Psychopharmacology

, Volume 222, Issue 2, pp 225–235 | Cite as

The effects of acute and chronic steady state methadone on memory retrieval in rats

  • Erin Cummins
  • Craig P. Allen
  • Alexander Ricchetti
  • Emily Boughner
  • Kayla Christenson
  • Megan Haines
  • Cheryl L. Limebeer
  • Linda A. Parker
  • Francesco Leri
Original Investigation
  • 254 Downloads

Abstract

Rationale

Although widely prescribed to treat opioid addiction, little is known about the possible side effects of methadone on memory functions.

Objectives

The aim of this study is to compare the effects of acute and chronic methadone on memory retrieval in rats and to explore the selectivity of possible deficits.

Methods

Administration of acute (0, 1.25, 2.5, and 5 mg/kg SC) and chronic steady state methadone (0, 10, 30, and 55 mg/kg/day SC by osmotic mini-pump) was tested on recall of three different types of information: stimulus–reward (10-arm parallel maze), stimulus–response (8-arm radial maze), and stimulus–stimulus (Barnes maze). Acute and steady state methadone doses were also compared on tests of locomotor activity and reactivity to aversive stimuli (i.e., swimming and acoustic startle).

Results

In the stimulus–reward task, acute methadone impaired performance as a result of severe depression of locomotion. This motor deficit, however, was modulated by the motivational valence of environmental stimulation. In fact, acute methadone did not eliminate forced swimming behavior. In the stimulus–response and stimulus–stimulus tasks, accuracy was impaired independently of direct motor deficits, but rats were hyper-reactive to aversive stimulation and, in fact, 5 mg/kg enhanced acoustic startle. Importantly, chronic steady state methadone did not affect accuracy of memory retrieval, did not depress motor or swimming activity, and did not change startle reactivity.

Conclusion

Only acute methadone impaired accuracy and/or performance on three tests of memory retrieval. These findings in rats suggest that memory deficits reported in methadone-maintained individuals may not be directly attributable to methadone.

Keywords

Methadone Retrieval Memory Startle Locomotion Acute Chronic Steady state 

Notes

Acknowledgment

This work was supported by the Discovery Grant program of the Natural Sciences and Engineering Research Council of Canada.

