison subjects. Severity of chronic cocaine use was significantly related to [³H]WIN 35428 binding level. [³H]DTBZ binding was significantly lower in the cocaine users (mean=330 nCi/mg, SD=42) than in the comparison subjects (mean=374, SD=68). CONCLUSIONS: The present results confirm that cocaine users have a high number of dopamine transporter binding sites on dopaminergic neurons, despite an apparent low number of total dopamine terminals. These abnormalities may contribute to the abnormalities in subjective experience and behavior characteristic of chronic cocaine abusers.

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