, Volume 235, Issue 12, pp 3423–3434 | Cite as

Adolescent morphine exposure induces immediate and long-term increases in impulsive behavior

  • Parisa Moazen
  • Hossein Azizi
  • Hamed Salmanzadeh
  • Saeed Semnanian
Original Investigation



Adolescence in humans represents a unique and critical developmental time point associated with increased risk-taking behavior. Converging clinical and epidemiological studies report a peak of drug use during adolescence, leading to the hypothesis that the developing adolescents brain is at risk to lose control over drug intake. Both adolescence and drug abuse are associated with significant cognitive and psychological changes such as lack of impulse control. A simple definition for impulsive behavior is the tendency to act prematurely without foresight. Increase in impulsivity is evident in acute morphine consumption, but to date, little is known with respect to subchronic morphine administration in impulsive behavior, particularly comparing time-dependent effects in adults, young adults, and adolescents.


To evaluate this, adult, young adult, and adolescent rats were treated with a subchronic regimen of morphine or saline during 5 days (s.c.). Thereafter, we examined impulsive behavioral effects of morphine administration, 24 h and 25 days after administration in rats, while responding under a five-choice serial reaction time task (5-CSRTT).


Subchronic morphine administration increased premature responding 24 h after the last injection of morphine in adult, young adult, and adolescent rats without increasing motor activity but a significant change in motivation in adult and young adult rats only. After 25 days of abstinence, premature responses were significantly increased in comparison with baseline in adolescent rats but not in adults and young adults.


The main conclusion of this study is that morphine exposure in adolescents has a long-term profound effect on motor impulsive behavior later in adulthood. An implication of our findings might be that we should be especially careful about consuming and prescribing opioid drugs in adolescents.


Adolescence Morphine Impulsivity 5-CSRTT 



This work would not have been possible without the generous help provided by Professor Trevor Robbins (Department of Psychology, University of Cambridge), presenting outstanding comments during the study and revising the manuscript. We are immensely grateful to Dr. Mohammad Reza Raoufy, who provided expertise in statistical analysis that greatly improved this manuscript.

