5.2 M4 receptors
M4 receptors are expressed by striatal neurons including spiny projection neurons and cholinergic interneurons but are not found on midbrain dopamine neurons. Mice lacking M4 receptors have elevated accumbal dopamine levels, suggesting that M4 tonically inhibits dopamine release (Tzavara et al., 2004). Interestingly, the non-selective muscarinic agonist oxotremorine potentiates dopamine release evoked by high potassium concentrations, an effect that is lost in M4 knockout mice and likely mediated by inhibition of striatal GABA release (Zhang et al., 2002). These seemingly contradictory findings suggest complex modulatory mechanisms that are differentially engaged by different methods to drive dopamine release. Although earlier studies suggested that M4-mediated inhibition of striatal dopamine release is likely mediated by inhibition of ACh release from CINS (Shin et al., 2015; Threlfell et al., 2010), more recent studies in which M4 was conditionally deleted from D1-expressing SPNs demonstrated that activation of M4 in this population of neurons mobilized eCB release to inhibit dopamine release (Foster et al., 2016). Thus, M4 has the potential to regulate dopamine release driven by somatic firing and local acetylcholine-dependent release by distinct mechanisms.
Consistent with the inhibitory role of M4 observed under normal conditions, M4 PAMs reduce psychostimulant-induced dopamine releasein vivo and inhibit the locomotor enhancing effects of psychostimulant drugs (Byun et al., 2014; Dall et al., 2017; Dencker et al., 2012; Foster et al., 2021). Likewise, M4 PAM administration reduces cocaine self-administration (Dencker et al., 2012). Consistent with the importance of M4 receptors expressed by D1-SPNs for inhibiting dopamine release, selective deletion of M4 from D1-SPNs impairs the ability of an M4 PAM to reduce cocaine self-administration (Dencker et al., 2012). However, M4 activation does not prevent all psychostimulant-induced rewarding effects; for example, mice treated with an M4 PAM still showed cocaine-conditioned place preference (Dall et al., 2017). M4 activation can constrain responses to non-stimulant drugs as well, as intrastriatal infusion of an M4 PAM reduces ethanol self-administration and cue-induced reinstatement (Walker et al., 2020). Based on these findings and others, M4 PAMs have been proposed for treatment of a variety of substance use disorders as well as other psychiatric disorders involving dopamine dysregulation (Foster et al., 2021; Walker et al., 2020).