M4 PAM's antipsychotic-like effect works through striatal M4, not dopamine normalization
- In mice, fiber photometry showed the M4 PAM VU0467154 lowered basal dopamine release events but left amphetamine-evoked dopamine largely intact, even though it still blunted antipsychotic-like behavior.
- Mice lacking M4 in the dorsal striatum did not respond to the compound, pointing to postsynaptic striatal M4 signaling as the driver.
💡 Points Based on the abstract
This weakens the neat story that M4 agents work by pulling dopamine back to normal, and that matters for biomarker choice: a dopamine readout may not tell you whether a clinical M4 candidate is engaging its mechanism. The striatal knockout is the convincing part. It is still one PAM in rodent behavioral models, so I'd hold off on reading it across to patients.