Upregulation of CB1 receptor binding in the ventromedial prefrontal cortex promotes proactive stress-coping strategies following chronic stress exposure

Accumulating evidence has revealed that dysregulation of the endocannabinoid system could contribute to the development of major depression. Studies carried out post-mortem in depressed suicide victims have revealed increased CB1 receptor binding site density in the prefrontal cortex (PFC). Accordingly, exposure of rodents to chronic unpredictable stress (CUS) results in phenotypic changes that mirror those of human depression, including increased CB1 receptor binding site density in the PFC. Our goal in these studies was to examine the effects of CUS on the density of CB1 receptor binding sites in the rodent medial PFC and to explore the role of this alteration in the behavioral changes invoked by CUS. Rodents exposed to CUS exhibited increased CB1 receptor maximal binding site density (B-max) within the ventromedial PFC, but not the dorsomedial PFC. To determine whether this change in the ventromedial PFC is an adaptive response, or alternatively, a consequence of chronic stress that contributes to the adoption of passive coping, we examined whether local CB1 receptor blockade within the ventromedial PFC following CUS would significantly alter behaviors in the forced swim test (FST). CUS exposure significantly increased passive coping in the FST, and this was further augmented by discrete ventromedial PFC microinfusions of the CB1 receptor antagonist AM251 prior to swim stress. Moreover, local CB1 receptor blockade reduced active coping responses in CUS-exposed rats. These findings suggest that the increase in CB1 receptor B-max observed in the ventromedial PFC of rodents exposed to CUS maintains proactive coping strategies following chronic stress exposure. (C) 2012 Elsevier B.V. All rights reserved.