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).