M₄ Positive Allosteric Modulator VU0467154Impacts Amphetamine Sensitization and Spontaneous Locomotion in MaleMice

This study investigates the effects of the muscarinic acetylcholine receptor subtype 4 (M₄) positive allosteric modulator (PAM) VU0467154 on the development, incubation, and expression of amphetamine sensitization in mice, the expression of immediate early genes in the medial prefrontal cortex after induction and expression of sensitization, as well as on spontaneous locomotion and several aspects of sensorimotor function. Mice were pretreated with VU0467154 during the induction phase, before the challenge test, or both. A separate cohort was treated during the incubation period. Tests of spontaneous locomotion and sensorimotor function were conducted after VU0467154 administration to evaluate potential side effects. Treatment with VU0467154 inhibited the development and expression of amphetamine sensitization. This was paralleled by effects on immediate early gene expression in the medial prefrontal cortex. Additionally, previous pretreatment with VU0467154 during the induction phase attenuated the expression of sensitization after a two-week incubation period. However, treatment with VU0467154 during the incubation period did not affect the expression of a sensitized response. VU0467154 significantly reduced spontaneous locomotion without impairing other aspects of sensorimotor function, as assessed by the mesh, adhesive removal, horizontal bar, and negative geotaxis tests. Global M₄ knockout mice confirmed that the inhibitory effect on spontaneous locomotion was specific to M₄ receptors. Our findings provide new insights into the therapeutic potential of M₄ PAMs in modulating the neuroadaptations associated with psychostimulant abuse. Collectively, these results suggest that activation of M₄ receptors could be a promising strategy for modulating dopaminergic signaling and reducing some behaviors associated with substance use disorder.