Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review

Several groups have provided evidence that positron emission tomography (PE T) and single-photon emission computed tomography (SPECT) neuroreceptor ima ging techniques might be applied to measure acute fluctuations in dopamine (DA) synaptic concentration in the living human brain. Competition between DA and radioligands for binding to D-2 receptor is the principle underlying this approach. This new application of neuroreceptor imaging provides a dy namic measurement of neurotransmission that is likely to be informative to our understanding of neuropsychiatric conditions. This article reviews and discusses the body of data supporting the feasibility and potential of this imaging paradigm. Endogenous competition studies performed in rodents, non human primates, and humans are first summarized. After this overview, the v alidity of the model underlying the interpretation of these imaging data is critically assessed. The current reference model is defined as the occupan cy model, since changes in radiotracer binding potential (BP) are assumed t o be directly caused by changes in occupancy of D-2 receptors by DA. Experi mental data supporting this model are presented. The evidence that manipula tion of DA synaptic levels induces change in the BP of several D2 radiotrac ers (catecholamines and benzamides) is unequivocal. The fact that these cha nges in BP are mediated by changes in DA synaptic concentration is well doc umented. The relationship between the magnitude of BP changes measured with PET or SPECT and the magnitude of changes in DA concentration measured by microdialysis supports the use of these noninvasive techniques to measure c hanges in neurotransmission. On the other hand, several observations remain unexplained. First, the amphetamine-induced changes in the BP of D-2 recep tor antagonists [I-123]IBZM and [C-11]raclopride last longer than amphetami ne-induced changes in DA extracellular concentration. Second, nonbenzamide D-2 receptor antagonists, such as spiperone and pimozide, are not affected by changes in DA release, or are affected in a direction opposite to that p redicted by the occupancy model. Similar observations are reported with D-1 radiotracers. These results suggest that the changes in BP following chang es in DA concentration might not be fully accounted by a simple occupancy m odel. Specifically, the data are reviewed supporting that agonist-mediated receptor internalization might play an important role in characterizing rec eptor-ligand interactions. Finally, it is proposed that a better understand ing of the mechanism underlying the effects observed with benzamides is ess ential to develop this imaging technique to other receptor systems.