Abstract
Rationale
Stark differences exist between adult (>PND 70) and juvenile (∼PND 21–34) rodents in how DCC (deleted in colorectal cancer) receptors and sensitization to amphetamine interact. In adults, repeated amphetamine upregulates DCC receptor expression selectively in the ventral tegmental area (VTA), an effect that is critical for sensitization. In contrast, amphetamine administered to juveniles downregulates VTA DCC expression. Moreover, whereas adult dcc heterozygous mice fail to sensitize when repeatedly treated with amphetamine, drug treatment during the juvenile period actually abolishes this adult “protective” phenotype.
Objectives
We set out to determine whether adolescence (PND ∼35–55) is a period during which: (1) amphetamine-induced alterations in VTA DCC expression switch from downregulation to upregulation; (2) the “protective” phenotype of adult dcc heterozygotes against sensitization becomes evident; and (3) the adult “protective” phenotype of dcc heterozygotes can still be abolished by repeated amphetamine treatment.
Results
Repeated amphetamine did not significantly alter VTA DCC expression in adolescent rodents when assessed 1 week later. Both wild-type and dcc heterozygous mice exhibited sensitization at this time. Remarkably, wild-type mice, but not dcc heterozygotes, exhibited sensitization when tested during adulthood.
Conclusions
Adolescence is a time of transition for dcc heterozygotes as related to sensitization. Our results support the hypothesis that DCC may be a key factor in determining age-dependent individual differences in vulnerability to sensitization. Given that exposure to drugs of abuse during adolescence can have profound consequences for adulthood, the resilience of adult dcc heterozygous mice against adolescent exposure to amphetamine is particularly salient.
Similar content being viewed by others
References
Antonopoulos J, Dori I, Dinopoulos A, Chiotelli M, Parnavelas JG (2002) Postnatal development of the dopaminergic system of the striatum in the rat. Neuroscience 110:245–256
Benes FM, Vincent SL, Molloy R, Khan Y (1996) Increased interaction of dopamine-immunoreactive varicosities with GABA neurons of rat medial prefrontal cortex occurs during the postweaning period. Synapse 23:237–245
Benoit-Marand M, O’Donnell P (2008) D2 dopamine modulation of corticoaccumbens synaptic responses changes during adolescence. Eur J Neurosci 27:1364–1372
Boudreau AC, Wolf ME (2005) Behavioral sensitization to cocaine is associated with increased AMPH receptor surface expression in the nucleus accumbens. J Neurosci 25:9144–9151
Colon-Ramos DA, Margeta MA, Shen K (2007) Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans. Science 318:103–106
Depienne C, Cincotta M, Billot S, Bouteiller D, Groppa S, Brochard V, Flamand C, Hubsch C, Meunier S, Giovannelli F, Klebe S, Corvol JC, Vidailher M, Brice A, Roze E (2011) A novel DCC mutation and genetic heterogeneity in congenital mirror movements. Neurology 76: 260-4
Ernst M, Romeo RD, Andersen SL (2009) Neurobiology of the development of motivated behaviors in adolescence: a window into a neural systems model. Parmacol Biochem Behav 93:199–211
Flores C (2011) Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system. J Psychiatry Neurosci 36:296–310
Flores C, Manitt C, Rodaros D, Thompson KM, Rajabi H, Luk KC, Tritsch NX, Sadikot AF, Stewart J, Kennedy TE (2005) Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine. Mol Psychiatry 10:606–612
Garske AK, Lawyer CR, Peterson BM, Illig KR (2013) Adolescent changes in dopamine d1 receptor expression in orbitofrontal cortex and piriform cortex accompany an associative learning deficit. PLoS One 8:e56191
Grant A, Hoops D, Labelle-Dumais C, Prevost M, Rajabi H, Kolb B, Stewart J, Arvanitogiannis A, Flores C (2007) Netrin-1 receptor-deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine. Eur J Neurosci 26:3215–3228
Heng L, Markham JA, Hu X-T, Tseng KY (2011) Concurrent upregulation of postsynaptic L-type Ca2+ channel and protein kinase A signaling is required for the periadolescent facilitation of Ca2+ plateau potentials and dopamine D1 receptor modulation in the prefrontal cortex. Neuropharmacology 60:953–962
Huppe-Gourgues F, O’Donnell P (2012a) Periadolescent changes of D2-AMPA interactions in the rat nucleus accumbens. Synapse 66:1–8
Huppe-Gourgues F, O’Donnell P (2012b) D1-NMDA receptor interactions in the rat nucleus accumbens change during adolescence. Synapse 66:584–591
