Crosstalk between Dopamine D₂ receptors and cannabinoid CB₁ receptors regulates CNR1 promoter activity via ERK1/2 signaling

Previously, we found that chronic methamphetamine treatment altered cannabinoid type 1 receptor (CB 1 R)‐dependent cAMP /PKA/dopamine and cAMP‐regulated phosphoprotein of Mr 32 000 (DARPP‐32)/T34/PP2B signaling and decreased levels of CB 1 R protein and mRNA in the nucleus accumbens. These findings suggested the existence of signaling interplay between mesolimbic dopamine and CB 1 R. In this study, we further investigate interactions between CB 1 R and dopamine D2 receptor (D 2 R) signaling. Activation of either CB 1 R or D 2 R increased extracellular signal‐regulated kinases 1 and 2 (ERK1/2) phosphorylation, while co‐stimulation of CB 1 R and D 2 R evoked an additive effect on the phospho‐ERK1/2 signal. This effect was mediated through a pertussis toxin‐sensitive Gαi/o pathway in primary striatal cells. Furthermore, the mRNA level of CB 1 R was increased via dopamine D2 receptor short form (D 2S R) by treatment with D 2 R agonist quinpirole in D 2S R/C6 glioma cells. This effect could be suppressed by co‐treatment with the ERK1/2 inhibitor U0126. To test if D 2S R could transcriptionally regulate CB 1 R, the 5′‐untranslated region (5′‐UTR) of the cannabinoid receptor 1 ( CNR1 ) gene was sequenced from rat brain. Results showed that the CNR1 gene includes two exons, which contain 375 bp of 5′‐UTR and are separated by a 17‐kb intron. A luciferase reporter assay showed that the maximal D 2S R‐responsive promoter activity is located in the −1 to −222 region of CNR1 promoter. Overall, we demonstrate previously unidentified crosstalk between D 2 R and CB 1 R via ERK1/2 signaling that enhances the expression of CB 1 R by modulating its promoter activity. image Cannabinoid CB 1 R and dopamine D 2 R cross‐talk at ERK1/2 signal. Activation of D 2S R increases the CB 1 R transcription, which is ERK1/2 dependent and enhances CB 1 R promoter activity that requires up‐stream −1 to −222 region. The results implicate pre‐synaptic D 2S R could functionally regulate the retrograde cannabinoid signal in the striatum.