Striatal M4 Receptors Mediate M4 PAM Antipsychotic-like Efficacy Independently of Normalizing Striatal Dopamine Release

In awake behaving mice, the M4 PAM VU0467154 (VU'154) reduces basal striatal dopamine release amplitude and shows antipsychotic-like efficacy that is abolished by dorsal striatum M4 knockout.

• Why it matters: The circuit basis for M4 PAM antipsychotic-like efficacy is unclear, especially whether it depends on normalizing dopamine transmission during psychostimulant challenge.
• What they did: Using fiber photometry, the study tested VU'154 effects on basal and amphetamine-stimulated striatal dopamine, and validated dorsal striatum-specific M4 knockout mice (DS-M4-KO) to assess receptor dependence.
• The result: VU'154 dose-dependently reduced basal dopamine release amplitude without changing event frequency or tonic levels, attenuated amphetamine-induced DA release little to none, and its antipsychotic-like efficacy in amphetamine-hallucination-like behavior was absent in DS-M4-KO.