Consistent with an increase in ACh leading to symptoms of depression, antagonism of mAChRs or nAChRs, or blockade of ACh signaling through nAChRs with partial agonists, can decrease depression-like behavior in rodents (Caldarone et al., 2004; De Pablo et al., 1991; Mineur et al., 2007; Picciotto et al., 2002; Rabenstein et al., 2006). Consistent with a role for increased ACh signaling in affective disorders in humans, clinical trials have suggested that blockade of either mAChRs (Furey and Drevets, 2006; Furey et al., 2010) or nAChRs (George et al., 2008; Shytle et al., 2002) can decrease symptoms of depression. While an increase in cholinergic tone appears to be sufficient to induce depression-like symptoms in humans, a recent study has shown that decreasing striatal cholinergic tone in the mouse can lead to depression-like symptoms, likely through interneuron-dependent disinhibition of striatal neurons (Warner-Schmidt et al., 2012), highlighting the fact that ACh can induce heterogeneous effects in different brain areas that appear to have opposite behavioral consequences. The behavioral effect of ACh signaling in vivo likely depends on the baseline conditions in the particular
