5.3 M5 receptors
The highest levels of M5 receptor expression in the CNS are found in dopamine neurons in both the VTA and SNc (Vilaro et al., 1990; Weiner et al., 1990), where M5 regulates dopamine neuron physiology at both somatic and terminal sites. In the NAc shell, M5 activation potentiates dopamine release driven by optogenetic stimulation of dopamine neurons, and also potentiates glutamate co-release from a subset of VTA dopamine neurons (Shin et al., 2015). Activating M5 receptors also decreases dopamine clearance, likely by promoting PKC-dependent internalization of DAT (Shin et al., 2015; Underhill & Amara, 2021). In SNc neurons, M5 activation produces an inward current and increases firing rate (Foster et al., 2014). Contrary to observations in the NAc shell, M5 activation in the dorsal striatum reduced electrically-evoked dopamine release (Foster et al., 2014), suggesting that the direction of M5-mediated modulation of dopamine transmission could be region-specific.
Because M5 expression is relatively restricted to dopamine neurons, there has been significant interest in targeting M5 in disorders that involve dopamine dysregulation, including substance use disorders (Teal et al., 2019; Walker & Lawrence, 2020). For example, M5-selective negative allosteric modulators (NAMs) that block oxotremorine-induced firing of VTA neurons reduce opioid self-administration and opioid-associated cue reactivity in rats (Garrison et al., 2022; Gould et al., 2019). An M5 NAM also reduces cocaine self-administration in both fixed ratio and progressive ratio tasks (Gunter et al., 2018). In rats selectively bred for high ethanol preference, systemic administration of an M5 NAM decreased ethanol self-administration and cue-induced ethanol seeking (Berizzi et al., 2018). Interestingly, intra-dorsolateral striatum (but not intra-dorsomedial striatum) injection of the M5 NAM reduced ethanol self-administration in rats with extensive prior ethanol experience (Berizzi et al., 2018). Based on the overall conclusion from ex vivo experiments that M5 activation facilitates dopamine neuron firing and release, M5 blockade could reduce drug taking by reducing the reinforcing properties of a variety of psychoactive drugs and inhibiting dopamine responses to drug-associated cues.