Sensitivity of striatal [11C]cocaine binding to decreases in synaptic dopamine

Abstract

We have previously shown that tracer concentrations of [¹¹C]cocaine binding to the dopamine transporter (DAT) in human and baboon striatum can be visualized using positron emission tomography (PET). To determine whether the concentration of dopamine normally present in the synaptic cleft can compete with [¹¹C]cocaine for transporter binding sites, we conducted baboon PET studies with drugs (sodium 4‐hydroxybutyrate, four studies, 200 mg/kg gamma‐vinylGABA, three studies, 300 mg/kg and citalopram, three studies, 2 mgkg) expected to decrease synaptic dopamine. Each study involved two [¹¹C]cocaine injections and PET scans separated by 2‐4 h, with drug administration after the first injection, and without movement of the subject between scans. Time‐activity data from striatum and from cerebellum were used with the arterial plasma input function to determine graphically by Logan plotting [¹¹C]cocaine distribution volumes for the brain regions. Specific binding of [¹¹C]cocaine to DAT in striatum was calculated as the distribution volume ratio (DVR) for striatum and cerebellum. In nine of the ten studies drug treatment produced a small increase in DVR (range, 1‐ll%), and in seven of these studies the increase was >7%. The mean increase was 6.2 ± 4.1%. The reproducibility of the DVR measure was assessed by comparing [¹¹C]cocaine studies conducted without pharmacological treatments using individual baboons on separate days, and thus involving possible repositioning errors, as well as long‐term changes in the state of the striatal dopamine system. For four individual baboons with three or four studies per animal the mean (±s.d.) values of DVR were 1.73 ± 0.03, 1.39 ± 0.03, 1.53 ± 0.06, and 1.54 ± 0.12. The maximum differences between baseline DVRs, expressed as percentage of the lowest value, were 5%, 5%, 9%, and 20%. For two other baboons with two studies each, the between study differences were 1% and 9%. Thus within‐subject variability was quite low, even with repositioning. The results suggest that [¹¹C]cocaine binding to the DAT is sensitive to pharmacological alterations in the concentration of synaptic dopamine. However, the sensitivity of [¹¹C]cocaine to dopamine‐depletion is less than that of the D2 receptor radioligand [¹¹C]raclopride, in agreement with literature in vitro binding studies, and is unlikely to be a serious issue in PET evaluations of DAT density.