References

  1. Adams JU, Holtzman SG (1990) Tolerance and dependence after continuous morphine infusion from osmotic pumps measured by operant responding in rats. Psychopharmacology 100:451–458PubMedCrossRefGoogle Scholar
  2. Babbini M, Davis WM (1972) Time-dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46:213–224PubMedGoogle Scholar
  3. Bach ME, Hawkins RD, Osman M, Kandel ER, Mayford M (1995) Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency. Cell 81:905–915PubMedCrossRefGoogle Scholar
  4. Barnes CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93:74–104PubMedCrossRefGoogle Scholar
  5. Cador M, Robbins TW, Everitt BJ (1989) Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum. Neuroscience 30:77–86PubMedCrossRefGoogle Scholar
  6. Castellano C, McGaugh J (1989) Effect of morphine on one-trial inhibitory avoidance in mice: lack of state-dependency. Psychobiology 17:89–92Google Scholar
  7. Cherrier MM, Amory JK, Ersek M, Risler L, Shen DD (2009) Comparative cognitive and subjective side effects of immediate-release oxycodone in healthy middle-aged and older adults. J Pain 10:1038–1050PubMedCrossRefGoogle Scholar
  8. Coda B, Hill H, Hunt E, Kerr E, Jacobson R, Chapman C (1993) Cognitive and motor function impairments during continuous opioid analgesic infusions. Hum Psychopharmacol 8:383–400CrossRefGoogle Scholar
  9. Codd EE, Shank RP, Schupsky JJ, Raffa RB (1995) Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 274:1263–1270PubMedGoogle Scholar
  10. Cummins E, Leri F (2008) Unreinforced responding during limited access to heroin self-administration. Pharmacol Biochem Behav 90:420–427PubMedCrossRefGoogle Scholar
  11. Curran HV, Kleckham J, Bearn J, Strang J, Wanigaratne S (2001) Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: a dose–response study. Psychopharmacology 154:153–160PubMedCrossRefGoogle Scholar
  12. Darke S, Sims J, McDonald S, Wickes W (2000) Cognitive impairment among methadone maintenance patients. Addiction 95:687–695PubMedCrossRefGoogle Scholar
  13. Davis M (1979) Morphine and naloxone: effects on conditioned fear as measured with the potentiated startle paradigm. Eur J Pharmacol 54:341–347PubMedCrossRefGoogle Scholar
  14. Davis AM, Inturrisi CE (1999) d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther 289:1048–1053PubMedGoogle Scholar
  15. Davis PE, Liddiard H, McMillan TM (2002) Neuropsychological deficits and opiate abuse. Drug Alcohol Depend 67:105–108PubMedCrossRefGoogle Scholar
  16. Deacon RM, Rawlins JN (2002) Learning impairments of hippocampal-lesioned mice in a paddling pool. Behav Neurosci 116:472–478PubMedCrossRefGoogle Scholar
  17. Devidze N, Zhou Y, Ho A, Zhang Q, Pfaff DW, Kreek MJ (2008) Steady-state methadone effect on generalized arousal in male and female mice. Behav Neurosci 122:1248–1256PubMedCrossRefGoogle Scholar
  18. Djahanguiri B, Richelle M, Fontaine O (1966) Behavioural effects of a prolonged treatment with small doses of morphine in cats. Psychopharmacologia 9:363–372PubMedCrossRefGoogle Scholar
  19. Eap CB, Buclin T, Baumann P (2002) Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 41:1153–1193PubMedCrossRefGoogle Scholar
  20. Ebert B, Andersen S, Krogsgaard-Larsen P (1995) Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 187:165–168PubMedCrossRefGoogle Scholar
  21. Ebert B, Thorkildsen C, Andersen S, Christrup LL, Hjeds H (1998) Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem Pharmacol 56:553–559PubMedCrossRefGoogle Scholar
  22. Everitt BJ, Morris KA, O'Brien A, Robbin TW (1991) The basolateral amygdala-ventral striatal system and conditioning place preference: further evidence of limbic-striatal interactions underlying reward-related processes. Neuroscience 42:1–18PubMedCrossRefGoogle Scholar
  23. Friswell J, Phillips C, Holding J, Morgan CJ, Brandner B, Curran HV (2008) Acute effects of opioids on memory functions of healthy men and women. Psychopharmacology 198:243–250PubMedCrossRefGoogle Scholar
  24. Geyer MA, Swerdlow NR (2001) Measurement of startle response, prepulse inhibition, and habituation. Curr Protoc Neurosci Chapter: 8Google Scholar
