Selective targeting of M1 receptors (M1R) presents a promising therapeutic approach for managing cocaine use disorder. In this study, we investigated the acute cellular and synaptic effects of the M1R modulator VU0364572 on medium spiny neurons (MSNs) in the core of the nucleus accumbens. MSNs are targets of dopaminergic projections from the ventral tegmental area, which play a key role in signaling saliency of drug-related stimuli, and they receive glutamatergic inputs from the cortex that regulate the development, reinstatement, and extinction of drug dependence. For the first time, we demonstrate that VU0364572 modulates both the excitability of MSNs and excitatory neurotransmission onto these neurons in a concentration- and sex-dependent manner. In female C57/BL/6J mice, at 90 μM, VU0364572 increased postsynaptic and presynaptic excitability, while 30 μM reduced MSNs excitability without significantly affecting neurotransmission. In male C57/BL/6J mice, 60 μM enhanced glutamatergic neurotransmission, while 90 μM resulted in a reduction of excitatory synaptic activity. At all three concentrations cellular excitability was decreased in MSNs from male mice. These findings provide novel insight into the cellular and synaptic actions of VU0364572 and highlight the potential for sex-specific treatment strategies in cocaine use disorder.