Brain Structure and Function

, Volume 223, Issue 4, pp 1829–1838 | Cite as

Adolescent cocaine exposure induces prolonged synaptic modifications in medial prefrontal cortex of adult rats

  • Wei Zhu
  • Xuhui Ge
  • Peng Gao
  • Min Li
  • Yun Guan
  • Xiaowei Guan
Original Article


Substance used during adolescent period increases the risk of psychiatric disorders in later life, but the underlying neural mechanisms remain unclear. We hypothesize that synaptic remodeling and changes of homeostasis in the medial prefrontal cortex (mPFC) following adolescent cocaine exposure may last for a long time, and these modifications may contribute to behavioral deficiencies in adulthood. To address this hypothesis, rats were exposed to cocaine hydrochloride from postnatal day 28 (P28) to P42. When reared to adulthood, rats were subjected to behavioral tests. On P75 and P76, cocaine-experienced rats exhibited increased locomotive and anxiety-like behaviors, as well as impaired non-selective attention. In the cocaine-experienced rats, both levels of synapse-related proteins (synapsin I and PSD-95) and density of synapse and dendrite spine in mPFC were significantly decreased when compared to controls. Unexpected, the expression of molecules related to oxidative stress, inflammation and apoptosis showed no significant changes in mPFC following adolescent cocaine exposure. These findings suggested that adolescent exposure to cocaine induce long-term modification on synapses in mPFC, which might contribute to long-term behavioral outcomes in adulthood.


Cocaine Adolescent exposure Medial prefrontal cortex Synapse Dendrite spine Abnormal behaviors 



This work was supported by the National Natural Science Foundation of China (no. 81571303). We thank Prof. Gang Chen and Dr. Wenda Xue, Nanjing University of Chinese Medicine, China, for their assistance in behavioral tests.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.


