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From receptor availability to receptor reactivity
Abstracts / NeuroImage 41 (2008) T14–T57
T17
Oral Presentation No.: O4
From receptor availability to receptor reactivity Albert Gjeddea,c and J. Gedaya,b a
Pathophysiology and Experimental Tomography Centre, Aarhus University Hospitals, Aarhus, Denmark b Department of Neurology, Aarhus University Hospitals, Aarhus, Denmark c Center of Functionally Integrative Neuroscience (CFIN), Aarhus University, Aarhus, Denmark
Introduction: The binding potential is the most commonly reported outcome measure in PET studies of radioligand interaction with neuroreceptors. As the ratio of bound and unbound ligand, the concept of binding potential applies individually to all ligands of a receptor that may at any time interact with the receptor. The binding potential is often described as an index of receptor “availability”, equal to the number of unoccupied receptors relative to the affinity to the ligand to which the binding potential refers, i.e., P B Bmax B Bmax Kd ¼ BP0 ¼ BP0 ð1 rÞ BPND ¼ ¼ ¼ C Kd K Vd þ C K Vd þ C where the symbols have their conventional meaning, including K Vd , the Michaelis constant in the presence of competitors (IC50), and σ, the occupancy. Unfortunately, the terms “potential” and “availability” promise a capacity for increased reception that may not be reachable. The binding potential is in fact a biased index of the additional effect of increased binding that can be reached when the ligand concentration increases. Method: Here we define a related measure, the receptor reactivity at a given ligand concentration, which more accurately expresses the gain of binding effect achieved by a given increase, i.e., P dB Bmax B Bmax Kd RRND ¼ ¼ ¼ ¼ BPND ð1 rÞ ¼ BP0 ð1 rÞ2 dC K Vd þ C ð K Vd þ C Þ2 where the receptor reactivity is the incremental binding obtained with a unit increase of ligand concentration, in the simplest case equal to the slope of the Michaelis–Menten curve at that particular point, as shown in the left panel of the figure. The reactivity is the magnitude of this slope. Result: The slope of the Michaelis–Menten curve declines as a function of the ligand occupancy as shown in the right panel of the figure. The definition of the receptor reactivity implies that the reactivity is proportional to the square of the binding potential (with 1/BP0 as the proportionality factor). Thus, if the binding potential declines by 50% (for example from 3 to 1.5), the receptor reactivity has declined by 75%.
Conclusion: The decline of receptor reactivity as a function of ligand occupancy is relevant to the understanding of the relationship between tonic and phasic release modes of monoamines in brain. Increasing the steady-state concentration of a neuromodulator may substantially decrease the reactivity of the receptors to phasic release. In highly sensation-seeking individuals, this may explain how elevated steady-state levels of dopamine may inhibit the effect of normal sensations. Also, if receptors of opposing action coexist, changing the steady-state level of a common ligand may switch the net action from inhibitory to excitatory or vice versa. doi:10.1016/j.neuroimage.2008.04.191
T17
Oral Presentation No.: O4
From receptor availability to receptor reactivity Albert Gjeddea,c and J. Gedaya,b a
Pathophysiology and Experimental Tomography Centre, Aarhus University Hospitals, Aarhus, Denmark b Department of Neurology, Aarhus University Hospitals, Aarhus, Denmark c Center of Functionally Integrative Neuroscience (CFIN), Aarhus University, Aarhus, Denmark
Introduction: The binding potential is the most commonly reported outcome measure in PET studies of radioligand interaction with neuroreceptors. As the ratio of bound and unbound ligand, the concept of binding potential applies individually to all ligands of a receptor that may at any time interact with the receptor. The binding potential is often described as an index of receptor “availability”, equal to the number of unoccupied receptors relative to the affinity to the ligand to which the binding potential refers, i.e., P B Bmax B Bmax Kd ¼ BP0 ¼ BP0 ð1 rÞ BPND ¼ ¼ ¼ C Kd K Vd þ C K Vd þ C where the symbols have their conventional meaning, including K Vd , the Michaelis constant in the presence of competitors (IC50), and σ, the occupancy. Unfortunately, the terms “potential” and “availability” promise a capacity for increased reception that may not be reachable. The binding potential is in fact a biased index of the additional effect of increased binding that can be reached when the ligand concentration increases. Method: Here we define a related measure, the receptor reactivity at a given ligand concentration, which more accurately expresses the gain of binding effect achieved by a given increase, i.e., P dB Bmax B Bmax Kd RRND ¼ ¼ ¼ ¼ BPND ð1 rÞ ¼ BP0 ð1 rÞ2 dC K Vd þ C ð K Vd þ C Þ2 where the receptor reactivity is the incremental binding obtained with a unit increase of ligand concentration, in the simplest case equal to the slope of the Michaelis–Menten curve at that particular point, as shown in the left panel of the figure. The reactivity is the magnitude of this slope. Result: The slope of the Michaelis–Menten curve declines as a function of the ligand occupancy as shown in the right panel of the figure. The definition of the receptor reactivity implies that the reactivity is proportional to the square of the binding potential (with 1/BP0 as the proportionality factor). Thus, if the binding potential declines by 50% (for example from 3 to 1.5), the receptor reactivity has declined by 75%.
Conclusion: The decline of receptor reactivity as a function of ligand occupancy is relevant to the understanding of the relationship between tonic and phasic release modes of monoamines in brain. Increasing the steady-state concentration of a neuromodulator may substantially decrease the reactivity of the receptors to phasic release. In highly sensation-seeking individuals, this may explain how elevated steady-state levels of dopamine may inhibit the effect of normal sensations. Also, if receptors of opposing action coexist, changing the steady-state level of a common ligand may switch the net action from inhibitory to excitatory or vice versa. doi:10.1016/j.neuroimage.2008.04.191