Finally, the enhanced DSI is not likely to be mediated through enhanced CB1 receptor sensitivity as our data indicate that CB1 receptor sensitivity to agonist is decreased, rather than increased by repeated restraint stress. These data are consistent with a recent report showing a decrease in CB1 receptor-mediated inhibition of GABA release in the striatum after 3 days of social defeat stress (Rossi et al, 2008). We have shown earlier that CB1 receptor number and affinity are unchanged in the amygdala after 10 days of restraint stress (Rademacher et al, 2008). These data seem discordant, however, earlier studies have shown that in vivo exposure to CB1 agonists can decrease CB1 receptor sensitivity without affecting receptor number or signaling efficacy (Mato et al, 2004). This form of ‘functional tolerance’ may be occurring in our model as a result of increased CB1 receptor activation by endogenous 2-AG in response to repeated restraint exposures. Further studies into the molecular determinants of stress-induced increases in 2-AG levels will be required to gain insight into the mechanisms responsible for enhanced eCB signaling observed in this study.