  1. Adhikari A, Topiwala MA, Gordon JA (2011) Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity. Neuron 71(5):898–910. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aguilar-Rivera MI, Casanova JP, Gatica RI, Quirk GJ, Fuentealba JA (2015) Amphetamine sensitization is accompanied by an increase in prelimbic cortex activity. Neuroscience 288:1–9. CrossRefPubMedGoogle Scholar
  3. Alvaro-Bartolomé M, La Harpe R, Callado LF, Meana JJ, García-Sevilla JA (2011) Molecular adaptations of apoptotic pathways and signaling partners in the cerebral cortex of human cocaine addicts and cocaine-treated rats. Neuroscience 24:196:1–15. CrossRefGoogle Scholar
  4. Bull C, Syed WA, Minter SC, Bowers MS (2015) Differential response of glial fibrillary acidic protein-positive astrocytes in the rat prefrontal cortex following ethanol self-administration. Alcohol Clin Exp Res 39(4):650–658. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Butkovich LM, DePoy LM, Allen AG, Shapiro LP, Swanson AM, Gourley SL (2015) Adolescent-onset GABAA α1 silencing regulates reward-related decision making. Eur J Neurosci 42(4):2114–2121. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Caffino L, Giannotti G, Malpighi C, Racagni G, Filip M, Fumagalli F (2014) Long-term abstinence from developmental cocaine exposure alters Arc/Arg3.1 modulation in the rat medial prefrontal cortex. Neurotox Res 26(3):299–306. CrossRefPubMedGoogle Scholar
  7. Caffino L, Calabrese F, Giannotti G, Barbon A, Verheij MM, Racagni G, Fumagalli F (2015a) Stress rapidly dysregulates the glutamatergic synapse in the prefrontal cortex of cocaine-withdrawn adolescent rats. Addict Biol 20(1):158–169. CrossRefPubMedGoogle Scholar
  8. Caffino L, Giannotti G, Malpighi C, Racagni G, Fumagalli F (2015b) Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics. Eur Neuropsychopharmacol 25(10):1832–1841. CrossRefPubMedGoogle Scholar
  9. Caffino L, Giannotti G, Mottarlini F, Racagni G, Fumagalli F (2017a) Developmental exposure to cocaine dynamically dysregulates cortical Arc/Arg3.1 Modulation in response to a challenge. Neurotox Res 31(2):289–297. CrossRefPubMedGoogle Scholar
  10. Caffino L, Giannotti G, Racagni G, Fumagalli F (2017b) A single cocaine exposure disrupts actin dynamics in the cortico-accumbal pathway of adolescent rats: modulation by a second cocaine injection. Psychopharmacology 234(8):1217–1222. CrossRefPubMedGoogle Scholar
  11. Chocyk A, Bobula B, Dudys D, Przyborowska A, Majcher-Maślanka I, Hess G, Wędzony K (2013) Early-life stress affects the structural and functional plasticity of the medial prefrontal cortex in adolescent rats. Eur J Neurosci 38(1):2089–2107. CrossRefPubMedGoogle Scholar
  12. Cooper ZD, Jones JD, Comer SD (2012) Glial modulators: a novel pharmacological approach to altering the behavioral effects of abused substances. Expert Opin Investig Drugs 21(2):169–178. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Crabtree GW, Sun Z, Kvajo M, Broek JA, Fénelon K, McKellar H, Xiao L, Xu B, Bahn S, O’Donnell JM, Gogos JA (2017) Alteration of neuronal excitability and short-term synaptic plasticity in the prefrontal cortex of a mouse model of mental illness. J Neurosci. PubMedPubMedCentralGoogle Scholar
  14. Cunha-Oliveira T, Rego AC, Cardoso SM, Borges F, Swerdlow RH, Macedo T, de Oliveira CR (2006) Mitochondrial dysfunction and caspase activation in rat cortical neurons treated with cocaine or amphetamine. Brain Res 1089(1):44–54. CrossRefPubMedGoogle Scholar
  15. DePoy LM, Gourley SL (2015) Synaptic cytoskeletal plasticity in the prefrontal cortex following psychostimulant exposure. Traffic 16(9):919–940. CrossRefPubMedPubMedCentralGoogle Scholar
  16. DePoy LM, Noble B, Allen AG, Gourley SL (2013) Developmentally divergent effects of Rho-kinase inhibition on cocaine- and BDNF-induced behavioral plasticity. Behav Brain Res 243:171–175. CrossRefPubMedPubMedCentralGoogle Scholar
  17. DePoy LM, Perszyk RE, Zimmermann KS, Koleske AJ, Gourley SL (2014) Adolescent cocaine exposure simplifies orbitofrontal cortical dendritic arbors. Front Pharmacol 27:5:228. Google Scholar
  18. DePoy LM, Zimmermann KS, Marvar PJ, Gourley SL (2017) Induction and blockade of adolescent cocaine-induced habits. Biol Psychiatry 81(7):595–605. CrossRefPubMedGoogle Scholar
