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.