ACh signals through two classes of receptors: metabotropic muscarinic receptors (mAChRs) and ionotropic nicotinic receptors (nAChRs) (reviewed in (Picciotto et al., 2000; Wess, 2003a)). Muscarinic receptors are coupled either to Gq proteins (M1, M3, and M5 subtypes) that activate phospholipase C (PLC) or Gi/o proteins (M2 and M4 subtypes) that negatively couple to adenylate cyclase (reviewed in (Wess, 2003a)), linking ACh activity to a variety of biochemical signaling cascades. Moreover, mAChRs are located both pre- and post-synaptically throughout the brain, producing diverse consequences for brain activity (Figure 1). As examples of the heterogeneous effects of mAChR stimulation, presynaptic M2/M4 mAChRs can act as inhibitory autoreceptors on cholinergic terminals (Douglas et al., 2002; Raiteri et al., 1984) and reduce glutamate release from corticocortical and corticostriatal synapses (Higley et al 2009, Gil et al 1997). In contrast, M1/M5 receptors can stimulate dopamine (DA) release from striatal synaptosomes (Zhang et al., 2002) and postsynaptic M1/M5 receptors can increase excitability of cortical pyramidal neurons (Douglas et al., 2002; McCormick and Prince, 1985).