  19. Giannotti G, Caffino L, Calabrese F, Racagni G, Riva MA, Fumagalli F (2014) Prolonged abstinence from developmental cocaine exposure dysregulates BDNF and its signaling network in the medial prefrontal cortex of adult rats. Int J Neuropsychopharmacol 17(4):625–634. CrossRefPubMedGoogle Scholar
  20. Giannotti G, Caffino L, Malpighi C, Melfi S, Racagni G, Fumagalli F (2015) A single exposure to cocaine during development elicits regionally-selective changes in basal basic Fibroblast Growth Factor (FGF-2) gene expression and alters the trophic response to a second injection. Psychopharmacology 232(4):713–719. CrossRefPubMedGoogle Scholar
  21. Gulley JM, Juraska JM (2013) The effects of abused drugs on adolescent development of corticolimbic circuitry and behavior. Neuroscience 249:3–20. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hanson KL, Cummins K, Tapert SF, Brown SA (2011) Changes in neuropsychological functioning over 10 years following adolescent substance abuse treatment. Psychol Addict Behav 25:127–142. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hu P, Zhu W, Zhu C, Jin L, Guan Y, Guan X (2016) Resveratrol fails to affect cocaine conditioned place preference behavior, but alleviates anxiety-like behaviors in cocaine withdrawn rats. Psychopharmacology 233(7):1279–1287. CrossRefPubMedGoogle Scholar
  24. Hung KL, Wang SJ, Wang YC, Chiang TR, Wang CC (2014) Upregulation of presynaptic proteins and protein kinases associated with enhanced glutamate release from axonal terminals (synaptosomes) of the medial prefrontal cortex in rats with neuropathic pain. Pain 155(2):377–387. CrossRefPubMedGoogle Scholar
  25. Jang EY, Ryu YH, Lee BH, Chang SC, Yeo MJ, Kim SH, Folsom RJ, Schilaty ND, Kim KJ, Yang CH, Steffensen SC, Kim HY (2015) Involvement of reactive oxygen species in cocaine-taking behaviors in rats. Addict Biol 20(4):663–675. CrossRefPubMedGoogle Scholar
  26. Kenneson A, Funderburk JS, Maisto SA (2013) Risk factors for secondary substance use disorders in people with childhood and adolescent-onset bipolar disorder: opportunities for prevention. Compr Psychiatry 54(5):439–446. CrossRefPubMedGoogle Scholar
  27. Koss WA, Belden CE, Hristov AD, Juraska JM (2014) Dendritic remodeling in the adolescent medial prefrontal cortex and the basolateral amygdala of male and female rats. Synapse 68(2):61–72. CrossRefPubMedGoogle Scholar
  28. Lander SS, Linder-Shacham D, Gaisler-Salomon I (2017) Differential effects of social isolation in adolescent and adult mice on behavior and cortical gene expression. Behav Brain Res 316:245–254. CrossRefPubMedGoogle Scholar
  29. Lin KY, Cherng CG, Yang FR, Lin LC, Lu RB, Yu L (2011) Memantine abolishes the formation of cocaine-induced conditioned place preference possibly via its IL-6-modulating effect in medial prefrontal cortex. Behav Brain Res 220(1):126–131. CrossRefPubMedGoogle Scholar
  30. Ma YY, Lee BR, Wang X, Guo C, Liu L, Cui R, Lan Y, Balcita-Pedicino JJ, Wolf ME, Sesack SR, Shaham Y, Schlüter OM, Huang YH, Dong Y (2014) Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83(6):1453–1467. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Marsh AA, Blair KS, Vythilingam M, Busis S, Blair RJ (2007) Response options and expectations of reward in decision-making: the differential roles of dorsal and rostral anterior cingulate cortex. Neuroimage 35(2):979–988. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Meyza KZ, Boguszewski PM, Nikolaev E, Zagrodzka J (2009) Diverse sensitivity of RHA/Verh and RLA/Verh rats to emotional and spatial aspects of a novel environment as a result of a distinct pattern of neuronal activation in the fear/anxiety circuit. Behav Genet 39(1):48–61. CrossRefPubMedGoogle Scholar
  33. Miguel-Hidalgo JJ (2009) The role of glial cells in drug abuse. Curr Drug Abuse Rev 2(1):72–82CrossRefPubMedGoogle Scholar
  34. Morrow BA, Hajszan T, Leranth C, Elsworth JD, Roth RH (2007) Prenatal exposure to cocaine is associated with increased number of spine synapses in rat prelimbic cortex. Synapse 61(10):862–865. CrossRefPubMedGoogle Scholar
  35. Moss HB, Chen CM, Yi HY (2014) Early adolescent patterns of alcohol, cigarettes, and marijuana polysubstance use and young adult substance use outcomes in a nationally representative sample. Drug Alcohol Depend 136:51–62. CrossRefPubMedGoogle Scholar
  36. Nassogne MC, Louahed J, Evrard P, Courtoy PJ (1997) Cocaine induces apoptosis in cortical neurons of fetal mice. J Neurochem 68(6):2442–2450CrossRefPubMedGoogle Scholar
