, Volume 230, Issue 4, pp 607–616 | Cite as

Netrin-1 receptor-deficient mice show age-specific impairment in drug-induced locomotor hyperactivity but still self-administer methamphetamine

  • Jee Hyun Kim
  • Doron Lavan
  • Nicola Chen
  • Cecilia Flores
  • Helen Cooper
  • Andrew J. Lawrence
Original Investigation



The mesocorticolimbic dopamine system undergoes significant reorganization of neuronal connectivity and functional refinement during adolescence. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, is involved in this reorganization. Previous studies have shown that adult mice with a heterozygous (het) loss-of-function mutation in DCC exhibit impairments in sensitization and conditioned place preference (CPP) to psychostimulants. However, the commonly abused psychostimulant methamphetamine (METH) has not been assessed, and the role of DCC in drug self-administration remains to be established.


Using dcc het mice and wildtype (WT) littermates, we extended previous findings on dcc haplodeficiency by examining self-administration of METH in adult mice, including cue-induced drug seeking following abstinence. We also examined hyperactivity, sensitization, and CPP to a METH-paired context in adult and adolescent mice.


While adult dcc het mice expressed largely similar METH self-administration and cue-induced drug seeking as WT littermates, they failed to modulate responding according to dose of METH. Compared to WT, both adult and adolescent dcc het mice expressed impaired locomotor hyperactivity to acute METH but nevertheless showed comparable behavioral sensitization. Conditioned hyperactivity increased with age in WT but not in dcc het mice.


Impaired METH-induced hyperactivity and dose-related responding in adult dcc het mice suggest that reduced DCC alters METH-related behaviors. Adolescence is identified as a vulnerable period during which impairment in hyperactivity due to reduced DCC can be overcome with repeated METH injections. Nevertheless, DCC appears to have a somewhat limited role in METH-consumption and seeking following abstinence.


