Psychopharmacology

, Volume 196, Issue 4, pp 649–660 | Cite as

Effects of the NMDA receptor antagonist memantine on the expression and development of acute opiate dependence as assessed by withdrawal-potentiated startle and hyperalgesia

  • Andrew C. Harris
  • Patrick E. Rothwell
  • Jonathan C. Gewirtz
Original Investigation

Abstract

Rationale

While the N-methyl-d-aspartate (NMDA) glutamate receptor has been strongly implicated in chronic opiate dependence, relatively few studies have examined the effects of NMDA receptor antagonists on withdrawal from acute opiate exposure.

Objectives

The current study examined the effects of memantine, a well-tolerated NMDA receptor antagonist, on acute opiate dependence as assessed by elevations in rodent startle responding (i.e., “withdrawal-potentiated startle”) and increased pain sensitivity (i.e., hyperalgesia).

Results

Administration of memantine either attenuated (5 mg/kg) or blocked (10 mg/kg) the expression of withdrawal-potentiated startle during naloxone (2.5 mg/kg)-precipitated withdrawal from a single dose of morphine sulfate (10 mg/kg). Pre-treatment with the NMDA receptor antagonist also inhibited the exacerbation of withdrawal-potentiated startle across repeated acute opiate exposures. Memantine blocked the expression of acute dependence, but was less effective in inhibiting its escalation, when hyperalgesia was used as a measure of withdrawal. These doses of memantine did not affect startle responding or nociception in otherwise drug-free animals. Data from additional control groups indicated that the effects of memantine on the expression of withdrawal were not influenced by nonspecific interactions between the NMDA antagonist and either morphine or naloxone.

Conclusions

These findings suggest that the NMDA receptor may play a key role in the earliest stages of opiate dependence and provide further evidence that memantine may be useful for the treatment of opiate withdrawal.