Funding information

This study was funded by the Cognitive Sciences and Technologies Council of Iran (CSTC, Grant No. 95P31), National Institutes for Medical Research Development (NIMAD, Grant No. 942885), the Iran National Science Foundation (INSF), and the Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Arnett JJ (1999) Adolescent storm and stress, reconsidered. Am Psychol 54(5):317–326CrossRefGoogle Scholar
  2. Arnsten AFT (2006) Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry 67(Suppl 8):7–12PubMedGoogle Scholar
  3. Babbini M, DAVIS WM (1972) Time-dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46(2):213–224. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Baldacchino A, Balfour DJK, Passetti F, Humphris G, Matthews K (2012) Neuropsychological consequences of chronic opioid use. A quantitative review and meta-analysis. Neurosci Biobehav Rev 36(9):2056–2068. CrossRefPubMedGoogle Scholar
  5. Bari A, Robbins TW (2013) Inhibition and impulsivity. Behavioral and neural basis of response control. Prog Neurobiol 108:44–79. CrossRefPubMedGoogle Scholar
  6. Bari A, Dalley JW, Robbins TW (2008) The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc 3(5):759–767. CrossRefPubMedGoogle Scholar
  7. Basar K, Sesia T, Groenewegen H, Steinbusch HWM, Visser-Vandewalle V, Temel Y (2010) Nucleus accumbens and impulsivity. Prog Neurobiol 92(4):533–557. CrossRefPubMedGoogle Scholar
  8. Biederman J, Spencer T (1999) Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry 46(9):1234–1242CrossRefGoogle Scholar
  9. Boyette-Davis JA, Thompson CD, Fuchs PN (2008) Alterations in attentional mechanisms in response to acute inflammatory pain and morphine administration. Neuroscience 151(2):558–563. CrossRefPubMedGoogle Scholar
  10. Bradshaw CM, Szabadi E (1992) Choice between delayed reinforcers in a discrete-trials schedule. The effect of deprivation level. Q J Exp Psychol B Comp Physiol Psychol 44(1):1–6. CrossRefGoogle Scholar
  11. Chen C-Y, Storr CL, Anthony JC (2009) Early-onset drug use and risk for drug dependence problems. Addict Behav 34(3):319–322. CrossRefPubMedGoogle Scholar
  12. Clark L, Robbins TW, Ersche KD, Sahakian BJ (2006) Reflection impulsivity in current and former substance users. Biol Psychiatry 60(5):515–522. CrossRefPubMedGoogle Scholar
  13. Cole BJ, Robbins TW (1987) Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task. New evidence for central dopaminergic-noradrenergic interactions. Psychopharmacology 91(4):458–466CrossRefGoogle Scholar
  14. Cole BJ, Robbins TW (1989) Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats. Implications for theories of selective attention and arousal. Behav Brain Res 33(2):165–179CrossRefGoogle Scholar
  15. Crews FT, Boettiger CA (2009) Impulsivity, frontal lobes and risk for addiction. Pharmacol Biochem Behav 93(3):237–247. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity, and top-down cognitive control. Neuron 69(4):680–694. CrossRefPubMedGoogle Scholar
  17. de Wit H (2009) Impulsivity as a determinant and consequence of drug use. A review of underlying processes. Addict Biol 14(1):22–31. CrossRefPubMedGoogle Scholar
  18. Devoto P, Flore G, Pira L, Diana M, Gessa GL (2002) Co-release of noradrenaline and dopamine in the prefrontal cortex after acute morphine and during morphine withdrawal. Psychopharmacology 160(2):220–224. CrossRefPubMedGoogle Scholar
  19. Eisenberger R, Masterson FA, Lowman K (1982) Effects of previous delay of reward, generalized effort, and deprivation on impulsiveness. Learn Motiv 13(3):378–389. CrossRefGoogle Scholar
  20. Ersche KD, Barnes A, Jones PS, Morein-Zamir S, Robbins TW, Bullmore ET (2011) Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain 134(Pt 7):2013–2024. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Fillmore MT, Rush CR (2002) Impaired inhibitory control of behavior in chronic cocaine users. Drug Alcohol Depend 66(3):265–273CrossRefGoogle Scholar
  22. Goriounova NA, Mansvelder HD (2012) Short- and long-term consequences of nicotine exposure during adolescence for prefrontal cortex neuronal network function. Cold Spring Harb Perspect Med 2(12):a012120. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Goto Y, Grace AA (2008) Limbic and cortical information processing in the nucleus accumbens. Trends Neurosci 31(11):552–558. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hand TH, Franklin KBJ (1986) Associative factors in the effects of morphine on self-stimulation. Psychopharmacology 88(4).
  25. Harrison AA, Everitt BJ, Robbins TW (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance. Interactions with dopaminergic mechanisms. Psychopharmacology 133(4):329–342. CrossRefPubMedGoogle Scholar
