Carbon-11-cocaine binding compared at subpharmacological and pharmacological doses: a PET study.
We have characterized cocaine binding in the brain to a high-affinity site on the dopamine transporter using PET and tracer doses of [11C]cocaine in the baboon in vivo. The binding pattern, however, of cocaine at tracer (subpharmacological) doses may differ from that observed when the drug is taken in behaviorally active doses particularly since in vitro studies have shown that cocaine also binds to low affinity binding sites.


METHODS
PET was used to compare and characterize [11C]cocaine binding in the baboon brain at low subpharmacological (18 micrograms average dose) and at pharmacological (8000 micrograms) doses. Serial studies on the same day in the same baboon were used to assess the reproducibility of repeated measures and to assess the effects of drugs which inhibit the dopamine, norepinephrine and serotonin transporters. Time-activity curves from brain and the arterial plasma input function were used to calculate the steady-state distribution volume (DV).


RESULTS
At subpharmacological doses, [11C]cocaine had a higher binding and slower clearance in striatum than in other brain regions. At pharmacological doses, [11C]cocaine had a more homogeneous distribution. Bmax/Kd for sub-pharmacological [11C]cocaine corresponded to 0.5-0.6 and for pharmacological [11C]cocaine it corresponded to 0.1-0.2. Two-point Scatchard analysis gave Bmax = 2300 pmole/g and Kd' = 3600 nM. Bmax/Kd for sub-pharmacological doses of [11C]cocaine was decreased by cocaine and drugs that inhibit the dopamine transporter, to 0.1-0.2, but not by drugs that inhibit the serotonin or the norepinephrine transporter. None of these drugs changed Bmax/Kd for a pharmacological dose of [11C]cocaine.


CONCLUSIONS
At subpharmacological doses, [11C]cocaine binds predominantly to a high-affinity site on the dopamine transporter.
Volkow
N D
ND
Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
Fowler
J S
JS
Logan
J
J
Gatley
S J
SJ
Dewey
S L
SL
MacGregor
R R
RR
Schlyer
D J
DJ
Pappas
N
N
King
P
P
wang
G J
GJ
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D003042:Cocaine / Q000378:metabolism* / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D010215:Papio; D012701:Serotonin / Q000378:metabolism; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D005473:Fluoxetine; D015283:Citalopram; D012701:Serotonin; D003042:Cocaine; D009638:Norepinephrine