DELTA(9)-TETRAHYDROCANNABINOL INCREASES SEQUENCE-SPECIFIC AP-1 DNA-BINDING ACTIVITY AND FOS-RELATED ANTIGENS IN THE RAT-BRAIN

Delta-9-tetrahydrocannabinol (Delta(9)-THC), the psychoactive principl e of marijuana, has been shown to upregulate the mRNA levels of immedi ate-early genes in the rat brain. Using electrophoretic mobility-shift assay and one-dimensional Western blot, we here report that Delta(9)- THC increases Activator protein-1 (AP-1) DNA-binding and Fos-related a ntigen activity in discrete areas of the rat brain. One hour after the intraperitoneal administration of Delta(9)-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 bo th c-Fos, FosB, Fra-1 (Fos-related antigen) and Fra-2. in the cingulat e cortex and caudate-putamen, Delta(9)-THC significantly increased AP- 1 DNA-binding activity only at the highest dose used (57 and 71%, resp ectively). While in the caudate-putamen the increase in AP-I DNA bindi ng 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 Delta(9)-THC on the AP-1. DNA binding and the Fos-related antigens in the nucleus accumbens was blocked by t he specific cannabinoid antagonist SR141716 A (3 mg/kg i.p.). Delta(9) -THC failed to modify Specificity protein 1 (Spl) DNA-binding activity . The results indicate that Delta(9)-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 th e Fos family, in different areas in the rat brain, suggesting that thi s mechanism might be involved in the central actions of cannabinoids.