  26. Harvey-Lewis C, Perdrizet J, Franklin KBJ (2012) The effect of morphine dependence on impulsive choice in rats. Psychopharmacology 223(4):477–487. CrossRefPubMedGoogle Scholar
  27. Jacobs EH, Smit AB, de Vries TJ, Schoffelmeer ANM (2003) Neuroadaptive effects of active versus passive drug administration in addiction research. Trends Pharmacol Sci 24(11):566–573. CrossRefPubMedGoogle Scholar
  28. Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12(2):483–488CrossRefGoogle Scholar
  29. Kieres AK, Hausknecht KA, Farrar AM, Acheson A, de Wit H, Richards JB (2004) Effects of morphine and naltrexone on impulsive decision making in rats. Psychopharmacology 173(1–2):167–174. CrossRefPubMedGoogle Scholar
  30. Kirby KN, Petry NM (2004) Heroin and cocaine abusers have higher discount rates for delayed rewards than alcoholics or non-drug-using controls. Addiction (Abingdon, England) 99(4):461–471. CrossRefGoogle Scholar
  31. Koek W (2014) Effects of repeated exposure to morphine in adolescent and adult male C57BL/6J mice. Age-dependent differences in locomotor stimulation, sensitization, and body weight loss. Psychopharmacology 231(8):1517–1529. CrossRefPubMedGoogle Scholar
  32. Koek W, France CP, Javors MA (2012) Morphine-induced motor stimulation, motor incoordination, and hypothermia in adolescent and adult mice. Psychopharmacology 219(4):1027–1037. CrossRefPubMedGoogle Scholar
  33. Laviola G, Adriani W, Terranova ML, Gerra G (2000) Fattori psicobiologici di rischio e vulnerabilità agli psicostimolanti in soggetti adolescenti e modelli animali. Ann Ist Super Sanita 36(1):47–62PubMedGoogle Scholar
  34. Maguire DR, Henson C, France CP (2016) Daily morphine administration increases impulsivity in rats responding under a 5-choice serial reaction time task. Br J Pharmacol 173(8):1350–1362. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Mendez IA, Simon NW, Hart N, Mitchell MR, Nation JR, Wellman PJ, Setlow B (2010) Self-administered cocaine causes long-lasting increases in impulsive choice in a delay discounting task. Behav Neurosci 124(4):470–477. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Mitchell SH (2004) Measuring impulsivity and modeling its association with cigarette smoking. Behav Cogn Neurosci Rev 3(4):261–275. CrossRefPubMedGoogle Scholar
  37. Osborne GL, Butler AC (1983) Enduring effects of periadolescent alcohol exposure on passive avoidance performance in rats. Psychobiology 11(3):205–208. CrossRefGoogle Scholar
  38. Pachenari N, Azizi H, Ghasemi E, Azadi M, Semnanian S (2018) Exposure to opiates in male adolescent rats alters pain perception in the male offspring. Behav Pharmacol 29(2 and 3 - Special Issue):255–260. CrossRefPubMedGoogle Scholar
  39. Paine TA, Olmstead MC (2004) Cocaine disrupts both behavioural inhibition and conditional discrimination in rats. Psychopharmacology 175(4):443–450. CrossRefPubMedGoogle Scholar
  40. Pattij T, de Vries TJ (2013) The role of impulsivity in relapse vulnerability. Curr Opin Neurobiol 23(4):700–705. CrossRefPubMedGoogle Scholar
  41. Pattij T, Janssen MCW, Vanderschuren LJMJ, Schoffelmeer ANM, van Gaalen MM (2007) Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control. Psychopharmacology 191(3):587–598. CrossRefPubMedGoogle Scholar
  42. Pattij T, Schetters D, Janssen MCW, Wiskerke J, Schoffelmeer ANM (2009) Acute effects of morphine on distinct forms of impulsive behavior in rats. Psychopharmacology 205(3):489–502. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Perry JL, Carroll ME (2008) The role of impulsive behavior in drug abuse. Psychopharmacology 200(1):1–26. CrossRefPubMedGoogle Scholar
  44. Pezze MA, Dalley JW, Robbins TW (2009) Remediation of attentional dysfunction in rats with lesions of the medial prefrontal cortex by intra-accumbens administration of the dopamine D(2/3) receptor antagonist sulpiride. Psychopharmacology 202(1–3):307–313. CrossRefPubMedGoogle Scholar
  45. Potenza MN, Taylor JR (2009) Found in translation. Understanding impulsivity and related constructs through integrative preclinical and clinical research. Biol Psychiatry 66(8):714–716. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Robbins TW (2002) The 5-choice serial reaction time task. Behavioural pharmacology and functional neurochemistry. Psychopharmacology 163(3–4):362–380. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Robinson ESJ, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X, Dalley JW, Robbins TW (2008) Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology 33(5):1028–1037. CrossRefPubMedGoogle Scholar
  48. Rossetti ZL, Longu G, Mercuro G, Gessa GL (1993) Extraneuronal noradrenaline in the prefrontal cortex of morphine-dependent rats. Tolerance and withdrawal mechanisms. Brain Res 609(1–2):316–320CrossRefGoogle Scholar
