CRH receptor 1 (CRHR1) and the cannabinoid receptor 1 (CB1) are both G protein-coupled receptors. Activation of CRHR1 leads to increases in cAMP production and phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In contrast, CB1 is negatively coupled to the cAMP signaling cascade. In this study we analyzed a putative interaction between these two systems focusing on the regulation of the expression of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene. In situ hybridization revealed co-expression of CRHR1 and CB1 receptors in the granular layer of the cerebellum. Therefore, we analyzed the effects of CRH and the CB1 agonist WIN-55,212-2 on BDNF expression in primary cerebellar neurons from rats and mice. We observed that application of CRH for 48 h led to an increase in BDNF mRNA and protein levels. This effect was inhibited by WIN-55,212-2. At the level of intracellular signaling, short-term application of WIN-55,212-2 inhibited CRH-induced cAMP accumulation and CREB phosphorylation. Pharmacological analysis demonstrated that the CRHR1 antagonist R121919, the protein kinase A (PKA) inhibitor H89 and the calcium chelator BAPTA-AM inhibited CRH-mediated BDNF expression. Moreover, depolarization-induced BDNF synthesis was also inhibited by long-term application of WIN-55,212-2 in wild-type, but not CB1-deficient mice. Thus, these data highlight an interaction between the CRH and the cannabinoid system in the regulation of BDNF expression by influencing cAMP and Ca²⁺ signaling pathways.