Activation of VTA/CeA/mPFC cannabinoid CB1 receptors induced conditioned drug effects via interacting with hippocampal CAMKII-CREB-BDNF signaling pathway in rats.

The present study intended to investigate whether the activation of cannabinoid CB1 receptors of the ventral tegmental area (VTA), the central amygdala (CeA) and the medial prefrontal cortex (mPFC) could induce conditioned place preference or aversion (CPP or CPA) in adult male Wistar rats. The involvement of hippocampal signaling pathway of Ca/calmodulin-dependent protein kinase II (CaMKII)/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) was also examined following a 3-day schedule of conditioning with the injection of arachidonylcyclopropylamide (ACPA; a selective cannabinoid CB1 receptors agonist) into the targeted sites. The results showed that intra-VTA injection of the higher dose of ACPA (5 ng/rat) caused a significant CPP associating with the increased hippocampal level of the phosphorylated (p)-CAMKII/CAMKII. Intra-mPFC injection of ACPA at 3 ng/rat caused a significant CPA associating with the decreased p-CAMKII and p-CREB levels and the increased BDNF level in the hippocampus. Moreover, intra-CeA injection of the ACPA (5 ng/rat) induced a significant CPP which was associated with the increased hippocampal levels of p-CAMKII/total (t) CAMKII, p-CREB/tCREB, and BDNF. Exposing the animals to the CPP apparatus after receiving intra-cerebral vehicle injection increased the hippocampal CAMKII/CREB/BDNF signaling pathway, confirming that CPP is an associative learning task. In all experiments, the conditioning treatment with the different doses of ACPA did not affect locomotor activity in the testing phase. Taken together, it can be concluded that cannabinoid CB1 receptors of the VTA, the CeA, and the mPFC are involved in rewarding/aversion effects through the changes in the hippocampal signaling pathways.