Keywords

NMDA Opiate Withdrawal Startle Hyperalgesia 

References

  1. Adams JU, Holtzman SG (1990) Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats. J Pharmacol Exp Ther 253:483–489PubMedGoogle Scholar
  2. Aron A, Aron E (1994) Statistics for Psychology, 2nd edn. Prentice Hall, Upper Saddle River, NJGoogle Scholar
  3. Badiani A, Robinson TE (2004) Drug-induced neurobehavioral plasticity: the role of environmental context. Behav Pharmacol 15:327–339PubMedCrossRefGoogle Scholar
  4. Badoer E, Chalmers J (1992) Interactions of endogenous opioid and excitatory amino acid inputs to the caudal ventrolateral medulla of the rat. Neuropharmacology 31:857–862PubMedCrossRefGoogle Scholar
  5. Bespalov AY, Medvedev IO, Sukhotina IA, Zvartau EE (2001) Effects of the NMDA receptor antagonist, D-CPPene, on sensitization to the operant decrement produced by naloxone in morphine-treated rats. Behav Pharmacol 12:135–142PubMedGoogle Scholar
  6. Bickel WK, Stitzer ML, Liebson IA, Bigelow GE (1988) Acute physical dependence in man: effects of naloxone after brief morphine exposure. J Pharmacol Exp Ther 244:126–132PubMedGoogle Scholar
  7. Bisaga A, Popik P (2000) In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-d-aspartate (NMDA) antagonists. Drug Alcohol Depend 59:1–15PubMedCrossRefGoogle Scholar
  8. Bisaga A, Comer SD, Ward AS, Popik P, Kleber HD, Fischman MW (2001) The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology (Berl) 157:1–10CrossRefGoogle Scholar
  9. Blokhina EA, Sukhotina IA, Bespalov AY (2000) Pretreatment with morphine potentiates naloxone-conditioned place aversion in mice: effects of NMDA receptor antagonists. Eur J Pharmacol 406:227–232PubMedCrossRefGoogle Scholar
  10. Carlton SM, Hargett GL (1995) Treatment with the NMDA antagonist memantine attenuates nociceptive responses to mechanical stimulation in neuropathic rats. Neurosci Lett 198:115–118PubMedCrossRefGoogle Scholar
  11. Cestari V, Ciamei A, Castellano C (1999) Strain-dependent effects of MK-801 on passive avoidance behaviour in mice: interactions with morphine and immobilization stress. Psychopharmacology (Berl) 146:144–152CrossRefGoogle Scholar
  12. Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, Lipton SA (1992) Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci 12:4427–4436PubMedGoogle Scholar
  13. Creeley C, Wozniak DF, Labruyere J, Taylor GT, Olney JW (2006) Low doses of memantine disrupt memory in adult rats. J Neurosci 26:3923–3932PubMedCrossRefGoogle Scholar
  14. Danysz W, Parsons CG, Kornhuber J, Schmidt WJ, Quack G (1997) Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents–preclinical studies. Neurosci Biobehav Rev 21:455–468PubMedCrossRefGoogle Scholar
  15. Davis M (1979) Morphine and naloxone: effects on conditioned fear as measured with the potentiated startle paradigm. Eur J Pharmacol 54:341–347PubMedCrossRefGoogle Scholar
  16. Davis M, Walker DL, Myers KM (2003) Role of the amygdala in fear extinction measured with potentiated startle. Ann NY Acad Sci 985:218–232PubMedCrossRefGoogle Scholar
  17. Dravolina OA, Belozertseva IV, Sukhotina IA, Bespalov AY (1999) Morphine tolerance and dependence in mice with history of repeated exposures to NMDA receptor channel blockers. Pharmacol Biochem Behav 63:613–619PubMedCrossRefGoogle Scholar
  18. Eisenberg E, LaCross S, Strassman AM (1995) The clinically tested N-methyl-d-aspartate receptor antagonist memantine blocks and reverses thermal hyperalgesia in a rat model of painful mononeuropathy. Neurosci Lett 187:17–20PubMedCrossRefGoogle Scholar
  19. Fundytus ME, Coderre TJ (1994) Effect of activity at metabotropic, as well as ionotropic (NMDA), glutamate receptors on morphine dependence. Br J Pharmacol 113:1215–1220PubMedGoogle Scholar
  20. Gonzalez P, Cabello P, Germany A, Norris B, Contreras E (1997) Decrease of tolerance to, and physical dependence on morphine by, glutamate receptor antagonists. Eur J Pharmacol 332:257–262PubMedCrossRefGoogle Scholar
  21. Gravetter FJ, Wallnau LB (2007) Essentials of statistics for behavioral science. Wadsworth, Belmont, CAGoogle Scholar
  22. Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88PubMedCrossRefGoogle Scholar
  23. Harris AC, Gewirtz JC (2004) Elevated startle during withdrawal from acute morphine: a model of opiate withdrawal and anxiety. Psychopharmacology (Berl) 171:140–147CrossRefGoogle Scholar
  24. Harris AC, Gewirtz JC (2005) Acute opioid dependence: characterizing the early adaptations underlying drug withdrawal. Psychopharmacology (Berl) 178:353–366CrossRefGoogle Scholar
  25. Harris AC, Hanes SL, Gewirtz JC (2004) Potentiated startle and hyperalgesia during withdrawal from acute morphine: effects of multiple opiate exposures. Psychopharmacology (Berl) 176:266–273CrossRefGoogle Scholar
