The relevance of a reduction in CB1 expression for tolerance mechanisms is somewhat obvious given the preponderance of evidence suggesting that ethanol acts, in part, to facilitate EC release. However, it is much less clear what effect reduced CB1 expression has on withdrawal symptoms. Ethanol withdrawal is characterized by enhanced CNS excitability that can result in hallucinations and seizures (Saitz, 1998). Because CB1 is located at both GABAergic and glutamatergic terminals, activation of this receptor could produce either a facilitation or inhibition of withdrawal symptoms. Consequently, it is not surprising that there is some discrepancy in the literature as to the effect of CB1 on withdrawal. Two studies report decreased HIC scores in CB1 KO mice following chronic ethanol vapor inhalation (Vinod et al., 2008b) and 4 week forced consumption (Racz et al., 2003) while a third reports enhanced HICs following a 12-day forced consumption paradigm (Naassila et al., 2004). Importantly, Vinod et al (2008b) also observed that the reduction in withdrawal severity could be reconstituted in wt mice by treating them with SR. Taken in the context of earlier
