Chronic handling produced stable changes in the endocannabinoid signaling system in both Papez circuitry and input-output loops of the basal ganglia (see Figure 9). Here, we demonstrate for the first time that chronic handling alters both cannabinoid receptor densities and endocannabinoid content within brain structures that control emotional expression (i.e., lateral globus pallidus, prefrontal, piriform, and cingulate cortices, hippocampus, nucleus accumbens). In the prefrontal cortex, handling increased 2-AG without reliably altering anandamide levels, compared to non-handling. Handling accounted for about half of the variance in 2-AG content in the prefrontal cortex, as assessed by effect size calculations (Cohen, 1998). To a lesser extent, in the nucleus accumbens, handling increased anandamide levels without altering levels of 2-AG, compared to non-handling. Further, the reliable main effect of handling we observed in the piriform cortex for anandamide content may potentially be attributable to increased anandamide levels observed in non-handled isolates. Our data are consistent with the observation that handling decreased the anxiolytic effect of the FAAH inhibitor URB597 (Haller et al., 2009). Handling and URB597 may rely on similar endocannabinoid system-dependent mechanisms. Chronic
