Ex vivo [11C]‐(+)‐PHNO binding is unchanged in animal models displaying increased high‐affinity states of the D2receptor in vitro

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Abstract
Dopamine (DA) D2receptor supersensitivity has been linked to an increase in the density of the D2high‐affinity state as measured in vitro. The two‐ affinity‐state model of the D2receptor predicts that the ex vivo specific binding of [11C]‐(+)‐PHNO, an agonist radiotracer thought to bind selectively to the high‐affinity state in vivo, should be increased in animal models that display in vitro increases in the proportion of receptors in the D2high‐affinity state. Here, we test this hypotheses by comparing the ex vivo SBR of [11C]‐(+)‐PHNO with that of the antagonist radiotracer [3H]‐raclopride in three dopaminergically supersensitive rat models—AMPH‐sensitized rats, rats withdrawn from chronic ethanol, and unilaterally 6‐OHDA‐lesioned rats—using ex vivo dual‐radiotracer biodistribution studies. We find that in AMPH‐sensitized rats and rats withdrawn from chronic ethanol treatment, models that exhibited ∼4‐fold increases in the D2high‐affinity state in vitro, the SBRs of [11C]‐(+)‐PHNO and [3H]‐raclopride are unchanged relative to control rats. In unilaterally 6‐OHDA‐lesioned rats, we find that the increase in [11C]‐(+)‐PHNO SBR is no different than that observed for the antagonist radiotracer [3H]‐raclopride (54% ± 16% and 52% ± 14%, respectively). In addition, the effect of acute AMPH pretreatment (4 mg/kg, i.v.) on the SBRs of [11C]‐(+)‐PHNO and [3H]‐raclopride is equivalent in AMPH‐sensitized (−38% ± 12% and −36% ± 8%, respectively) and in control rats (−40% ± 11% and −38% ± 7%). These data emphasize a significant discrepancy between in vitro and in vivo measures of D2agonist binding, indicating that the two‐affinity‐state model of the D2receptor may not apply veridically to living systems. The potential implications of this discrepancy are discussed. Synapse 63:998–1009, 2009.

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