Kalsbeek A, Voorn P, Buijs RM, Pool CM, Uylings HB (1988) Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol 269:58–72
Manitt C, Kennedy TE (2002) Where the rubber meets the road: netrin expression and function in developing and adult nervous systems. Prog Brain Res 137:425–442
Manitt C, Nikolakopoulou AM, Almario DR, Nguyen SA, Cohen-Cory S (2009) Netrin participates in the development of retinotectal synaptic connectivity by modulating axon arborization and synapse formation in the developing brain. J Neurosci 29:11065–11077
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:e11463
Manitt C, Mimee A, Eng C, Pokinko M, Stroh T, Cooper HM, Kolb B, Flores C (2011) The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. J Neurosci 31:8381–8394
Mason I (2007) Initiation to end point: the multiple roles of fibroblast growth factors in neural development. Nat Rev Neurosci 8:583–596
McCutcheon JE, Marinelli M (2009) Age matters. Eur J Neurosci 209:997-1014
Naneix F, Marchand AR, Di Scala G, Pape JR, Coutureau E (2012) Parallel maturation of goal-directed behavior and dopaminergic systems during adolescence. J Neurosci 32:16223–16232
O’Donnell P (2010) Adolescent maturation of cortical dopamine. Neurotox Res 18:306–312
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 131:671–681
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego
Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego
Perreault ML, Hasbi A, Alijaniaram M, O’Dowd BF, George SR (2012) Reduced striatal dopamine D1-D2 receptor heteromer expression and behavioral subsensitivity in juvenile rats. Neuroscience 6:130–139
Romero-Calvo I, Ocon B, Martinez-Moya P, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F (2010) Reversible Ponceau staining as a loading control alternative to actin in Western blots. Anal Biochem 401:318–320
Russo SJ, Mazei-Robison MS, Ables JL, Nestler EJ. Neurotrophic factors and structural plasticity in addiction. Neuropharmacol 56 Suppl 1: 73-82
Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463
Srour M, Riviere JB, Pham JM, Dube MP, Girard S, Morin S, Dion PA, Asselin G, Rochefort D, Hince P, Diab S, Sharafaddinzadeh N, Chouinard S, Theoret H, Charron F, Rouleau GA (2010) Mutations in DCC cause congenital mirror movements. Science 328:592
Sturman DA, Moghaddam B (2011a) Reduced neuronal inhibition and coordination of adolescent prefrontal cortex during motivated behavior. J Neurosci 31:1471–1478
Sturman DA, Moghaddam B (2011b) The neurobiology of adolescence: changes in brain architecture, functional dynamics, and behavioral tendencies. Neurosci Biobehav Rev 35:1704–1712
Sturman DA, Moghaddam B (2012) Striatum processes reward differently in adolescents versus adults. PNAS 109:1719–1724
Tarazi FI, Tomasini EC, Baldessarini RJ (1998) Postnatal development of dopamine and serotonin transporters in rat caudate–putamen and nucleus accumbens septi. Neurosci Lett 254:21–24
Tseng KY, O’Donnell (2005) Post-pubertal emergence of prefrontal cortical up states induced by D1-NMDA co-activation. Cereb Cortex 15:49–57
Tseng KY, O’Donnell P (2007) Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex 17:1235–1240
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 25:857–887
Yetnikoff L, Labelle-Dumais C, Flores C (2007) Regulation of netrin-1 receptors by amphetamine in the adult brain. Neuroscience 150:764–773
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 31:1292–1302
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 217:505–514
Acknowledgments
We thank Susan Ackerman (The Jackson Laboratory) for the original dcc heterozygous breeders. All experimental procedures were performed in accordance with the guidelines of the Canadian Council on Animal Care, the Animal Committee of the Douglas Mental Health University Institute/McGill University, and the Concordia University Animal Research Ethics Committee. This work was funded by the Natural Science and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Fonds de la Recherche en Santé du Québec, and the Fonds Québécois de la Recherche sur la Nature et les Technologies.
Disclosure/conflict of interest
The authors declare that they have no conflict of interests.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yetnikoff, L., Pokinko, M., Arvanitogiannis, A. et al. Adolescence: a time of transition for the phenotype of dcc heterozygous mice. Psychopharmacology 231, 1705–1714 (2014). https://doi.org/10.1007/s00213-013-3083-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-013-3083-z