A consistent finding from studies using sub-chronic or chronic ethanol treatments is that CB1 expression is reduced either immediately after treatment or during acute withdrawal. Why does this occur, and what is the molecular machinery responsible for this process? The CB1 receptor is known to be rapidly internalized and transported to lysosomal degradation pathways in periods of saturable activation, and the tolerance that develops to the analgesic effects of CB1 agonists is attributed to this process. One mechanism by which this can occur is through binding proteins like G-protein-associated sorting protein 1 (GASP1) that target CB1 for degradation (Martini et al., 2007; Tappe-Theodor et al., 2007), and a recent study has found that mice lacking the GASP1 gene do not develop the analgesic tolerance to WIN observed in wt mice (Martini et al., 2010). Our lab has recently reported that sub-chronic treatment with ethanol induces a cross-tolerance to several WIN-induced behaviors including its antinociceptive effects (Pava et al., 2012), and it is possible that this reduction in CB1 function may be mediated by GASP1. Alternatively, cross-tolerance between the analgesic effects
