M1 receptor modulator VU0364572 attenuates cortico-thalamo-striatal transmission and facilitates cocaine CPP extinction

Cocaine use disorder (CUD), marked by persistent drug-seeking and frequent relapse, remains without an effective pharmacological therapy. Modulation of the M1 muscarinic receptor has emerged as a promising therapeutic strategy. VU0364572, a reported M1 receptor bitopic partial agonist, has been shown to reduce excitatory transmission onto the nucleus accumbens (NAc), a key region implicated in addiction. However, its effects on specific excitatory inputs to the NAc remain unclear. In this study, we combined whole-cell electrophysiology with viral circuit tracing to examine how VU0364572 modulates excitatory transmission of the prefrontal cortex (PFC)➜NAc and paraventricular nucleus of the thalamus (PVT)➜NAc pathways. We found that VU0364572 attenuates excitatory input from both PFC and PVT regions. Notably, we also observed a reduction in excitatory transmission from PFC to PVT neurons that project to the NAc, suggesting suppression of excitation within the polysynaptic PFC➜PVT➜NAc pathway. In cocaine-conditioned place preference experiments, repeated VU0364572 facilitated the extinction of cocaine-seeking behavior, suggesting an inhibitory effect on CUD behavior. Reductions in excitatory synaptic transmission in the NAc were present two weeks post administration, indicating a sustained action of VU0364572. These findings suggest that M1 receptor modulation by VU0364572 suppresses excitatory drive to the NAc through both direct (PFC➜NAc) and polysynaptic (PFC➜PVT➜NAc) pathways. Further, inhibitory actions in the NAc are persistent, which could underlie long-term behavioral effects. Taken together, our findings support the potential of VU0364572 as a therapeutic targeting both motivational and affective-related circuits in CUD. VU0364572, a reported muscarinic M1 receptor bitopic partial agonist, suppresses excitatory synaptic input through both direct (PFC➜NAc) and polysynaptic (PFC➜PVT➜NAc) pathways. Modulation of these pathways likely plays a role in VU0364572-associated facilitation of the extinction of cocaine CPP. The figure was created using BioRender. https://BioRender.com/bqenq19 ).