  26. Harris AC, Atkinson DM, Aase DM, Gewirtz JC (2006) Double dissociation in the neural substrates of acute opiate dependence as measured by withdrawal-potentiated startle. Neuroscience 139:1201–1210PubMedCrossRefGoogle Scholar
  27. Higgins GA, Nguyen P, Sellers EM (1992) The NMDA antagonist dizocilpine (MK801) attenuates motivational as well as somatic aspects of naloxone precipitated opioid withdrawal. Life Sci 50:PL167–PL172PubMedCrossRefGoogle Scholar
  28. Hijzen TH, Houtzager SW, Joordens RJ, Olivier B, Slangen JL (1995) Predictive validity of the potentiated startle response as a behavioral model for anxiolytic drugs. Psychopharmacology (Berl) 118:150–154CrossRefGoogle Scholar
  29. Holter SM, Danysz W, Spanagel R (1996) Evidence for alcohol anti-craving properties of memantine. Eur J Pharmacol 314:R1–R2PubMedCrossRefGoogle Scholar
  30. Jackisch R, Link T, Neufang B, Koch R (1992) Studies on the mechanism of action of the antiparkinsonian drugs memantine and amantadine: no evidence for direct dopaminomimetic or antimuscarinic properties. Arch Int Pharmacodyn Ther 320:21–42PubMedGoogle Scholar
  31. Jeziorski M, White FJ, Wolf ME (1994) MK-801 prevents the development of behavioral sensitization during repeated morphine administration. Synapse 16:137–147PubMedCrossRefGoogle Scholar
  32. Jin C, Araki H, Kawasaki Y, Nagata M, Suemaru K, Shibata K, Hamamura T, Kawasaki H, Gomita Y (2006) The glutamate release inhibitor riluzole attenuates the formation of conditioned place aversion induced by naloxone in rats undergoing a single morphine exposure. Brain Res 1069:120–126PubMedCrossRefGoogle Scholar
  33. Kalinichev M, Holtzman SG (2003) Changes in urination/defecation, auditory startle response, and startle-induced ultrasonic vocalizations in rats undergoing morphine withdrawal: similarities and differences between acute and chronic dependence. J Pharmacol Exp Ther 304:603–609PubMedCrossRefGoogle Scholar
  34. Kawasaki Y, Jin C, Suemaru K, Kawasaki H, Shibata K, Choshi T, Hibino S, Gomita Y, Araki H (2005) Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats. Br J Pharmacol 145:751–757PubMedCrossRefGoogle Scholar
  35. Kim DH, Fields HL, Barbaro NM (1990) Morphine analgesia and acute physical dependence: rapid onset of two opposing, dose-related processes. Brain Res 516:37–40PubMedCrossRefGoogle Scholar
  36. Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129PubMedCrossRefGoogle Scholar
  37. Koob GF, Le Moal M (2005) Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci 8:1442–1444PubMedCrossRefGoogle Scholar
  38. Kornhuber J, Weller M (1997) Psychotogenicity and N-methyl-d-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 41:135–144PubMedCrossRefGoogle Scholar
  39. Koyuncuoglu H, Aricioglu F (1991) Previous chronic blockade of NMDA receptors intensifies morphine dependence in rats. Pharmacol Biochem Behav 39:575–579PubMedCrossRefGoogle Scholar
  40. Koyuncuoglu H, Dizdar Y, Aricioglu F, Sayin U (1992) Effects of MK 801 on morphine physical dependence: attenuation and intensification. Pharmacol Biochem Behav 43:487–490PubMedCrossRefGoogle Scholar
  41. Lang PJ, Davis M, Ohman A (2000) Fear and anxiety: animal models and human cognitive psychophysiology. J Affect Disord 61:137–159PubMedCrossRefGoogle Scholar
  42. Larcher A, Laulin JP, Celerier E, Le Moal M, Simonnet G (1998) Acute tolerance associated with a single opiate administration: involvement of N-methyl-d-aspartate-dependent pain facilitatory systems. Neuroscience 84:583–589PubMedCrossRefGoogle Scholar
  43. Laulin JP, Larcher A, Celerier E, Le Moal M, Simonnet G (1998) Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time. Eur J Neurosci 10:782–785PubMedCrossRefGoogle Scholar
  44. Lee Y, Davis M (1997a) Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex. J Neurosci 17:6434–6446PubMedGoogle Scholar
  45. Lee Y, Davis M (1997b) Role of the septum in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex. J Neurosci 17:6424–6433PubMedGoogle Scholar
  46. Maldonado C, Cauli O, Rodriguez-Arias M, Aguilar MA, Minarro J (2003) Memantine presents different effects from MK-801 in motivational and physical signs of morphine withdrawal. Behav Brain Res 144:25–35PubMedCrossRefGoogle Scholar
  47. Manning BH, Mao J, Frenk H, Price DD, Mayer DJ (1996) Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance. Pain 67:79–88PubMedCrossRefGoogle Scholar
  48. Mansbach RS, Gold LH, Harris LS (1992) The acoustic startle response as a measure of behavioral dependence in rats. Psychopharmacology 108:40–46PubMedCrossRefGoogle Scholar
  49. Mao J, Price DD, Mayer DJ (1994) Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 14:2301–2312PubMedGoogle Scholar
  50. Miczek KA (1991) Tolerance to the analgesic, but not discriminative stimulus effects of morphine after brief social defeat in rats. Psychopharmacology (Berl) 104:181–186CrossRefGoogle Scholar
