Previously, we found that chronic methamphetamine treatment altered CB₁ R-dependent cAMP/PKA/DARPP-32/T34/PP2B signaling and decreased levels of CB₁ R protein and mRNA in the nucleus accumbens. These findings suggested the existence of signaling interplay between mesolimbic dopamine and CB₁ R. In the current study, we further investigate interactions between CB₁ R and D₂ R signaling. Activation of either CB₁ R or D₂ R increased ERK1/2 phosphorylation, while co-stimulation of CB₁ R and D₂ R evoked an additive effect on the phospho-ERK1/2 signal. This effect was mediated through a PTX-sensitive Gαi/o pathway in primary striatal cells. Furthermore, the mRNA level of CB₁ R was increased via D_2S R by treatment with D₂ 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 CB₁ R, the 5′-untranslated region (5′-UTR) of the 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 D₂ R and CB₁ R via ERK1/2 signaling that enhances the expression of CB₁ R by modulating its promoter activity. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

PMID:

 

23952963

 

[PubMed – as supplied by publisher]