Δ9‐Tetrahydrocannabinol increases sequence‐specific AP‐1 DNA‐binding activity and Fos‐related antigens in the rat brain

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Abstract
Delta‐9‐tetrahydrocannabinol (Δ9‐THC), the psychoactive principle of marijuana, has been shown to upregulate the mRNA levels of immediate‐early genes in the rat brain. Using electrophoretic mobility‐shift assay and one‐dimensional Western blot, we here report that Δ9‐THC increases Activator protein‐1 (AP‐1) DNA‐binding and Fos‐related antigen activity in discrete areas of the rat brain. One hour after the intraperitoneal administration of Δ9‐THC at a dose of 10 or 15 mg/kg, AP‐1 DNA‐binding activity in the nucleus accumbens increased by 33 and 49%, respectively, while Western blot showed an increase in both c‐Fos, FosB, Fra‐1 (Fos‐related antigen) and Fra‐2. In the cingulate cortex and caudate‐putamen, Δ9‐THC significantly increased AP‐1 DNA‐binding activity only at the highest dose used (57 and 71%, respectively). While in the caudate‐putamen the increase in AP‐1 DNA binding was mainly due to an elevation of the c‐Fos and FosB proteins, the same phenomenon depended on the FosB, Fra‐1 and Fra‐2 peptides in the cingulate cortex. The effect of Δ9‐THC on the AP‐1 DNA binding and the Fos‐related antigens in the nucleus accumbens was blocked by the specific cannabinoid antagonist SR141716 A (3 mg/kg i.p.). Δ9‐THC failed to modify Specificity protein 1 (Sp1) DNA‐binding activity. The results indicate that Δ9‐THC activates gene coding for AP‐1 DNA‐binding proteins by acting on cannabinoid receptors, and induces a different transcriptional program on the early‐immediate gene of the Fos family, in different areas in the rat brain, suggesting that this mechanism might be involved in the central actions of cannabinoids.