Amphetamine pretreatment induces a change in both D2-Receptor density and apparent affinity: a [11C]raclopride positron emission tomography study in cats.
BACKGROUND
Measuring changes in dopamine (DA) levels in humans using radioligand-displacement studies and positron emission tomography (PET) has provided important empirical findings in disease and normal neurophysiology. These studies are based on the assumption that DA exerts a competitive inhibition on radioligand binding. To test this, we used PET and a Scatchard approach to investigate whether the decrease in [11C]raclopride binding following amphetamine results from competitive or noncompetitive interactions with DA.


METHODS
Scatchard analyses of [11C]raclopride/PET data were used to quantify changes in apparent D2-receptor density (Bmax) and radioligand apparent affinity (K'D) at baseline and after amphetamine pretreatment (2 mg/kg; intravenous) in cats.


RESULTS
Amphetamine induced a 46% decrease in [11C]raclopride binding in the striatum of five cats. Scatchard analyses revealed that this decrease in binding was due to a 28% decrease in Bmax and a concomitant 35% increase in K'D.


CONCLUSIONS
Competition with DA is an insufficient explanation for the decrease in [11C]raclopride binding observed after amphetamine. Noncompetitive interactions, likely representing D2-receptor internalization, also play an important role in this phenomenon. This finding may have important implications for the interpretation of amphetamine-raclopride PET studies in schizophrenia because dysregulation of the agonist-induced internalization of D2 receptors was recently suggested in this disorder.
Ginovart
Nathalie
N
Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Wilson
Alan A
AA
Houle
Sylvain
S
Kapur
Shitij
S
D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007839:Functional Laterality / Q000502:physiology; D007275:Injections, Intravenous; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D020891:Raclopride / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism*; D014055:Tomography, Emission-Computed
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D020891:Raclopride; D000661:Amphetamine