  25. Glover EM, Davis M (2008) Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance, cross-tolerance, and blockade by naloxone. Psychopharmacology 198:167–180PubMedCrossRefGoogle Scholar
  26. Gorman AL, Elliott KJ, Inturrisi CE (1997) The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 223:5–8PubMedCrossRefGoogle Scholar
  27. Gritz ER, Shiffman SM, Jarvik ME, Haber J, Dymond AM, Coger R, Charuvastra V, Schlesinger J (1975) Physiological and psychological effects of methadone in man. Arch Gen Psychiatry 32:237–242PubMedCrossRefGoogle Scholar
  28. Hepner IJ, Homewood J, Taylor AJ (2002) Methadone disrupts performance on the working memory version of the Morris water task. Physiol Behav 76:41–49PubMedCrossRefGoogle Scholar
  29. Hilsabeck RC, Perry W, Hassanein TI (2002) Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 35:440–446PubMedCrossRefGoogle Scholar
  30. Isbell H, Vogel VH (1949) The addiction liability of methadon (amidone, dolophine, 10820) and its use in the treatment of the morphine abstinence syndrome. Am J Psychiatry 105:909–914PubMedGoogle Scholar
  31. Izquierdo I (1980) Effect of beta-endorphin and naloxone on acquisition, memory, and retrieval of shuttle avoidance and habituation learning in rats. Psychopharmacology 69:111–115PubMedCrossRefGoogle Scholar
  32. 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
  33. Kerr B, Hill H, Coda B, Calogero M, Chapman CR, Hunt E, Buffington V, Mackie A (1991) Concentration-related effects of morphine on cognition and motor control in human subjects. Neuropsychopharmacology 5:157–166PubMedGoogle Scholar
  34. Kleber HD (2008) Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA 300:2303–2305PubMedCrossRefGoogle Scholar
  35. Kreek MJ (2000) Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine. Ann N Y Acad Sci 909:186–216PubMedCrossRefGoogle Scholar
  36. Kristensen K, Christensen CB, Christrup LL (1995) The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 56:L45–L50CrossRefGoogle Scholar
  37. Lemberg K, Kontinen VK, Viljakka K, Kylanlahti I, Yli-Kauhaluoma J, Kalso E (2006) Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat. Anesth Analg 102:1768–1774PubMedCrossRefGoogle Scholar
  38. Leri F, Flores J, Rajabi H, Stewart J (2003) Effects of cocaine in rats exposed to heroin. Neuropsychopharmacology 28:2102–2116PubMedGoogle Scholar
  39. Leri F, Tremblay A, Sorge RE, Stewart J (2004) Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use. Neuropsychopharmacology 29:1312–1320PubMedCrossRefGoogle Scholar
  40. Leri F, Zhou Y, Goddard B, Cummins E, Kreek MJ (2006) Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain. Neuropsychopharmacology 31:1462–1474PubMedCrossRefGoogle Scholar
  41. Leri F, Sorge RE, Cummins E, Woehrling D, Pfaus JG, Stewart J (2007) High-dose methadone maintenance in rats: effects on cocaine self-administration and behavioral side effects. Neuropsychopharmacology 32:2290–2300PubMedCrossRefGoogle Scholar
  42. Leri F, Zhou Y, Goddard B, Levy A, Jacklin D, Kreek MJ (2009) Steady-state methadone blocks cocaine seeking and cocaine-induced gene expression alterations in the rat brain. Eur Neuropsychopharmacol 19:238–249Google Scholar
  43. Levy A, Choleris E, Leri F (2009) Enhancing effect of heroin on social recognition learning in male Sprague–Dawley rats: modulation by heroin pre-exposure. Psychopharmacology 204:413–421PubMedCrossRefGoogle Scholar
  44. Liu JG, Liao XP, Gong ZH, Qin BY (1999) The difference between methadone and morphine in regulation of delta-opioid receptors underlies the antagonistic effect of methadone on morphine-mediated cellular actions. Eur J Pharmacol 373:233–239PubMedCrossRefGoogle Scholar
  45. Macht D, Mora C (1920) Effect of opium alkaloids on the behavior of rats in the circular maze. Pharmacological and Psychological Laboratories, Johns Hopkins University 219-235Google Scholar
  46. Mansbach RS, Gold LH, Harris LS (1992) The acoustic startle response as a measure of behavioral dependence in rats. Psychopharmacology (Berl) 108:40–46CrossRefGoogle Scholar
  47. McDonald RJ, White NM (1993) A triple dissociation of memory systems: hippocampus, amygdala and dorsal striatum. Behav Neurosci 107:3–22PubMedCrossRefGoogle Scholar
