, Volume 219, Issue 3, pp 763–773 | Cite as

Heroin self-administration and reinstatement of heroin-seeking in adolescent vs. adult male rats

  • James M. Doherty
  • Kyle J. Frantz
Original Investigation



Heroin abuse is prevalent among teenagers, and early onset drug use might predict long-term drug dependence. However, adolescent sensitivity to drug reinforcement has not been explored thoroughly in animal models.


This study aimed to compare intravenous (i.v.) self-administration of heroin, as well as extinction and reinstatement of heroin-seeking, in adolescent vs. adult male rats.


Adolescent (35 days old at start) and adult (86 days old at start) male Sprague–Dawley rats spontaneously acquired lever pressing maintained by i.v. heroin infusions. In experiment 1, self-administration was tested on a fixed ratio 1 schedule of reinforcement (0.05 and 0.025 mg/kg per infusion), followed by within-session extinction and reinstatement tests after 1 or 12 days of abstinence. In experiment 2, self-administration was tested on a progressive ratio schedule (0.0125–0.1 mg/kg per infusion), followed 12 days later by a single test of extinction responding in the presence of cues.


In experiment 1, adolescent rats self-administered more heroin than adults. After 1 or 12 days of abstinence, adolescents exhibited less heroin-seeking than adults, although levels of heroin-seeking increased over abstinence period for both age groups. In experiment 2, adolescents and adults reached the same maximal response ratio (breakpoint), although adolescents earned more infusions when response requirements were low. For extinction responding in the presence of cues, heroin-seeking was similar across ages.


Lower levels of heroin-seeking suggest that younger rats are less sensitive than adults to some residual effects of heroin intake.


Adolescence Periadolescence Opiate Opioid Cue-induced Extinction Incubation Relapse Addiction 



The authors would like to thank Chen Li, Bonnie Williams, Patrick Dunigan, and Adria Lee for their excellent technical assistance, as well as Dr. D.C.S. Roberts for helpful comments on the data. This research was supported in part by a National Institute on Drug Abuse B/START grant to KJF (1 RO3 DA020110-01), the Center for Behavioral Neuroscience NSF Science & Technology Center (IBN-9876754), and a seed grant from the Brains & Behavior program at Georgia State University. These experiments complied with the current laws of the USA.


