The effect of vitamin C on morphine self-administration in rats

Authors

1 Department of Biology, Isfahan University, Isfahan, Iran

2 Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Recent studies have shown that addiction may be caused by abnormality of neurotransmission in the brain. Two neurotransmitters that involve into morphine addiction are dopamine and glutamate. The glutamatergic and dopaminergic systems are also involved in morphine tolerance and morphine withdrawal syndrome signs. Ascorbic acid (AA), as the antioxidant releases from the glutamatergic neurons, modulates the action of the dopamine and glutamate systems. In this study, the effect of AA on morphine self-administration and morphine withdrawal symptoms has been investigated.
Materials and Methods: Male Wistar rats (250 - 300g) were anesthetized with ketamine (11%) and xailazine (15%). The cannula was inserted into the right jugular vein, and it was fixed subcutaneously on the skull. After surgery the animals were placed in individual home cages, and they were allowed to recover from the operation for five days, before the test. The animals were subjected to self-administration morphine for12 consecutive days, two-hour/sessions. The number of infusions and number of active and passive lever pressings were recorded.
Results: An intra peritoneal injection of Ascorbic acid (AA) (400 mg/kg, i.p.), 30 minutes before morphine self-administration, produced a significant decrease in 12 days self-administration of morphine and withdrawal syndrome signs (P < 0.05).The morphine withdrawal signs (MWS) were recorded after naloxone precipitation, which decreased significantly with the injection of AA (400,700mg/kg), (<0.05). The number of self-infusions and the number of active lever pressings had significantly decreased after AA injection (P < 0.05).
Conclusion: The chronic administration of AA may prevent the development of tolerance and physical dependence on morphine self-administration via the glutamatergic system.

Keywords

1. Siggins GR, Martin G, Roberto M, Nie Z, Madamba S, De Lecea L. Glutamatergic tranmission in opiate and alcohol dependence. Ann NY Acad Sci 2003;1003:196-211.  Back to cited text no. 1
    
2. Ozawa T, Nakagawa T, Sekiya Y, Minami M, Satoh M. Effect of gene transfer of GLT-1, a glutamate transporter, into the locus coerulesus by recombinant adenoviruses on morphine physical dependence in rats. Eur J Neurosci 2004;19:221-6.  Back to cited text no. 2
    
3. Aghajanian GK, Kogan JH, Moghaddam B. Opiate withdrawal increases glutamate and aspartate efflux in the locus ceoruleus: An in vivo microdialysis study. Brain Res 1994;636:126-30.  Back to cited text no. 3
    
4. Schenk S, Valadez A, Worley CM, Mcnamara C. Blokade of the acquisition of cocaine self-administration by the NMDA antagonist MK-801. Behav Pharmacol 1993;4:652-9.  Back to cited text no. 4
    
5. Schenk S, Valadez A, Worley CM, Mcnamara C, House DT, Higley D, et al. Development and expression of sensitization to cocaine's reinforcing properties: Role of NMDA receptors. Psychopharmacology (Berl) 1993;111:332-8.  Back to cited text no. 5
    
6. Alaei H, Esmaeili M, Nasimi A, Pourshanazari A. Ascorbic acid decrease morphine self-administrationand withdrawal symptoms in rats. Pathophysiology 2005;12:103.  Back to cited text no. 6
    
7. Alaei H, Esmaeily M. Low doses of ascorbic reduced withdrawal syndrome sign in rats. J Gazvin Univ 2001;5:24-9.  Back to cited text no. 7
    
8. Fan SF, Yazulla S. Modulation of voltage-dependent K+currents (IK (V)) inretinal bipolar cells by ascorbate is mediated by dopamine D1 resptors. Vis Neurosci 1999;16:923-31.  Back to cited text no. 8
    
9. Fornai F, Piaggi S, Gesi M, Saviozzi M, Lenzi P, Paparelli A, et al. Subcellular localization of a glutathione-dependent dehydroascorbatereductate within specific rat brain region. Neuroscience 2001;104:15-31.  Back to cited text no. 9
    
10. Garcia MM, Anderson AT, Edwards R, Harlan RE. Morphine induction of c-fos expression in the rat forebrain though glutamatergic mechanisms: Role of non-n-methyl-D-aspartate receptors. Neuroscience 2003;119:787-94.  Back to cited text no. 10
    
11. Bockaert J, Manzoni OJ, Robbe D. Metabortopic glutamate receptor 2/3-dependent long-term depression in the nucleus accombens is blocked in morphine- withdrawal mice. Eur J Neurosci 2002;16:2231-5.  Back to cited text no. 11
    
12. Popik P, Kozela E, Wrobel M, Wozniak KM, Slusher BS. Morphine dependence are inhibited by the selective glutamate carboxypeptidase 2 (GCP2, NAALADase) inhibitor, 2-Pmpa. Neuropsychopharmacology 2003;28:457-67.  Back to cited text no. 12
    
13. Xu NJ, Bao L, Fan HP, Bao GB, Pu L, Lu YJ, et al. Morphine withdrawal increases glutamate uptake and surface experssion of glutamate transporter GLT1 at hippocampal synapses. J Neurosci 2003;23:4775-84.  Back to cited text no. 13
    
14. Demidchchik V, Sokolik A, Yurin V. Characteristics of non-specific permeability and H+-ATPase inhibition induced in the plasma membrane of Nitellaflexilis by excessive Cu+. Planta 2001;212:583-90.  Back to cited text no. 14
    
15. Goldshleger R, Patchornik G, Shimon MB, Tal DM, Post RL, Karlish SJ. Structural organization and energy transduction mechanism of Na+, K+-ATPase studied with transition metal: Catalyzed oxidative cleavage. J Bioenerg Biomembr 2001;33:387-99.  Back to cited text no. 15
    
16. Evangelou A, Kalfakakou V. Ascorbic acid (vitamin C) effects on withdrawal syndrome of heroin abusers. In Vivo 2000;14:363-6.  Back to cited text no. 16
    
17. Hong M, Milne B. Evidence for the involvement of excitatory amino acid pathway in the development of precipitated withdrawal from acute morphine. Brain Res 1993;623:131-41.  Back to cited text no. 17
    
18. Koyuncuoglu H, Nurten A, Enginar N, Ozerman B, Kara I. The effects of different 4-aminopyridine and morphine combination on the intensity of morphine abstinence. Pharmacol Res 2001;43:245-50.  Back to cited text no. 18
    
19. Willette RE, Thomas BL, Barnett G. Inhibition of morphine analgesia by ascorbate. Res Commun Chem Pathol Pharmacol 1983;42:485-91.  Back to cited text no. 19