  48. Mintzer MZ, Stitzer ML (2002) Cognitive impairment in methadone maintenance patients. Drug Alcohol Depend 67:41–51PubMedCrossRefGoogle Scholar
  49. O'Leary TP, Brown RE (2011) The effects of apparatus design and test procedure on learning and memory performance of C57BL/6J mice on the Barnes maze. J Neurosci Methods 203:315–324PubMedCrossRefGoogle Scholar
  50. O'Neill WM, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnes K (2000) The cognitive and psychomotor effects of morphine in healthy subjects: a randomized controlled trial of repeated (four) oral doses of dextropropoxyphene, morphine, lorazepam and placebo. Pain 85:209–215PubMedCrossRefGoogle Scholar
  51. Ornstein TJ, Iddon JL, Baldacchino AM, Sahakian BJ, London M, Everitt BJ, Robbins TW (2000) Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers. Neuropsychopharmacology 23:113–126PubMedCrossRefGoogle Scholar
  52. Packard MG, Hirsh R, White NM (1989) Differential effects of fornix and caudate nucleus lesions on two radial maze tasks: evidence for multiple memory systems. J Neurosci 9:1465–1472PubMedGoogle Scholar
  53. Prosser J, Cohen LJ, Steinfeld M, Eisenberg D, London ED, Galynker II (2006) Neuropsychological functioning in opiate-dependent subjects receiving and following methadone maintenance treatment. Drug Alcohol Depend 84:240–247PubMedCrossRefGoogle Scholar
  54. Saarialho-Kere U, Mattila MJ, Seppala T (1989) Psychomotor, respiratory and neuroendocrinological effects of a mu-opioid receptor agonist (oxycodone) in healthy volunteers. Pharmacol Toxicol 65:252–257PubMedCrossRefGoogle Scholar
  55. Seip KM, Reed B, Ho A, Krrek MJ (2011) Measuring the incentive value of escalating doses of heroin in heroin-dependent Fischer rats during acute spontaneous withdrawal. Psychopharmacology. doi:10.1007/s00213-011-2380-7
  56. Soyka M, Lieb M, Kagerer S, Zingg C, Koller G, Lehnert P, Limmer C, Kuefner H, Hennig-Fast K (2008) Cognitive functioning during methadone and buprenorphine treatment: results of a randomized clinical trial. J Clin Psychopharmacol 28:699–703PubMedCrossRefGoogle Scholar
  57. Spain JW, Newsom GC (1991) Chronic opioids impair acquisition of both radial maze and Y-maze choice escape. Psychopharmacology (Berl) 105:101–106CrossRefGoogle Scholar
  58. Spieglar BJ, Mishkin M (1981) Evidence for the sequential participation of inferior temporal cortex and amygdala in the acquisition of stimulus-reward associations. Behav Brain Res 3:303–317CrossRefGoogle Scholar
  59. Tramullas M, Martinez-Cue C, Hurle MA (2007) Chronic methadone treatment and repeated withdrawal impair cognition and increase the expression of apoptosis-related proteins in mouse brain. Psychopharmacology (Berl) 193:107–120CrossRefGoogle Scholar
  60. Tramullas M, Martinez-Cue C, Hurle MA (2008) Chronic administration of heroin to mice produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and memory. Neuropharmacology 54:640–652PubMedCrossRefGoogle Scholar
  61. Vasko MR, Domino EF (1978) Tolerance development to the biphasic effects of morphine on locomotor activity and brain acetylcholine in the rat. J Pharmacol Exp Ther 207:848–858PubMedGoogle Scholar
  62. Veldhuijzen DS, van Wijck AJ, Wille F, Verster JC, Kenemans JL, Kalkman CJ, Olivier B, Volkerts ER (2006) Effect of chronic nonmalignant pain on highway driving performance. Pain 122:28–35PubMedCrossRefGoogle Scholar
  63. Verdejo A, Toribio I, Orozco C, Puente KL, Perez-Garcia M (2005) Neuropsychological functioning in methadone maintenance patients versus abstinent heroin abusers. Drug Alcohol Depend 78:283–288PubMedCrossRefGoogle Scholar
  64. Zhou Y, Spangler R, Maggos CE, LaForge KS, Ho A, Kreek MJ (1996) Steady-state methadone in rats does not change mRNA levels of corticotropin-releasing factor, its pituitary receptor or proopiomelanocortin. Eur J Pharmacol 315:31–35PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Erin Cummins
    • 1
  • Craig P. Allen
    • 1
  • Alexander Ricchetti
    • 1
  • Emily Boughner
    • 1
  • Kayla Christenson
    • 1
  • Megan Haines
    • 1
  • Cheryl L. Limebeer
    • 1
  • Linda A. Parker
    • 1
  • Francesco Leri
    • 1
  1. 1.Department of PsychologyUniversity of GuelphGuelphCanada

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