Delta9-tetrahydrocannabinol increases sequence-specific AP-1 DNA-binding activity and Fos-related antigens in the rat brain.
Delta-9-tetrahydrocannabinol (delta9-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 delta9-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 delta9-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, delta9-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 delta9-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.). delta9-THC failed to modify Specificity protein 1 (Sp1) DNA-binding activity. The results indicate that delta9-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.
Porcella
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B.B. Brodie Department of Neuroscience, University of Cagliari, Italy.
Gessa
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Pani
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D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006179:Gyrus Cinguli / Q000187:drug effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009714:Nucleus Accumbens / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011699:Putamen / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000941:Antigens; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011619:Psychotropic Drugs; D011720:Pyrazoles; D018808:Transcription Factor AP-1; D013759:Dronabinol; D000077285:Rimonabant