Dopamine agonist radioligand binds to both D2High and D2Low receptors, explaining why alterations in D2High are not detected in human brain scans
Bibliographic record
Abstract
The features of schizophrenia are consistent with increased sensitivity to endogenous dopamine. Animal models of schizophrenia reveal an increase in the in vitro proportion of striatal dopamine D2 receptors in the high-affinity state for dopamine (i.e., D2High), as measured by dopamine/[(3) H]domperidone competition. However, in vivo studies did not reveal the dopamine agonist [(11) C](+)PHNO to be elevated in amphetamine-sensitized rats. Also, no increase was found in the in vivo binding of [(11) C](+)PHNO in schizophrenia patients. This work was done to resolve the contradictory findings. It was found that the in vitro density of rat striatal D2 receptors was 18 pmol/g for [(3) H]raclopride and 12 pmol/g for [(3) H](+)PHNO; most of the latter sites disappeared in the presence of guanine nucleotide. Using 2 nM [(3) H](+)PHNO (K(d) of 0.72 nM at D2) to label D2 receptors in the striata and the human D2 clone, 10 nM to 100 nM dopamine inhibited 10-20% of the [(3) H](+)PHNO bound, representing high-affinity binding of [(3) H](+)PHNO, with the remainder inhibited above 100 nM dopamine, representing low-affinity binding of [(3) H](+)PHNO. It was found that (+)PHNO and (-)NPA dissociated from the D2 clone with half-times of 96 and 600 s, respectively. These rates are slower than the reported sub-second dissociation of the G protein from a receptor, suggesting that these two ligands still occupy the D2Low receptor after the G protein has separated. Thus, the radio-agonist label for (+)PHNO is not selective for dopamine D2High receptors, but also binds to the D2Low state of the dopamine receptor.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".