title: Lithium attenuates cannabinoid-induced dependence in the animal model: involvement of phosphorylated ERK1/2 and GSK-3β signaling pathways.
abstract: Cannabis is one of the most banned drugs in the world. Cannabinoid-induced dependence or withdrawal signs are indicated by the result of complex molecular mechanisms including upstream protein kinases (PKs), such as an extracellular signal regulated kinase1/2 (ERK1/2) and downstream glycogen synthase kinase-3β (GSK-3β), which lead to neuronal plasticity. In this study, we examined the protective effect of lithium (Li) as a potent ERK1/2 and GSK-3β modulator to prevent the development of dependence on cannabinoids. For this purpose, rats were treated twice daily with increasing doses of WIN 55,212-2 (WIN, 2-8 mg/kg, intraperitoneally (i.p.), for five consecutive days. AM251 (AM, 2 mg/kg), a cannabinoid antagonist, was injected i.p to induce manifestations of abstinence in rat dependency on WIN, and the subsequent withdrawal signs were recorded. To evaluate the preventive effect of Li, the rats were pre-treated with Li (10 mg/kg, i.p.) twice daily, 30 minutes before every injection of WIN. SL327, as an ERK1/2 inhibitor, was also injected (SL, 50 mg/kg, i.p.) 30 minutes before the last doses of WIN in separate groups. The p-ERK1/2, total ERK1/2, p-GSK-3β and total GSK-3β expressions were determined with Western blot method after 60 minutes, prior to the Li, WIN or AM injections. Li and SL pre-treatment attenuated the global withdrawal signs in regarding their modulation effect on the up-regulation of p-ERK1/2 cascade enhanced by AM injection. Furthermore, the p-GSK-3β expression was up-regulated with SL and Li pre-treatment against AM injection, without alteration on the total contents of ERK1/2 and GSK-3β level. Therefore, p-ERK1/2 and p-GSK-3β pathways are involved in the cannabinoid-induced dependence. However, no crosstalk was indicated between these two pathways. In conclusion, Li neuroprotectionwith regard to cannabinoid abstinence may occur through the regulation of the p-ERK1/2 cascade inconsequent of p-GSK-3β signaling pathways in rats.
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmacy, Pharmaceutical Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran, Iran. hamidrrt@yahoo.com.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Rahimi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. dehpour@tums.ac.ir.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. ejtemam@tums.ac.ir.
authors.forename: Shahram Ejtemaei
authors.initials: SE
authors.lastname: Mehr
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmacy, Pharmaceutical Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran, Iran. msharifzadeh@sina.tums.ac.ir.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sharifzadeh
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmacy, Pharmaceutical Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran, Iran. mhghahremani@tums.ac.ir.
authors.forename: Mohammad Hossein
authors.initials: MH
authors.lastname: Ghahremani
authors.affiliation: Department of Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran. a.razmi@yahoo.com.
authors.forename: Ali
authors.initials: A
authors.lastname: Razmi
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmacy, Pharmaceutical Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran, Iran. ostadnas@tums.ac.ir.
authors.forename: Seyed Nasser
authors.initials: SN
authors.lastname: Ostad
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3