2-AG also did not substitute for THC in mice when it was administered in the absence of a metabolic inhibitor, although it reduced response rates at higher doses. When co-administered with 1 mg/kg of the MAGL inhibitor NAM (Saario et al., 2005), a dose that was shown to potentiate the cannabimimetic effects of 2-AG in the tetrad tests in mice (Burston et al., 2008), 2-AG still did not substitute for THC. At 5 mg/kg, NAM failed to produce a significant increase in cerebellar concentration of 2-AG, suggesting that 1 mg/kg NAM may have been insufficient to inhibit MAGL despite the observed decreases in response rates. This hypothesis is consistent with the relatively poor potency and selectivity of NAM for MAGL (Matuszak et al., 2009). In contrast, the more potent and selective MAGL inhibitor JZL184 (Long et al., 2009a; Matuszak et al., 2009) increased nose pokes in the THC-associated aperture in mice even in the absence of 2-AG co-administration (Long et al., 2009c). Cannabinoid CB1 receptor mediation of this effect is suggested by its rimonabant reversal, as well as by the