  1. Adriani W, Laviola G (2003) Elevated levels of impulsivity and reduced place conditioning with d-amphetamine: two behavioral features of adolescence in mice. Behav Neurosci 117:695–703PubMedCrossRefGoogle Scholar
  2. Anker J, Carroll M (2010) Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats. Psychopharmacology 208:211–222PubMedCrossRefGoogle Scholar
  3. Anthony JC, Petronis KR (1995) Early-onset drug use and risk of later drug problems. Drug and Alcohol Dependence 40:9–15PubMedCrossRefGoogle Scholar
  4. Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447PubMedCrossRefGoogle Scholar
  5. Beardsley P, Aceto M, Cook C, Bowman E, Newman J, Harris L (2004) Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys. Exp Clin Psychopharmacol 12:163–172PubMedCrossRefGoogle Scholar
  6. Bolanos CA, Garmsen GM, Clair MA, McDougall SA (1996) Effects of the kappa-opioid receptor agonist U-50,488 on morphine-induced place preference conditioning in the developing rat. Eur J Pharmacol 317:1–8PubMedCrossRefGoogle Scholar
  7. Bossert JM, Ghitza UE, Lu L, Epstein DH, Shaham Y (2005) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur J Pharmacol 526:36–50PubMedCrossRefGoogle Scholar
  8. Caine S, Lintz R, Koob G (1993) Intravenous drug-self-administration techniques in animals. In: Sahgal A (ed) Behavioural neuroscience: a practical approach. Oxford University Press, New York, pp 117–143Google Scholar
  9. Campbell JO, Wood RD, Spear LP (2000) Cocaine and morphine-induced place conditioning in adolescent and adult rats. Physiol Behav 68:487–493PubMedCrossRefGoogle Scholar
  10. Cardinal RN, Pennicott DR, Lakmali C, Sugathapala RTW, Everitt BJ (2001) Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 292:2499–2501PubMedCrossRefGoogle Scholar
  11. Carroll ME, Lac ST (1997) Acquisition of i.v. amphetamine and cocaine self-administration in rats as a function of dose. Psychopharmacology 129:206–214PubMedCrossRefGoogle Scholar
  12. Chaudhri N, Caggiula A, Donny E, Palmatier M, Liu X, Sved A (2006) Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology 184:353–366PubMedCrossRefGoogle Scholar
  13. Chung T, Maisto SA (2006) Relapse to alcohol and other drug use in treated adolescents: review and reconsideration of relapse as a change point in clinical course. Clin Psychol Rev 26:149–161PubMedCrossRefGoogle Scholar
  14. Clark DB, Kirisci L, Tarter RE (1998) Adolescent versus adult onset and the development of substance use disorders in males. Drug and Alcohol Dependence 49:115–121PubMedCrossRefGoogle Scholar
  15. Conrad K, Tseng K, Uejima J, Reimers J, Heng L-J, Shaham Y, Marinelli M, Wolf M (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454:118–121PubMedCrossRefGoogle Scholar
  16. Doherty J, Ogbomnwan Y, Williams B, Frantz K (2009) Age-dependent morphine intake and cue-induced reinstatement, but not escalation in intake, by adolescent and adult male rats. Pharmacol Biochem Behav 92:164–172PubMedCrossRefGoogle Scholar
  17. Doherty JM, Dunigan P, Lee A, Williams BF, Frantz KJ (2010) Attenuated effects of experimenter-administered heroin in periadolescent vs. adult male rats: locomotor sensitization and somatic signs of withdrawal. Program No. 305.14. 2010 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2010. OnlineGoogle Scholar
  18. Doremus TL, Brunell SC, Varlinskaya EI, Spear LP (2003) Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats. Pharmacol Biochem Behav 75:411–418PubMedCrossRefGoogle Scholar
  19. Everitt BJ, Dickinson A, Robbins TW (2001) The neuropsychological basis of addictive behaviour. Brain Research Reviews 36:129–138PubMedCrossRefGoogle Scholar
  20. Frantz KJ, Parsons LH (2001) Effects of MDMA on acquisition of cocaine self-administration in periadolescent and adult rats. Program No. 878.17. 2001 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2010. OnlineGoogle Scholar
  21. Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412:141–142PubMedCrossRefGoogle Scholar
  22. Grimm J, Lu L, Hayashi T, Hope B, Su T-P, Shaham Y (2003) Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23:742–747PubMedGoogle Scholar
  23. Hodgson SR, Hofford RS, Wellman PJ, Eitan S (2009) Different affective response to opioid withdrawal in adolescent and adult mice. Life Sci 84:52–60PubMedCrossRefGoogle Scholar
  24. Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944PubMedCrossRefGoogle Scholar
  25. Infurna RN, Spear LP (1979) Developmental changes in amphetamine-induced taste aversions. Pharmacol Biochem Behav 11:31–35PubMedCrossRefGoogle Scholar
  26. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE (2010) Monitoring the future national results on adolescent drug use: overview of key findings, 2009. NIH publication no. 10-7583Google Scholar
  27. Kandel DB, Yamaguchi K, Chen K (1992) Stages of progression in drug involvement from adolescence to adulthood: further evidence for the gateway theory. J Stud Alcohol 53:447–457PubMedGoogle Scholar
  28. Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF (2006) Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J Neurosci 26:5894–5900PubMedCrossRefGoogle Scholar
  29. Kerstetter KA, Kantak KM (2007) Differential effects of self-administered cocaine in adolescent and adult rats on stimulus-reward learning. Psychopharmacology 194:403–411PubMedCrossRefGoogle Scholar
  30. Koob GF, Le Moal M (2008) Addiction and the brain antireward system. Annu Rev Psychol 59:29–53PubMedCrossRefGoogle Scholar
  31. Koob GF, Pettit HO, Ettenberg A, Bloom FE (1984) Effects of opiate antagonists and their quaternary derivatives on heroin self-administration in the rat. J Pharmacol Exp Ther 229:481–486PubMedGoogle Scholar
  32. Li C, Frantz KJ (2009) Attenuated incubation of cocaine seeking in male rats trained to self-administer cocaine during periadolescence. Psychopharmacology (Berl) 204:725–733CrossRefGoogle Scholar
  33. Li C, Frantz KJ (2010) Time-dependent increases in cue-induced reinstatement of sucrose seeking after sucrose self-administration in adolescence. Behav Brain Res 213:109–112PubMedCrossRefGoogle Scholar