  37. Paule MG (2005) Chronic drug exposures during development in nonhuman primates: models of brain dysfunction in humans. Front Biosci 10:2240–2249CrossRefPubMedGoogle Scholar
  38. Rasakham K, Schmidt HD, Kay K, Huizenga MN, Calcagno N, Pierce RC, Spires-Jones TL, Sadri-Vakili G (2014) Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration. PLoS One 9(7):e102524. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Realini N, Rubino T, Parolaro D (2009) Neurobiological alterations at adult age triggered by adolescent exposure to cannabinoids. Pharmacol Res 60:132–138. CrossRefPubMedGoogle Scholar
  40. Ren WW, Liu Y, Li BM (2012) Stimulation of α(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Mol Cell Neurosci 49(2):205–216. CrossRefPubMedGoogle Scholar
  41. Reynolds LM, Makowski CS, Yogendran SV, Kiessling S, Cermakian N, Flores C (2015) Amphetamine in adolescence disrupts the development of medial prefrontal cortex dopamine connectivity in a DCC-dependent manner. Neuropsychopharmacology 40(5):1101–1112. CrossRefPubMedGoogle Scholar
  42. Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC (2014) Optogenetic dissection of medial prefrontal cortex circuitry. Front Syst Neurosci 8:230CrossRefPubMedPubMedCentralGoogle Scholar
  43. Robinson TE, Kolb B (1997) Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17(21):8491–8497CrossRefPubMedGoogle Scholar
  44. Robinson TE, Kolb B (1999) Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur J Neurosci 11(5):1598–1604CrossRefPubMedGoogle Scholar
  45. Robinson TE, Gorny G, Mitton E, Kolb B (2001) Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse 39(3):257–266CrossRefPubMedGoogle Scholar
  46. Ruocco LA, de Souza Silva MA, Topic B, Mattern C, Huston JP, Sadile AG (2009) Intranasal application of dopamine reduces activity and improves attention in Naples High Excitability rats that feature the mesocortical variant of ADHD. Eur Neuropsychopharmacol 19(10):693–701. CrossRefPubMedGoogle Scholar
  47. Rutherford HJ, Mayes LC, Potenza MN (2010) Neurobiology of adolescent substance use disorders: implications for prevention and treatment. Child Adolesc Psychiatr Clin N Am 19:479–492. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Selemon LD (2013) A role for synaptic plasticity in the adolescent development of executive function. Transl Psychiatry 3:e238. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Shapiro LP, Parsons RG, Koleske AJ, Gourley SL (2017) Differential expression of cytoskeletal regulatory factors in the adolescent prefrontal cortex: implications for cortical development. J Neurosci Res 95(5):1123–1143. CrossRefPubMedGoogle Scholar
  50. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463CrossRefPubMedGoogle Scholar
  51. Staff J, Schulenberg JE, Maslowsky J, Bachman JG, O’Malley PM, Maggs JL, Johnston LD (2010) Substance use changes and social role transitions: proximal developmental effects on ongoing trajectories from late adolescence through early adulthood. Dev Psychopathol 22:917–932. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, Adhikari A, Tye KM, Frank LM, Deisseroth K (2012) A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492(7429):428–432. CrossRefPubMedGoogle Scholar
  53. Yin P, Cao AH, Yu L, Guo LJ, Sun RP, Lei GF (2014) ABT-724 alleviated hyperactivity and spatial learning impairment in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Neurosci Lett 580:142–146. CrossRefPubMedGoogle Scholar
  54. Zhu W, Mao Z, Zhu C, Li M, Cao C, Guan Y, Yuan J, Xie G, Guan X (2016) Adolescent exposure to cocaine increases anxiety-like behavior and induces morphologic and neurochemical changes in the hippocampus of adult rats. Neuroscience 313:174–183. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Wei Zhu
    • 1
  • Xuhui Ge
    • 3
  • Peng Gao
    • 1
  • Min Li
    • 3
  • Yun Guan
    • 4
  • Xiaowei Guan
    • 1
    • 2
  1. 1.Department of Human Anatomy and Histoembryology, School of Medicine and Life SciencesNanjing University of Chinese MedicineNanjingChina
  2. 2.Key Laboratory of Drug Target and Drug for Degenerative Disease of JiangsuNanjing University of Chinese MedicineNanjingChina
  3. 3.Department of Human Anatomy, School of Basic MedicineNanjing Medical UniversityNanjingChina
  4. 4.Department of Anesthesiology and Critical Care MedicineJohns Hopkins University School of MedicineBaltimoreUSA

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