Ex vivo [<sup>11</sup>C]‐(+)‐PHNO binding is unchanged in animal models displaying increased high‐affinity states of the D<sub>2</sub>receptor in vitro
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Bibliographic record
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antagonist radiotracer [3H]-raclopride in three dopaminergically supersensitive rat models-AMPH-sensitized rats, rats withdrawn from chronic ethanol, and unilaterally 6-OHDA-lesioned rats-using ex vivo dual-radiotracer biodistribution studies. We find that in AMPH-sensitized rats and rats withdrawn from chronic ethanol treatment, models that exhibited approximately 4-fold increases in the D2 high-affinity state in vitro, the SBRs of [11C]-(+)-PHNO and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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it