Paradoxical Striatal Cellular Signaling Responses to Psychostimulants in Hyperactive Mice
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Bibliographic record
Abstract
Recent investigations have shown that three major striatal-signaling pathways (protein kinase A/DARPP-32, Akt/glycogen synthase kinase 3, and ERK) are involved in the regulation of locomotor activity by the monoaminergic neurotransmitter dopamine. Here we used dopamine transporter knock-out mice to examine which particular changes in the regulation of these cell signaling mechanisms are associated with distinct behavioral responses to psychostimulants. In normal animals, amphetamine and methylphenidate increase extracellular levels of dopamine, leading to an enhancement of locomotor activity. However, in dopamine transporter knock-out mice that display a hyperactivity phenotype resulting from a persistent hyperdopaminergic state, these drugs antagonize hyperactivity. Under basal conditions, dopamine transporter knock-out mice show enhanced striatal DARPP-32 phosphorylation, activation of ERK, and inactivation of Akt as compared with wild-type littermates. However, administration of amphetamine or methylphenidate to these mice reveals that inhibition of ERK signaling is a common determinant for the ability of these drugs to antagonize hyperactivity. In contrast, psychostimulants activate ERK and induce hyperactivity in normal animals. In hyperactive mice psychostimulant-mediated behavioral inhibition and ERK regulation are also mimicked by the serotonergic drugs fluoxetine and 5-carboxamidotryptamine, thereby revealing the involvement of serotonin-dependent inhibition of striatal ERK signaling. Furthermore, direct inhibition of the ERK signaling cascade in vivo using the MEK inhibitor SL327 recapitulates the actions of psychostimulants in hyperactive mice and prevents the locomotor-enhancing effects of amphetamine in normal animals. These data suggest that the inhibitory action of psychostimulants on dopamine-dependent hyperactivity results from altered regulation of striatal ERK signaling. In addition, these results illustrate how altered homeostatic state of neurotransmission can influence in vivo signaling responses and biological actions of pharmacological agents used to manage psychiatric conditions such as Attention Deficit Hyperactivity Disorder (ADHD).
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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 | 0.000 | 0.001 |
| 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 | 0.000 | 0.000 |
| Open science | 0.000 | 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