Skip to main content
SpringerLink
Log in

Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Filipowicz W BS, Sonenber N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008, 9:13.

    Google Scholar 

  2. Kalivas PW, Volkow ND. The neural basis of addiction: A pathology of motivation and choice. American Journal of Psychiatry 2005, 162: 1403–1413.

    Article  PubMed  Google Scholar 

  3. [3] Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology 2010, 35: 217–238.

    Article  PubMed  Google Scholar 

  4. Aldworth J AK, Bishop E. Results from the 2006 National Survey on Drug Use and Health: national findings. 2007.

  5. Niciu MJ, Kelmendi B, Sanacora G. Overview of glutamatergic neurotransmission in the nervous system. Pharmacol Biochem Behav 2012, 100: 656–664.

    Article  CAS  PubMed  Google Scholar 

  6. Kessels HW, Malinow R. Synaptic AMPA receptor plasticity and behavior. Neuron 2009, 61: 340–350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cunha-Oliveira T, Rego AC, Oliveira CR. Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. Brain Res Rev 2008, 58: 192–208.

    Article  CAS  PubMed  Google Scholar 

  8. Koob GF. Neuroadaptive mechanisms of addiction: studies on the extended amygdala. Eur Neuropsychopharmacol 2003, 13: 442–452.

    Article  CAS  PubMed  Google Scholar 

  9. Enrico P, Mura MA, Esposito G, Serra P, Migheli R, De Natale G, et al. Effect of naloxone on morphine-induced changes in striatal dopamine metabolism and glutamate, ascorbic acid and uric acid release in freely moving rats. Brain Res 1998, 797: 94–102.

    Article  CAS  PubMed  Google Scholar 

  10. Siggins GR, Martin G, Roberto M, Nie Z, Madamba S, De Lecea L. Glutamatergic transmission in opiate and alcohol dependence. Ann N Y Acad Sci 2003, 1003: 196–211.

    Article  CAS  PubMed  Google Scholar 

  11. Glass MJ, Kruzich PJ, Kreek MJ, Pickel VM. Decreased plasma membrane targeting of NMDA-NR1 receptor subunit in dendrites of medial nucleus tractus solitarius neurons in rats self-administering morphine. Synapse 2004, 53: 191–201.

    Article  CAS  PubMed  Google Scholar 

  12. Yu H, Chen ZY. The role of BDNF in depression on the basis of its location in the neural circuitry. Acta Pharmacol Sin 2011, 32: 3–11.

    Article  CAS  PubMed  Google Scholar 

  13. Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001, 81: 299–343.

    CAS  PubMed  Google Scholar 

  14. Berke JD, Eichenbaum HB. Drug addiction and the hippocampus. Science 2001, 294: 1235.

    Article  CAS  PubMed  Google Scholar 

  15. Farahmandfar M, Karimian SM, Zarrindast MR, Kadivar M, Afrouzi H, Naghdi N. Morphine sensitization increases the extracellular level of glutamate in CA1 of rat hippocampus via mu-opioid receptor. Neurosci Lett 2011, 494: 130–134.

    Article  CAS  PubMed  Google Scholar 

  16. Guo M, Xu NJ, Li YT, Yang JY, Wu CF, Pei G. Morphine modulates glutamate release in the hippocampal CA1 area in mice. Neurosci Lett 2005, 381: 12–15.

    Article  CAS  PubMed  Google Scholar 

  17. Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry 2003, 8: 373–382.

    Article  CAS  PubMed  Google Scholar 

  18. Sepehrizadeh Z, Sahebgharani M, Ahmadi S, Shapourabadi MB, Bozchlou SH, Zarrindast MR. Morphine-induced behavioral sensitization increased the mRNA expression of NMDA receptor subunits in the rat amygdala. Pharmacology 2008, 81: 333–343.

