The SP/NK1R system regulates stress and anxiety-related behaviors (reviewed in (Ebner and Singewald, 2006). NK1R antagonists have anxiolytic-like properties, even under basal, non-stressed conditions (Ebner et al., 2008a; Santarelli et al., 2001). Effects of NK1R activation by SP on stress-related behaviors are ultimately likely to be mediated through post-synaptic actions, and modulation of other transmitter systems, but NK1R also has a bidirectional effect on SP release itself (Singewald et al., 2008). NK1R activation suppresses SP release within the amygdala at baseline, but stimulates it during acute stress exposure. This shift is hypothesized to result from volume transmission during stress exposure, resulting in activation of extrasynaptic NK1Rs or other NK receptor subtypes, versus synaptically-restricted transmission at rest. Interestingly, it has been demonstrated that NK1Rs in the striatum are mostly extrasynaptic (Pickel et al., 2000), but this has not yet been confirmed in the amygdala.