  51. Morris RG, Moser EI, Riedel G, Martin SJ, Sandin J, Day M, O’Carroll C (2003) Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos Trans R Soc Lond B Biol Sci 358:773–786PubMedCrossRefGoogle Scholar
  52. Nichols ML, Lopez Y, Ossipov MH, Bian D, Porreca F (1997) Enhancement of the antiallodynic and antinociceptive efficacy of spinal morphine by antisera to dynorphin A (1–13) or MK-801 in a nerve-ligation model of peripheral neuropathy. Pain 69:317–322PubMedCrossRefGoogle Scholar
  53. Parsons CG, Danysz W, Quack G (1999) Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 38:735–767PubMedCrossRefGoogle Scholar
  54. Popik P, Skolnick P (1996) The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence. Pharmacol Biochem Behav 53:791–797PubMedCrossRefGoogle Scholar
  55. Popik P, Danysz W (1997) Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-d-aspartate receptor antagonist, memantine. J Pharmacol Exp Ther 280:854–865PubMedGoogle Scholar
  56. Popik P, Kozela E (1999) Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse tail flick test. Pol J Pharmacol 51:223–231PubMedGoogle Scholar
  57. Popik P, Wrobel M, Bisaga A (2006) Reinstatement of morphine-conditioned reward is blocked by memantine. Neuropsychopharmacology 31:160–170PubMedGoogle Scholar
  58. Rassnick S, Koob GF, Geyer MA (1992) Responding to acoustic startle during chronic ethanol intoxication and withdrawal. Psychopharmacology 106:351–358PubMedCrossRefGoogle Scholar
  59. Reiser G, Koch R (1989) Memantine inhibits serotonin-induced rise of cytosolic Ca2+ activity and of cyclic GMP level in a neuronal cell line. Eur J Pharmacol 172:199–203PubMedCrossRefGoogle Scholar
  60. Reiser G, Binmoller FJ, Koch R (1988) Memantine (1-amino-3,5-dimethyladamantane) blocks the serotonin-induced depolarization response in a neuronal cell line. Brain Res 443:338–344PubMedCrossRefGoogle Scholar
  61. Schulteis G, Heyser CJ, Koob GF (1997) Opiate withdrawal signs precipitated by naloxone following a single exposure to morphine: potentiation with a second morphine exposure. Psychopharmacology (Berl) 129:56–65CrossRefGoogle Scholar
  62. Schulteis G, Heyser CJ, Koob GF (1999) Differential expression of response-disruptive and somatic indices of opiate withdrawal during the initiation and development of opiate dependence. Behav Pharmacol 10:235–242PubMedCrossRefGoogle Scholar
  63. Schulteis G, Morse AC, Liu J (2004) Conditioning processes contribute to severity of naloxone-precipitated withdrawal from acute opioid dependence. Psychopharmacology (Berl) 175:463–472Google Scholar
  64. Semenova S, Danysz W, Bespalov A (1999) Low-affinity NMDA receptor channel blockers inhibit acquisition of intravenous morphine self-administration in naive mice. Eur J Pharmacol 378:1–8PubMedCrossRefGoogle Scholar
  65. Shoaib M, Benwell ME, Akbar MT, Stolerman IP, Balfour DJ (1994) Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists. Br J Pharmacol 111:1073–1080PubMedGoogle Scholar
  66. Spanagel R, Eilbacher B, Wilke R (1994) Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat—a pharmacokinetic microdialysis study. Eur J Pharmacol 262:21–26PubMedCrossRefGoogle Scholar
  67. Trujillo KA (2000) Are NMDA receptors involved in opiate-induced neural and behavioral plasticity? A review of preclinical studies. Psychopharmacology (Berl) 151:121–141CrossRefGoogle Scholar
  68. Trujillo KA, Akil H (1991a) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85–87PubMedCrossRefGoogle Scholar
  69. Trujillo KA, Akil H (1991b) The NMDA receptor antagonist MK-801 increases morphine catalepsy and lethality. Pharmacol Biochem Behav 38:673–675PubMedCrossRefGoogle Scholar
  70. Tzschentke TM, Schmidt WJ (1995) N-methyl-d-aspartic acid-receptor antagonists block morphine-induced conditioned place preference in rats. Neurosci Lett 193:37–40PubMedCrossRefGoogle Scholar
  71. Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587PubMedCrossRefGoogle Scholar
  72. Villetti G, Bergamaschi M, Bassani F, Bolzoni PT, Maiorino M, Pietra C, Rondelli I, Chamiot-Clerc P, Simonato M, Barbieri M (2003) Antinociceptive activity of the N-methyl-d-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 306:804–814PubMedCrossRefGoogle Scholar
  73. Winblad B, Poritis N (1999) Memantine in severe dementia: results of the 9M-Best Study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 14:135–146PubMedCrossRefGoogle Scholar
  74. Wolf ME, Jeziorski M (1993) Coadministration of MK-801 with amphetamine, cocaine or morphine prevents rather than transiently masks the development of behavioral sensitization. Brain Res 613:291–294PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Andrew C. Harris
    • 1
    • 3
  • Patrick E. Rothwell
    • 2
  • Jonathan C. Gewirtz
    • 1
    • 2
  1. 1.Department of PsychologyUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of NeuroscienceUniversity of MinnesotaMinneapolisUSA
  3. 3.Minneapolis Medical Research FoundationMinneapolisUSA

Personalised recommendations