5.1 M1 receptors
M1 receptors are the most abundant muscarinic receptor in the striatum (Weiner et al., 1990). Studies measuring dopamine transmission usingin vivo microdialysis in the striatum of freely moving rats demonstrated that M1 antagonism decreases dopamine release, suggesting that M1 activity tonically augments dopamine transmission (De Klippel et al., 1993; Smolders et al., 1997). Although the exact mechanisms for M1-mediated facilitation of dopamine transmission are not clear, reduced dopamine reuptake due to PKC-dependent internalization of DAT is one putative contributor (Underhill & Amara, 2021). Circuit-level effects that increase striatal glutamate transmission to enhance nicotinic receptor-dependent dopamine release could also play a role.
Although M1 appears to facilitate dopamine release under normal conditions, studies evaluating the effect of chronic M1 agonist treatment on cocaine-induced dopamine show decreased cocaine-induced dopamine transmission. Concordantly, M1 agonist treatment facilitates the reallocation of behavior from cocaine rewards to food pellets in operant cocaine vs. food choice task (Weikop et al., 2020). In addition, despite evidence that M1 blockade reduces dopamine release, both nonselective and M1-preferring muscarinic antagonists produce cocaine-like discriminative stimulus effects that are lost in mice lacking M1 receptors (Joseph & Thomsen, 2017). Based on these findings, enhancing M1 activity has been suggested as a putative treatment strategy for cocaine use disorder. Because M1 expression is not detected in dopamine neurons, further investigation will be required to determine the mechanisms by which M1 modulates dopamine transmission evoked by psychoactive drugs.