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.