title: Ex vivo [11C]-(+)-PHNO binding is unchanged in animal models displaying increased high-affinity states of the D2 receptor in vitro.
abstract: Dopamine (DA) D2 receptor supersensitivity has been linked to an increase in the density of the D2 high-affinity state as measured in vitro. The two- affinity-state model of the D2 receptor 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 D2 high-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antagonist radiotracer [3H]-raclopride in three dopaminergically supersensitive rat models-AMPH-sensitized rats, rats withdrawn from chronic ethanol, and unilaterally 6-OHDA-lesioned rats-using ex vivo dual-radiotracer biodistribution studies. We find that in AMPH-sensitized rats and rats withdrawn from chronic ethanol treatment, models that exhibited approximately 4-fold increases in the D2 high-affinity state in vitro, the SBRs of [11C]-(+)-PHNO and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 D2 agonist binding, indicating that the two-affinity-state model of the D2 receptor may not apply veridically to living systems. The potential implications of this discrepancy are discussed.
authors: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S1A8. patrick.mccormick@camhpet.ca
authors: Patrick N
authors: PN
authors: McCormick
authors: Shitij
authors: S
authors: Kapur
authors: Greg
authors: G
authors: Reckless
authors: Alan A
authors: AA
authors: Wilson
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D008297:Male; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D020891:Raclopride