Methamphetamine Self-administration Conditioning Mouse 


  1. Ahmed SH, Cador M (2005) Dissociation of psychomotor sensitization from compulsive cocaine consumption. Neuropsychopharmacology 31:563–571CrossRefGoogle Scholar
  2. Arnold JM, Roberts D (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 53:441–447CrossRefGoogle Scholar
  3. Barallobre MJ, Pascual M, Del Rio JA, Soriano E (2005) The Netrin family of guidance factors: emphasis on Netrin–1 signalling. Brain Res Rev 49:22–47PubMedCrossRefGoogle Scholar
  4. Benes FM, Taylor JB, Cunningham MC (2000) Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology. Cerebral Cortex 10(10):1014–1027PubMedCrossRefGoogle Scholar
  5. Berke JD, Hyman SE (2000) Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25:515–532PubMedCrossRefGoogle Scholar
  6. Brown RM, Short JL, Cowen MS, Ledent C, Lawrence AJ (2009) A differential role for the adenosine A2A receptor in opiate reinforcement vs opiate–seeking behavior. Neuropsychopharmacology 34:844–856PubMedCrossRefGoogle Scholar
  7. Brown RM, Short JL, Lawrence AJ (2010) Identification of brain nuclei implicated in cocaine–primed reinstatement of conditioned place preference: a behavior dissociable from sensitization. PLoS One 5:1–13Google Scholar
  8. Chen H, Yang Y, Yeh T, Cherng C, Hsu H, Hsiao S, Yu L (2003) Methamphetamine–induced conditioned place preference is facilitated by estradiol pretreatment in female mice. Chinese J Physiol 46:169–174Google Scholar
  9. Chesworth RM, Brown RM, Kim JH, Lawrence AJ (2013). The metabotropic glutamate 5 receptor modulates extinction and reinstatement of methamphetamine-seeking in mice. PLoS One, in pressGoogle Scholar
  10. Deroche-Gamonet V, Belin D, Piazza P-V (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017PubMedCrossRefGoogle Scholar
  11. Evans AH, Pavese N, Lawrence AD, Tai YF, Appel S, Doder M, Piccini P (2006) Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Annals Neurol 59:852–858CrossRefGoogle Scholar
  12. Fazeli A, Dickinson SL, Hermistonf ML, Tigne RV, Steen I, R. G, Small CG, Rayburnf H (1997) Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. PROBE, 1:1–8Google Scholar
  13. Flores C (2011) Role of netrin–1 in the organization and function of the mesocorticolimbic dopamine system. J Psychiatry Neurosci 36:296–310PubMedCrossRefGoogle Scholar
  14. Flores C, Manitt C, Rodaros D, Thompson KM, Rajabi H, Luk KC, Kennedy TE (2005) Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine. Mol Psych 10:606–612CrossRefGoogle Scholar
  15. Grant A, Hoops D, Labelle–Dumais C, Prevost M, Rajabi H, Kolb B, Flores C (2007) Netrin–1 receptor–deficient mice show enhanced mesocortical dopamine transmission and blunted behavioral responses to amphetamine. Eur J Neurosci 26:3215–3228PubMedCrossRefGoogle Scholar
  16. Grant A, Speed Z, Labelle–Dumais C, Flores C (2009) Post–pubertal emergence of a dopamine phenotype in netrin–1 receptor–deficient mice. Eur J Neurosci 30:1318–1328PubMedCrossRefGoogle Scholar
  17. Kalivas PW (2005) How do we determine which drug-induced neuroplastic changes are important? Nat Neurosci 8:1440–1441PubMedCrossRefGoogle Scholar
  18. Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413PubMedCrossRefGoogle Scholar
  19. Kalsbeek A, Voorn P, Buijs RM, Pool CW, Uylings HBM (1988) Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol 269:58–72PubMedCrossRefGoogle Scholar
  20. Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O et al (2010) Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328:1709–1712PubMedCrossRefGoogle Scholar
  21. Kasanetz F, Lafourcade M, Deroche-Gamonet V, Revest JM, Berson N, Balado E et al (2013) Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol Psych 18:729–737Google Scholar
  22. Keino-Masu K, Masu M, Hinck L, Leonardo ED, Chan S-Y, Culotti JG, Tessier-Lavigne M (1996) Deleted in colorectal cancer (DCC) encodes a netrin receptor. Cell 87:175–185Google Scholar
  23. Kelley AE, Berridge KC (2002) The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 22:3306–3311PubMedGoogle Scholar
  24. Lenoir M, Ahmed SH (2007) Heroin-induced reinstatement is specific to compulsive heroin use and dissociable from heroin reward and sensitization. Neuropsychopharmacology 32:616–624PubMedCrossRefGoogle Scholar
  25. Leonard BE, McCartan D, White J, King DJ (2004) Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Human Psychopharmacol: Clin Exp 19:151–180CrossRefGoogle Scholar
  26. Livesey F, Hunt S (1997) Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol Cellular Neurosci 8:417–429CrossRefGoogle Scholar
  27. Madsen HB, Brown RM, Short JL, Lawrence AJ (2012) Investigation of the neuroanatomical substrates of reward seeking following protracted abstinence in mice. J Physiol 590:2427–2442PubMedGoogle Scholar
