In the current study, the most parsimonious explanation for the WIN-induced increase in fEPSP magnitude in CMS animals is enhanced CB1 function at GABAergic terminals. We posit that this sensitization of CB1 function is compensating for the loss of receptors occurring during CMS exposure (Hill et al., 2005; Hill et al., 2008b; Reich et al., 2009). One possible mechanism for increased CB1 function within a decreased population is an increase in receptor binding affinity (Kd); although changes in hippocampal CB1 Kd were not observed following CMS exposure (Hill et al., 2008b; Hill et al., 2005). Kd properties of a receptor, however, may be independent of ligand-receptor efficacy (Feldman et al., 1997). That is, CMS-induced reductions in CB1 may increase efficacy, resulting in a compensatory gain in function. Lending evidence to this hypothesis, Wang et al., (2012) demonstrated that a single acute stressor (restraint) augmented depolarization-induced-suppression of inhibition (DSI), a short-term endocannabinoid-mediated plasticity of GABAergic neurotransmission in the rat hippocampus. This enhancement in endocannabinoid (eCB) signaling was due to a glucocorticoid (GC)-induced increase in 2-AG levels. Similar increases in eCB signaling