    Article  CAS  PubMed  Google Scholar 

  19. Sepehrizadeh Z, Bahrololoumi Shapourabadi M, Ahmadi S, Hashemi Bozchlou S, Zarrindast MR, Sahebgharani M. Decreased AMPA GluR2, but not GluR3, mRNA expression in rat amygdala and dorsal hippocampus following morphine-induced behavioural sensitization. Clin Exp Pharmacol Physiol 2008, 35: 1321–1330.

  20. Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain? Trends Pharmacol Sci 2000, 21: 187–193.

    Article  CAS  PubMed  Google Scholar 

  21. Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, et al. Agmatine: clinical applications after 100 years in translation. Drug Discov Today 2013, 18: 880–893.

    Article  CAS  PubMed  Google Scholar 

  22. Uzbay TI. The pharmacological importance of agmatine in the brain. Neurosci Biobehav Rev 2012, 36: 502–519.

    Article  CAS  PubMed  Google Scholar 

  23. Wei XL, Su RB, Lu XQ, Liu Y, Yu SZ, Yuan BL, et al. Inhibition by agmatine on morphine-induced conditioned place preference in rats. Eur J Pharmacol 2005, 515: 99–106.

    Article  CAS  PubMed  Google Scholar 

  24. Li J, Li X, Pei G, Qin BY. Analgesic effect of agmatine and its enhancement on morphine analgesia in mice and rats. Zhongguo Yao Li Xue Bao 1999, 20: 81–85.

    CAS  PubMed  Google Scholar 

  25. Li J, Li X, Pei G, Qin BY. Effects of agmatine on tolerance to and substance dependence on morphine in mice. Zhongguo Yao Li Xue Bao 1999, 20: 232–238.

    PubMed  Google Scholar 

  26. Aricioglu-Kartal F, Uzbay IT. Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine dependent rats. Life Sci 1997, 61: 1775–1781.

    Article  CAS  PubMed  Google Scholar 

  27. Kolesnikov Y, Jain S, Pasternak GW. Modulation of opioid analgesia by agmatine. Eur J Pharmacol 1996, 296: 17–22.

    Article  CAS  PubMed  Google Scholar 

  28. Wang XF, Wu N, Su RB, Lu XQ, Liu Y, Li J. Agmatine modulates neuroadaptations of glutamate transmission in the nucleus accumbens of repeated morphine-treated rats. Eur J Pharmacol 2011, 650: 200–205.

    Article  CAS  PubMed  Google Scholar 

  29. Wen ZH, Chang YC, Cherng CH, Wang JJ, Tao PL, Wong CS. Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats. Brain Res 2004, 995: 253–259.

    Article  CAS  PubMed  Google Scholar 

  30. Ortiz J, Fitzgerald LW, Charlton M, Lane S, Trevisan L, Guitart X, et al. Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. Synapse 1995, 21: 289–298.

    Article  CAS  PubMed  Google Scholar 

  31. Ullensvang K, Lehre KP, Storm-Mathisen J, Danbolt NC. Differential developmental expression of the two rat brain glutamate transporter proteins GLAST and GLT. Eur J Neurosci 1997, 9: 1646–1655.

    Article  CAS  PubMed  Google Scholar 

  32. Kalivas PW, Lalumiere RT, Knackstedt L, Shen H. Glutamate transmission in addiction. Neuropharmacology 2009, 56 Suppl 1: 169–173.

    Article  CAS  PubMed  Google Scholar 

  33. Wei XL, Su RB, Wu N, Lu XQ, Zheng JQ, Li J. Agmatine inhibits morphine-induced locomotion sensitization and morphine-induced changes in striatal dopamine and metabolites in rats. Eur Neuropsychopharmacol 2007, 17: 790–799.

    Article  CAS  PubMed  Google Scholar 

  34. Reissner KJ, Kalivas PW. Using glutamate homeostasis as a target for treating addictive disorders. Behav Pharmacol 2010, 21: 514–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Feng Y, LeBlanc MH, Regunathan S. Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: a potential mechanism for the anticonvulsive effects. Neurosci Lett 2005, 390: 129–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 2009, 10: 561–572.

