5. Modulation of dopamine transmission by muscarinic
acetylcholine receptors
Metabotropic effects of acetylcholine, including regulation of
dopaminergic transmission, are mediated by five subtypes of muscarinic
acetylcholine receptors (M1-M5) that signal through Gαq(M1, M3, M5) or Gαi/o (M2, M4) (Kruse et al., 2014). In
the midbrain and striatum, these receptors exert complex regulatory
control over dopamine release. Nonselective activation of muscarinic
receptors increases extracellular dopamine levels in freely moving rats
as measured by microdialysis (Smolders et al., 1997). In striatal
slices, nonselective mAChR activation decreases dopamine release evoked
by low-frequency electrical stimulation (Threlfell et al., 2010).
Conversely, muscarinic receptor activation can enhance dopamine release
evoked by high-frequency stimulation (Threlfell et al., 2010). Of the
five muscarinic receptor subtypes, pharmacological and genetic
approaches have identified roles for M1, M4, and M5 in modulating
dopamine release; these receptors act through a variety of mechanisms,
including direct modulation of somatic and terminal dopamine neuron
activity and indirect mechanisms such as modulation of striatal
acetylcholine and endocannabinoid (eCB) release. Muscarinic receptors
contribute to reward-associated learning and behaviors in a variety of
ways. For example, broad blockade of accumbal muscarinic receptors
attenuates cue-induced dopamine release and prevents cue-induced
invigoration of reward seeking in a Pavlovian-to-instrumental transfer
(PIT) task (Collins et al., 2016). Thus, multiple muscarinic receptor
subtypes are likely to play modulatory roles in responses to
psychoactive drugs that enhance dopamine transmission.