  34. Liu X, Caggiula AR, Palmatier MI, Donny EC, Sved AF (2008) Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose. Psychopharmacology 196:365–375PubMedCrossRefGoogle Scholar
  35. Martin TJ, Walker LE, Sizemore GM, Smith JE, Dworkin SI (1996) Within-session determination of dose-response curves for heroin self-administration in rats: comparison with between-session determination and effects of naltrexone. Drug Alcohol Depend 41:93–100PubMedCrossRefGoogle Scholar
  36. McNamara R, Dalley JW, Robbins TW, Everitt BJ, Belin D (2010) Trait-like impulsivity does not predict escalation of heroin self-administration in the rat. Psychopharmacology (Berl) 212:453–464CrossRefGoogle Scholar
  37. SAMHSA (Substance Abuse and Mental Health Services Administration) (2009) Results from the 2005 National Survey on Drug Use and Health: national findings. In: Department of Health and Human Services OoAS (ed), Rockville, MD, USAGoogle Scholar
  38. Natividad L, Tejeda H, Torres O, O’Dell L (2010) Nicotine withdrawal produces a decrease in extracellular levels of dopamine in the nucleus accumbens that is lower in adolescent versus adult male rats. Synapse 64:136–145PubMedCrossRefGoogle Scholar
  39. O’Dell LE, Bruijnzeel AW, Smith RT, Parsons LH, Merves ML, Goldberger BA, Richardson HN, Koob GF, Markou A (2006) Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction. Psychopharmacology 186:612–619PubMedCrossRefGoogle Scholar
  40. O’Dell LE, Torres OV, Natividad LA, Tejeda HA (2007) Adolescent nicotine exposure produces less affective measures of withdrawal relative to adult nicotine exposure in male rats. Neurotoxicol Teratol 29:17–22PubMedCrossRefGoogle Scholar
  41. O'Brien CP (1997) A range of research-based pharmacotherapies for addiction. Science 278:66–70PubMedCrossRefGoogle Scholar
  42. Palmer RH, Young SE, Hopfer CJ, Corley RP, Stallings MC, Crowley TJ, Hewitt JK (2009) Developmental epidemiology of drug use and abuse in adolescence and young adulthood: evidence of generalized risk. Drug Alcohol Depend 102:78–87PubMedCrossRefGoogle Scholar
  43. Perry J, Carroll M (2008) The role of impulsive behavior in drug abuse. Psychopharmacology 200:1–26PubMedCrossRefGoogle Scholar
  44. Roberts DC, Bennett SA (1993) Heroin self-administration in rats under a progressive ratio schedule of reinforcement. Psychopharmacology (Berl) 111:215–218CrossRefGoogle Scholar
  45. Sagvolden T, Sergeant JA (1998) Attention deficit/hyperactivity disorder—from brain dysfunctions to behaviour. Behavioural Brain Research 94:1–10PubMedCrossRefGoogle Scholar
  46. Schochet T, Kelley A, Landry C (2004) Differential behavioral effects of nicotine exposure in adolescent and adult rats. Psychopharmacology 175:265–273PubMedCrossRefGoogle Scholar
  47. Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20PubMedCrossRefGoogle Scholar
  48. Shahbazi M, Moffett AM, Williams BF, Frantz KJ (2008) Age- and sex-dependent amphetamine self-administration in rats. Psychopharmacology (Berl) 196:71–81CrossRefGoogle Scholar
  49. Shalev U, Morales M, Hope B, Yap J, Shaham Y (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology 156:98–107PubMedCrossRefGoogle Scholar
  50. Shram MJ, Funk D, Li Z, Le AD (2008a) Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence. Neuropsychopharmacology 33:739–748PubMedCrossRefGoogle Scholar
  51. Shram MJ, Siu ECK, Li Z, Tyndale RF, Lê AD (2008b) Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats. Psychopharmacology 198:181–190PubMedCrossRefGoogle Scholar
  52. Smith RF (2003) Animal models of periadolescent substance abuse. Neurotoxicol Teratol 25:291–301PubMedCrossRefGoogle Scholar
  53. Smith SG, Werner TE, Davis WM (1976) Effect of unit dose and route of administration on self-administration of morphine. Psychopharmacology 50:103–105PubMedCrossRefGoogle Scholar
  54. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463PubMedCrossRefGoogle Scholar
  55. Spear LP, Brake SC (1983) Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16:83–109PubMedCrossRefGoogle Scholar
  56. Spear LP, Horowitz GP, Lipovsky J (1982) Altered behavioral responsivity to morphine during the periadolescent period in rats. Behav Brain Res 4:279–288PubMedCrossRefGoogle Scholar
  57. Taylor JR, Olausson P, Quinn JJ, Torregrossa MM (2009) Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction. Neuropharmacology 56:186–195PubMedCrossRefGoogle Scholar
  58. Varlinskaya EI, Spear LP (2004) Acute ethanol withdrawal (hangover) and social behavior in adolescent and adult male and female Sprague–Dawley rats. Alcohol Clin Exp Res 28:40–50PubMedCrossRefGoogle Scholar
  59. Weeks JR, Collins RJ (1964) Factors affecting voluntary morphine intake in self-maintained addicted rats. Psychopharmacology 6:267–279CrossRefGoogle Scholar
  60. White DA, Holtzman SG (2005) Periadolescent morphine exposure alters subsequent behavioral sensitivity to morphine in adult rats. Eur J Pharmacol 528:119–123PubMedCrossRefGoogle Scholar
  61. Wilmouth CE, Spear LP (2004) Adolescent and adult rats’ aversion to flavors previously paired with nicotine. Ann N Y Acad Sci 1021:462–464PubMedCrossRefGoogle Scholar
  62. Zhang F, Zhou W, Tang S, Lai M, Liu H, Yang G (2004) Motivation of heroin-seeking elicited by drug-associated cues is related to total amount of heroin exposure during self-administration in rats. Pharmacol Biochem Behav 79:291–298PubMedCrossRefGoogle Scholar
  63. Zhang Y, Picetti R, Butelman ER, Schlussman SD, Ho A, Kreek MJ (2009) Behavioral and neurochemical changes induced by oxycodone differ between adolescent and adult mice. Neuropsychopharmacology 34:912–922PubMedCrossRefGoogle Scholar
  64. Zhou W, Zhang F, Liu H, Tang S, Lai M, Zhu H, Kalivas P (2009) Effects of training and withdrawal periods on heroin seeking induced by conditioned cue in an animal of model of relapse. Psychopharmacology 203:677–684PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Neuroscience InstituteGeorgia State UniversityAtlantaUSA

Personalised recommendations