    Article  CAS  PubMed  Google Scholar 

  37. Singewald N, Philippu A. Release of neurotransmitters in the locus coeruleus. Prog Neurobiol 1998, 56: 237–267.

    Article  CAS  PubMed  Google Scholar 

  38. Wang G, Gorbatyuk OS, Dayanithi G, Ouyang W, Wang J, Milner TA, et al. Evidence for endogenous agmatine in hypothalamo-neurohypophysial tract and its modulation on vasopressin release and Ca2 + channels. Brain Res 2002, 932: 25–36.

    Article  CAS  PubMed  Google Scholar 

  39. Weng XC, Gai XD, Zheng JQ, Li J. Agmatine blocked voltage-gated calcium channel in cultured rat hippocampal neurons. Acta Pharmacol Sin 2003, 24: 746–750.

    CAS  PubMed  Google Scholar 

  40. Xu NJ, Bao L, Fan HP, Bao GB, Pu L, Lu YJ, et al. Morphine withdrawal increases glutamate uptake and surface expression of glutamate transporter GLT1 at hippocampal synapses. J Neurosci 2003, 23: 4775–4784.

    CAS  PubMed  Google Scholar 

  41. Wilson NR, Kang J, Hueske EV, Leung T, Varoqui H, Murnick JG, et al. Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1. J Neurosci 2005, 25: 6221–6234.

    Article  CAS  PubMed  Google Scholar 

  42. Martin G, Guadano-Ferraz A, Morte B, Ahmed S, Koob GF, De Lecea L, et al. Chronic morphine treatment alters N-methyl-D-aspartate receptors in freshly isolated neurons from nucleus accumbens. J Pharmacol Exp Ther 2004, 311: 265–273.

    Article  CAS  PubMed  Google Scholar 

  43. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001, 11: 327–335.

    Article  CAS  PubMed  Google Scholar 

  44. Narita M, Aoki T, Suzuki T. Molecular evidence for the involvement of NR2B subunit containing N-methyl-D-aspartate receptors in the development of morphine-induced place preference. Neuroscience 2000, 101: 601–606.

    Article  CAS  PubMed  Google Scholar 

  45. Kao JH, Huang EY, Tao PL. NR2B subunit of NMDA receptor at nucleus accumbens is involved in morphine rewarding effect by siRNA study. Drug Alcohol Depend 2011, 118: 366–374.

    Article  CAS  PubMed  Google Scholar 

  46. Johansson T, Elfverson M, Zhou Q, Nyberg F. Allosteric modulation of the NMDA receptor by neurosteroids in rat brain and the impact of long term morphine administration. Biochem Biophys Res Commun 2010, 401: 504–508.

    Article  CAS  PubMed  Google Scholar 

  47. Turchan J, Maj M, Przewlocka B. The effect of drugs of abuse on NMDAR1 receptor expression in the rat limbic system. Drug Alcohol Depend 2003, 72: 193–196.

    Article  CAS  PubMed  Google Scholar 

  48. Oh S, Kim JI, Chung MW, Ho IK. Modulation of NMDA receptor subunit mRNA in butorphanol-tolerant and -withdrawing rats. Neurochem Res 2000, 25: 1603–1611.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Basic Research Development Program of China (2015CB553504), the National Natural Science Foundation of China (30930040 and 81102426), and was a Project of the National Science and Technology Support Program of China (2012BAI01B07).

Author information

Author notes

    Authors and Affiliations

    1. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China

      Xiao-Fei Wang, Tai-Yun Zhao, Rui-Bin Su, Ning Wu & Jin Li

    Authors
    1. Xiao-Fei Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Tai-Yun Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Rui-Bin Su
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Ning Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jin Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Ning Wu or Jin Li.

    Additional information

    Xiao-Fei Wang and Tai-Yun Zhao have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Wang, XF., Zhao, TY., Su, RB. et al. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats. Neurosci. Bull. 32, 523–530 (2016). https://doi.org/10.1007/s12264-016-0031-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12264-016-0031-z

    Keywords

    Search

    Navigation