Lithium Attenuates Cannabinoid-Induced Dependence in the Animal Model: Involvement of Phosphorylated ERK1/2 and GSK-3β Signaling Pathways
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.
Perkonigg A, Lieb R, Höfler M, et al. Patterns of cannabis use, abuse and dependence over time: incidence, progression and stability in a sample of 1228 adolescents. Addiction 1999;94(11):1663-78.
Crowley TJ, Macdonald MJ, Whitmore EA, et al. Cannabis dependence, withdrawal, and reinforcing effects among adolescents with conduct symptoms and substance use disorders. Drug Alcohol Depend 1998;50(1):27-37. Lithium attenuates cannabinoid-induced dependence
Kouri EM, Pope HG Jr, Lukas SE. Changes in aggressive behavior during withdrawal from long-term marijuana use. Psychopharmacology (Berl) 1999;143(3):302-8.
Valverde O, Maldonado R, Valjent E, et al. Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice. J Neurosci 2000;20(24):9284-9.
Castañé A, Maldonado R, Valverde O. Role of different brain structures in the behavioural expression of WIN 55,212-2 withdrawal in mice. Br J Pharmacol 2004;142(8):1309-17.
Pan B, Zhong P, Sun D, et al. Extracellular signalregulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects. J Neurosci 2011;31(31):11244-55.
Hutcheson DM, Tzavara ET, Smadja C, ValjentEet al. Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9- tetrahydrocannabinol. Br J Pharmacol 1998;125(7):1567-77.
Howlett AC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat 2002;68-69:619-31.
Valjent E, Pagès C, Rogard M, et al. Delta 9-tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation in vivo depend on dopaminergic transmission. Eur J Neurosci 2001;14(2):342-52.
Valjent E, Pagès C, Hervé D, et al. Addictive and nonaddictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 2004;19(7):1826-36.
Barbara JG, Auclair N, Roisin MP, et al. Direct and indirect interactions between cannabinoid CB1 receptor and group II metabotropic glutamate receptor signaling in layer V pyramidal neurons from the rat prefrontal cortex. Eur J Neurosci 2003;17(5):981-90.
Derkinderen P, Valjent E, Toutant M, et al. Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J Neurosci 2003;23(6):2371-82.
Rubino T, Forlani G, Viganò D, et al. Ras/ERKsignallingin cannabinoidtolerance: from behaviour to cellular aspects. J Neurochem 2005;93(4):984-91.
Wei YM, Li SX, Shi HS, et al. Protracted cocaine withdrawal produces circadian rhythmic alterations of phosphorylated GSK-3β in reward-related brain areas in rats. Behav Brain Res 2011;218(1):228-33.
Kim S, Lee KY, Koh SH, et al. Role of the phosphatidylinositol 3-kinase and extracellular signalregulated kinase pathways in the neuroprotective effects of cilnidipine against hypoxia in a primary culture of cortical neurons. NeurochemInt 2012;61(7):1172-82.
Linseman DA, Butts BD, Precht TA, Phelps RA, et al. Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 2004;24(44):9993-10002.
Hongisto V, Smeds N, Brecht S, et al. Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol 2003;23(17):6027-36.
Beaulieu JM, Gainetdinov RR, Caron MG. The Akt-GSK- 3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci 2007;28(4):166-72.
Chuang DM, Wang Z, Chiu CT. GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke. Front Mol Neurosci 2011;4(1):15.
Pardo R, Andreolotti AG, Ramos B, et al. Opposed effects of lithium on the MEK-ERK pathway in neural cells: inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms. J Neurochem 2003;87(2):417-26.
Rezania F, Mehr SE, Kheirkhah M, et al. The effect of lithium chloride on WIN 55,212-2-induced tolerance in isolated guinea pig ileum. Eur J Pharmacol 2010;627(1-3):265-8.
Dehpour AR, Farsam H, Azizabadi-Farahani M. Inhibition of the morphine withdrawal syndrome and the development of physical dependence by lithium in mice. Neuropharmacology 1995;34(1):115-21.
Dehpour AR, Sadr SS, Nouroddini M, et al. Comparison of simultaneous administration of lithium with L-NAME or L-arginine on morphine withdrawal syndrome in mice. Hum Psychopharmacol 2000;15(2):87-93.
Dehpour AR, Sadr SS, Azizi MR, et al. Lithium inhibits the development of physical dependence to clonidine in mice. Pharmacol Toxicol 2002;90(2):89-93.
Ghasemi M, Dehpour AR. Ethical considerations in animal studies. J Med Ethics Hist Med 2009;2(1):12.
Moranta D, Esteban S, García-Sevilla JA. Acute, chronic and withdrawal effects of the cannabinoid receptor agonist WIN55212-2 on the sequential activation of MAPK/Raf-mMEK-ERK signaling in the rat cerebral frontal cortex: short-term regulation by intrinsic and extrinsic pathways. J Neurosci Res 2007;85(3):656-67.
