Combined muscarinic receptor M 1 and M 4 stimulation reverses cocaine-induced attention deficits in male mice

Background: Cocaine use and cocaine use disorder (CUD) are increasing public health concerns that lack effective treatments. CUD is a chronic illness characterized by relapse, altered activity in the prefrontal cortex and neurocognitive symptoms. Pharmacologically stimulating muscarinic acetylcholine receptors M 1 and/or M 4 has been shown to counteract abuse-related effects of cocaine and, independently, to have pro-cognitive effects. Objectives: We tested the hypotheses that (1) withdrawal from a subchronic cocaine regimen in mice will negatively impact attention and impulsivity and (2) pharmacological stimulation of M 1 , M 4 , or M 1 + M 4 receptors will blunt or reverse these cocaine-induced impairments. Methods: Using a touchscreen rodent continuous performance test, male C57BL/6JRj mice were trained to respond to a target and withhold responses to a non-target stimulus. Mice received 20 mg/kg cocaine for 5 days and 30 mg/kg for 14 days. Then, the effect of treatment with the muscarinic M 1 agonist VU0364572 (3.2 mg/kg) and the M 4 PAM VU0152100 (1.8 mg/kg) was assessed in test probes challenging attention (variable stimulus duration) and impulsivity (variable intertrial interval), respectively. Results: Cocaine exposure significantly and consistently impaired measures of attention (discriminability, accuracy), with less consistent effects on impulsivity (false alarm rate, premature responses). Treatment with combined VU0364572 + VU0152100 reversed cocaine-induced attention deficits, while each drug alone had little effect. Conclusions: These findings support the hypothesis that targeting M 1 and M 4 receptors can rescue cocaine-induced cognitive symptoms. Because cognitive impairments are thought to contribute to relapse to cocaine use, these results further support M 1 /M 4 receptors as promising targets to treat CUD.