There is strong evidence that increasing ACh signaling in humans results in increased symptoms of depression (Janowsky et al., 1972; Risch et al., 1980). This has been observed with administration of the AChE blocker physostigmine to patients with a history of depression, individuals with Tourette’s syndrome and normal volunteers (Risch et al., 1980; Risch et al., 1981; Shytle et al., 2000). A similar effect has also been described with organophosphate inhibitors of AChE (Rosenstock et al., 1991). More recently, human imaging and post mortem studies suggested that there is increased occupancy of nAChRs by ACh that is highest in individuals who are actively depressed and intermediate in those who have a history of depression with no change in overall nAChR number (Saricicek et al., 2012). In rodent studies, the Flinders rat model was selected for its sensitivity to challenge with an AChE inhibitor, and sensitive rats also display a constellation of depression-like endophenotypes, supporting the idea that increasing ACh levels increases symptoms of depression (Overstreet, 1993).