Hosseini-Sharifabad A, Ghahremani MH, Sabzevari O, et al. Effects of protein kinase A and G inhibitors on hippocampal cholinergic markers expressions in rolipramand sildenafil-induced spatial memory improvement. Pharmacol Biochem Behav 2012;101(3):311-9.
Rahimi HR, Hasanli E, Jamalifar H.A mini review on new pharmacological and toxicological considerations of protease inhibitors' application in cancer prevention and biological research. Asian J Cell Biol 2012;7(1):1-12.
Sim-Selley LJ. Regulation of cannabinoid CB1 receptors H.R. Rahimi, et al. Acta Medica Iranica, Vol. 52, No. 9 (2014) 663 in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 2003;15(2):91-119.
Pourkhalili N, Ghahremani MH, Farsandaj N, et al. Evaluation of anti-invasion effect of cannabinoids on human hepatocarcinoma cells. Toxicol Mech Methods 2013;23(2):120-6.
Farsandaj N, Ghahremani MH, Ostad SN. Role of cannabinoid and vanilloid receptors in invasion of human breast carcinoma cells. J Environ Pathol Toxicol Oncol 2012;31(4):377-87.
Swift W, Hall W, Teesson M. Cannabis use and dependence among Australian adults: results from theNational Survey of Mental Health and Wellbeing. Addiction 2001;96(5):737-48.
Copeland J, Swift W. Cannabis use disorder: epidemiology and management. Int Rev Psychiatry 2009;21(2):96-103.
Alimoradi H, Pourmohammadi N, Mehr SE, et al. Effects of lithium on peripheral neuropathy induced by vincristine in rats. Acta Med Iran 2012;50(6):373-9.
Pourmohammadi N, Alimoradi H, Mehr SE, et al. Lithium attenuates peripheral neuropathy induced by paclitaxel in rats. Basic Clin Pharmacol Toxicol 2012;110(3):231-7.
Sharifzadeh M, Rezaei H, Ghamsari MR. InteractiveEffects of Acute and Chronic Lithium with Dopamine Receptor Antagonists on Naloxone-Induced Jumping in Morphine-Dependent Mice. Iran J Pharm Res 2003;2(4): 217-223.
Kiyani A, Javadi-Paydar M, Mohammadkhani H, et al. Lithium chloride disrupts consolidation of morphineinduced conditioned place preference in male mice: the nitric oxide/cyclic GMP signaling pathway. Behav Brain Res 2011;219(2):240-7.
De Vries TJ, Shaham Y, Homberg JR, et al. A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 2001;7(10):1151-4.
Karimi S, Azizi P, Shamsizadeh A, et al. Role of intraaccumbal cannabinoid CB1 receptors in the potentiation, acquisition and expression of morphine-induced conditioned place preference.Behav Brain Res 2013;247:125-31.
Huang CC, Chen YL, Lo SW, et al. Activation of cAMPdependent protein kinase suppresses the presynaptic cannabinoid inhibition of glutamatergic transmission at corticostriatal synapses. Mol Pharmacol 2002;61(3):578-85.
Filip M, Zaniewska M, Frankowska M, et al. The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction.Curr Med Chem 2012;19(3):317-55.
Ghasemi M, Dehpour AR. The NMDA receptor/nitric oxide pathway: a target for the therapeutic and toxic effects of lithium. Trends Pharmacol Sci 2011;32(7):420-34.
Cale JM, Bird IM. Inhibition of MEK/ERK1/2 signalling alters endothelial nitric oxide synthase activity in an agonistdependent manner. Biochem J 2006;398(2):279-88.
Tzavara ET, Valjent E, Firmo C, et al. Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum. Eur J Neurosci 2000;12(3),1038-46.
Hammonds MD, Shim SS, Feng P, Calabrese JR. Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus. Basic Clin Pharmacol Toxicol 2007;100(5):356-9.
Zhuang LL, Jin R, Zhu LH, Xu HG, Li Y, Gao S, Liu JY, Zhou GP. Promoter Characterization and Role of cAMP/PKA/CREB in the Basal Transcription of the Mouse ORMDL3 Gene. PLoS One 2013;8(4):e60630.
Cao JL, Liu HL, Wang JK, Zeng YM. Cross talk between nitric oxide and ERK1/2 signaling pathway in the spinal cord mediates naloxone-precipitated withdrawal in morphine-dependent rats. Neuropharmacology 2006;51(2):315-26.
Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R SocLond B Biol Sci 2012;367(1607):3353-63.
|Issue||Vol 52, No 9 (2014)|
|Protein kinase Cannabinoid receptor WIN 55 212- 2 Neuroprotection|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|