  49. Salimov RM, McBride WJ, McKinzie DL, Lumeng L, Li TK (1996) Effects of ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests. Alcohol (Fayetteville, N.Y.) 13(3):297–300CrossRefGoogle Scholar
  50. Salmanzadeh H, Azizi H, Semnanian S (2017) Adolescent chronic escalating morphine administration induces long lasting changes in tolerance and dependence to morphine in rats. Physiol Behav 174:191–196. CrossRefPubMedGoogle Scholar
  51. Salmanzadeh H, Azizi H, Ahmadi Soleimani SM, Pachenari N, Semnanian S (2018) Chronic adolescent morphine exposure alters the responses of lateral paragigantocellular neurons to acute morphine administration in adulthood. Brain Res Bull 137:178–186. CrossRefPubMedGoogle Scholar
  52. Schippers MC, Binnekade R, Schoffelmeer ANM, Pattij T, de Vries TJ (2012) Unidirectional relationship between heroin self-administration and impulsive decision-making in rats. Psychopharmacology 219(2):443–452. CrossRefPubMedGoogle Scholar
  53. Schramm-Sapyta NL, Morris RW, Kuhn CM (2006) Adolescent rats are protected from the conditioned aversive properties of cocaine and lithium chloride. Pharmacol Biochem Behav 84(2):344–352. CrossRefPubMedGoogle Scholar
  54. Schramm-Sapyta NL, Walker QD, Caster JM, Levin ED, Kuhn CM (2009) Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models. Psychopharmacology 206(1):1–21. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Schwarz JM, Bilbo SD (2013) Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction. J Neurosci 33(3):961–971. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Simon NW, Mendez IA, Setlow B (2007) Cocaine exposure causes long-term increases in impulsive choice. Behav Neurosci 121(3):543–549. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Simoni-Wastila L, Yang HK (2006) Psychoactive drug abuse in older adults. Am J Geriatr Pharmacother 4(4):380–394. CrossRefPubMedGoogle Scholar
  58. South SM, Edwards SR, Smith MT (2009) Antinociception versus serum concentration relationships following acute administration of intravenous morphine in male and female Sprague-Dawley rats. Differences between the tail flick and hot plate nociceptive tests. Clin Exp Pharmacol Physiol 36(1):20–28. CrossRefPubMedGoogle Scholar
  59. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24(4):417–463CrossRefGoogle Scholar
  60. Stain F, Barjavel MJ, Sandouk P, Plotkine M, Scherrmann JM, Bhargava HN (1995) Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-beta-d-glucuronide in the rat. J Pharmacol Exp Ther 274(2):852–857PubMedGoogle Scholar
  61. Stamford JA (1989) Development and ageing of the rat nigrostriatal dopamine system studied with fast cyclic voltammetry. J Neurochem 52(5):1582–1589. CrossRefPubMedGoogle Scholar
  62. Strandberg JJ, Kugelberg FC, Alkass K, Gustavsson A, Zahlsen K, Spigset O, Druid H (2006) Toxicological analysis in rats subjected to heroin and morphine overdose. Toxicol Lett 166(1):11–18. CrossRefPubMedGoogle Scholar
  63. Teicher MH, Andersen SL, Hostetter JC (1995) Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. In Brain research. Dev Brain Res 89(2):167–172CrossRefGoogle Scholar
  64. van Gaalen MM, Brueggeman RJ, Bronius PFC, Schoffelmeer ANM, Vanderschuren LJMJ (2006) Behavioral disinhibition requires dopamine receptor activation. Psychopharmacology 187(1):73–85. CrossRefPubMedGoogle Scholar
  65. Wahlstrom D, Collins P, White T, Luciana M (2010) Developmental changes in dopamine neurotransmission in adolescence. Behavioral implications and issues in assessment. Brain Cogn 72(1):146–159. CrossRefPubMedGoogle Scholar
  66. Ward RD, Odum AL (2005) Effects of morphine on temporal discrimination and color matching. General disruption of stimulus control or selective effects on timing? J Exp Anal Behav 84(3):401–415CrossRefGoogle Scholar
  67. Wiskerke J, Schetters D, van Es IE, van Mourik Y, den Hollander BRO, Schoffelmeer ANM, Pattij T (2011) μ-Opioid receptors in the nucleus accumbens shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice. J Neurosci 31(1):262–272. CrossRefPubMedGoogle Scholar
  68. Wu L-T, Pilowsky DJ, Patkar AA (2008) Non-prescribed use of pain relievers among adolescents in the United States. Drug Alcohol Depend 94(1–3):1–11. CrossRefPubMedGoogle Scholar
  69. Zosel A, Bartelson BB, Bailey E, Lowenstein S, Dart R (2013) Characterization of adolescent prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-related Surveillance (RADARS(®)) System. J Am Acad Child Adolesc Psychiatry 52(2):196–204.e2. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Parisa Moazen
    • 1
  • Hossein Azizi
    • 1
  • Hamed Salmanzadeh
    • 1
  • Saeed Semnanian
    • 1
  1. 1.Department of Physiology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran

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