ACh signals through two classes of receptors: metabotropic muscarinic receptors (mAChRs) and ionotropic nicotinic receptors (nAChRs) (reviewed in Picciotto et al., 2000 and Wess, 2003a). Muscarinic receptors are coupled either to Gq proteins (M1, M3, and M5 subtypes)

that activate phospholipase C 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 postsynaptically throughout the brain, producing diverse consequences for brain activity (Figure 1). As examples of the Selleck Bortezomib 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 selleckchem 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). Nicotinic receptors function as nonselective, excitatory cation channels (Changeux et al., 1998; Picciotto et al., 2001) and occur as homomeric or heteromeric assemblies of a large family of α- and β-subunits (α2-α7 and β2-β4; reviewed in Picciotto et al., 2000). While neuromodulators

are typically associated with metabotropic signaling, the role of the ionotropic nAChRs in the brain appears to be largely modulatory as well (Picciotto, 2003). For example, nAChRs are not clustered at postsynaptic membranes apposed to sites of ACh release, but are rather dispersed along the surface (and intracellular compartments) of neurons, including presynaptic terminals (McGehee et al., 1995; Vidal and Changeux, 1993), cell bodies, and even axons (Arroyo-Jiménez Ketanserin et al., 1999; Hill et al., 1993; Kawai et al., 2007). In addition, stimulation of nAChRs can increase the release of glutamate, GABA, DA, ACh, norepinephrine, and serotonin (McGehee et al., 1995; Wonnacott, 1997) (Figure 1). Nicotinic modulation of neurotransmitter release is often subtype-specific, and this specificity can vary across brain areas, with distinct nAChRs coupling to release of glutamate (α7) versus GABA (α4β2) (Mansvelder et al., 2002) in the ventral tegmental area (VTA), while β2-containing nAChRs can modulate the release of glutamate from thalamocortical projections (Parikh et al., 2010). Similarly, different nAChR subtypes mediate the release of DA (α4/α6β2) versus ACh (α3β4) (Grady et al., 2001). Presynaptic effects of nAChRs contribute to synaptic plasticity in the VTA (Mansvelder and McGehee, 2000; Wooltorton et al., 2003), hippocampus (Ge and Dani, 2005; Ji et al., 2001; Radcliffe and Dani, 1998), and prefrontal cortex (Couey et al., 2007).