  28. Manitt C, Labelle-Dumais C, Eng C, Grant A, Mimee A, Stroh T, Flores C (2010) Peri-pubertal emergence of UNC-5 homologue expression by dopamine neurons in rodents. PLoS One 5(7):e11463PubMedCrossRefGoogle Scholar
  29. Manitt C, Mimee A, Eng C, Pokinko M, Stroh T, Cooper HM et al (2011) The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. J Neurosci 31:8381–8394PubMedCrossRefGoogle Scholar
  30. Marshall BD, Werb D (2010) Health outcomes associated with methamphetamine use among young people: a systematic review. Addiction 105:991–1002PubMedCrossRefGoogle Scholar
  31. McLellan AT, Lewis DC, O'Brien CP, Kleber HD (2000) Drug dependence, a chronic medical illness. JAMA 284:1689–1695PubMedCrossRefGoogle Scholar
  32. Melega WP, Williams AE, Schmitz DA, DiStefano EW, Cho AK (1995) Pharmacokinetic and pharmacodynamic analysis of the actions of D–amphetamine and D–methamphetamine on the dopamine terminal. J Pharmacol Exp Ther 274:90–96PubMedGoogle Scholar
  33. Orsini C, Bonito-Oliva A, Conversi D, Cabib S (2005) Susceptibility to conditioned place preference induced by addictive drugs in mice of the C57BL/6 and DBA/2 inbred strains. Psychopharmacol 181:327–336CrossRefGoogle Scholar
  34. Osborne PB, Halliday GM, Cooper HM, Keast JR (2005) Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents. Neuroscience 131:671–681PubMedCrossRefGoogle Scholar
  35. Rauhut AS, Bialecki V (2011) Development and persistence of methamphetamine–conditioned hyperactivity in Swiss–Webster mice. Behav Pharmacol 22:228–238PubMedCrossRefGoogle Scholar
  36. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive–sensitization theory of addiction. Brain Res Rev 18:247PubMedCrossRefGoogle Scholar
  37. Rosenberg DR, Lewis DA (1995) Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol 358:383–400PubMedCrossRefGoogle Scholar
  38. Salo R, Ursu S, Buonocore MH, Leamon MH, Carter C (2009) Impaired prefrontal cortical function and disrupted adaptive cognitive control in methamphetamine abusers: a functional magnetic resonance imaging study. Biol Psych 65:706–709CrossRefGoogle Scholar
  39. Shoblock JR, Sullivan EB, Maisonneuve IM, Glick SD (2003) Neurochemical and behavioral differences between d–methamphetamine and d–amphetamine in rats. Psychopharmacology 165:359–369PubMedGoogle Scholar
  40. Soria G, Castañé A, Ledent C, Parmentier M, Maldonado R, Valverde O (2006) The lack of A2A adenosine receptors diminishes the reinforcing efficacy of cocaine. Neuropsychopharmacology 31:978–987PubMedCrossRefGoogle Scholar
  41. Srour M, Rivière JB, Pham JM, Dubé MP, Girard S, Morin S, Dion PA, Asselin G, Rochefort D, Hince P, Diab S, Sharafaddinzadeh N, Chouinard S, Théoret H, Charron F, Rouleau GA (2010) Mutations in DCC cause congenital mirror movements. Science 328:592PubMedCrossRefGoogle Scholar
  42. Steketee JD, Kalivas PW (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 63(2):348–365PubMedCrossRefGoogle Scholar
  43. Ventura R, Alcaro A, Cabib S, Conversi D, Mandolesi L, Puglisi–Allegra S (2004) Dopamine in the medial prefrontal cortex controls genotype–dependent effects of amphetamine on mesoaccumbens dopamine release and locomotion. Neuropsychopharmacology 29:72–80PubMedCrossRefGoogle Scholar
  44. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, Wong C (2006) Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci 26:6583–6588PubMedCrossRefGoogle Scholar
  45. Voorn P, Kalsbeek A, Jorritsma-Byham B, Groenewegen HJ (1988) The pre-and postnatal development of the dopaminergic cell groups in the ventral mesencephalon and the dopaminergic innervation of the striatum of the rat. Neuroscience 25(3):857–887PubMedCrossRefGoogle Scholar
  46. Yetnikoff L, Eng C, Benning S, Flores C (2010) Netrin–1 receptor in the ventral tegmental area is required for sensitization to amphetamine. Eur J Neurosci 31:1292–1302PubMedCrossRefGoogle Scholar
  47. Yetnikoff L, Almey A, Arvanitogiannis A, Flores C (2011) Abolition of the behavioral phenotype of adult netrin–1 receptor deficient mice by exposure to amphetamine during the juvenile period. Psychopharmacology 217:505–514PubMedCrossRefGoogle Scholar
  48. Yetnikoff L, Pokinko M, Arvanitogiannis A, Flores C (2013) Adolescence: a time of transition for the phenotype of dcc heterozygous mice. Psychopharmacology. doi: 10.1007/s00213-013-3083-z PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jee Hyun Kim
    • 1
  • Doron Lavan
    • 1
  • Nicola Chen
    • 1
  • Cecilia Flores
    • 2
  • Helen Cooper
    • 3
  • Andrew J. Lawrence
    • 1
  1. 1.Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
  2. 2.Department of PsychiatryMcGill UniversityMontrealCanada
  3. 3.Queensland Brain InstituteThe University of QueenslandBrisbaneAustralia

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