Brain Structure and Function

, Volume 224, Issue 2, pp 741–758 | Cite as

Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core

  • B. M. Siemsen
  • G. Giannotti
  • J. A. McFaddin
  • M. D. Scofield
  • Jacqueline F. McGintyEmail author
Original Article


Cocaine self-administration (SA) in rats dysregulates glutamatergic signaling in the prelimbic (PrL) cortex and glutamate release in the nucleus accumbens (NA) core, promoting cocaine seeking. PrL adaptations that affect relapse to drug seeking emerge during the first week of abstinence, switching from an early (2 h) hypoglutamatergic state to a later (7 days) hyperglutamatergic state. Different interventions that normalize glutamatergic signaling in PrL cortex at each timepoint are necessary to suppress relapse. We hypothesized that plasticity-related proteins that regulate glutamatergic neurotransmission as well as dendritic spine morphology would be biphasically regulated during these two phases of abstinence in PrL cortical neurons projecting to the NA core (PrL–NA core). A combinatorial viral approach was used to selectively label PrL–NA core neurons with an mCherry fluorescent reporter. Male rats underwent 2 weeks of cocaine SA or received yoked-saline infusions and were perfused either 2 h or 7 days after the final SA session. Confocal microscopy and 3D reconstruction analyses were performed for Fos and pCREB immunoreactivity (IR) in the nucleus of layer V PrL–NA core neurons and GluA1–IR and GluA2–IR in apical dendritic spines of the same neurons. Here, we show that cocaine SA decreased PrL–NA core spine head diameter, nuclear Fos–IR and pCREB–IR, and GluA1–IR and GluA2–IR in putative mushroom-type spines 2 h after the end of cocaine SA, whereas the opposite occurred following 1 week of abstinence. Our findings reveal biphasic, abstinence duration-dependent alterations in structural plasticity and relapse-related proteins in the PrL–NA core pathway after cocaine SA.


Cocaine Prelimbic cortex Nucleus accumbens Dendritic spines AMPA receptors Glutamate 



We thank Jordan Hopkins and Kaylee Hooker for excellent technical assistance. This work was supported by National Institute on Drug Abuse Grants: P50 DA15369 (JFM), R01 DA033479 (JFM), T32 DA007288 (JFM), F31 DA041021 (BMS), and R00 DA040004 (MDS).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

429_2018_1805_MOESM1_ESM.pdf (467 kb)
Supplementary material 1 (PDF 466 KB)


  1. Aghajanian GK, Marek GJ (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36:589–599CrossRefPubMedGoogle Scholar
  2. Anggono V, Huganir RL (2012) Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 22:461–469. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ball KT, Wellman CL, Fortenberry E, Rebec GV (2009) Sensitizing regimens of (±)3, 4-methylenedioxymethamphetamine (ecstasy) elicit enduring and differential structural alterations in the brain motive circuit of the rat. Neuroscience 160:264–274. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF (2000) Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci 20:89–102CrossRefPubMedGoogle Scholar
  5. Barrientos C, Knowland D, Wu MMJ, Lilascharoen V, Huang KW, Malenka RC, Lim BK (2018) Cocaine induced structural plasticity in input regions to distinct cell types in nucleus accumbens. Biol Psychiatry. PubMedGoogle Scholar
  6. Barry SM, McGinty JF (2017) Role of Src family kinases in BDNF-mediated suppression of cocaine-seeking and prevention of cocaine-induced ERK, GluN2A, and GluN2B dephosphorylation in the prelimbic cortex. Neuropsychopharmacology 42:1972–1980. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Berendse HW, Groenewegen HJ (1991) Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 42:73–102CrossRefPubMedGoogle Scholar
  8. Berglind WJ, Whitfield TW Jr, LaLumiere RT, Kalivas PW, McGinty JF (2009) A single intra-PFC infusion of BDNF prevents cocaine-induced alterations in extracellular glutamate within the nucleus accumbens. J Neurosci 29:3715–3719. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Berglind WJ, See RE, Fuchs RA, Ghee SM, Whitfield TW Jr, Miller SW, McGinty JF (2007) A BDNF infusion into the medial prefrontal cortex suppresses cocaine seeking in rats. Eur J Neurosci 26:757–766. CrossRefPubMedGoogle Scholar
  10. Borges K, Dingledine R (2001) Functional organization of the GluR1 glutamate receptor promoter. J Biol Chem 276:25929–25938. CrossRefPubMedGoogle Scholar
  11. Chen BT, Yau HJ, Hatch C, Kusumoto-Yoshida I, Cho SL, Hopf FW, Bonci A (2013) Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496:359–362. CrossRefPubMedGoogle Scholar
  12. Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y, Marinelli M, Wolf ME (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454:118–121. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dennis TS, Jhou TC, McGinty JF (2018) Cocaine self-administration and time-dependent decreases in prelimbic activity. bioRxiv. Google Scholar
  14. Dos Santos M, Salery M, Forget B, Garcia Perez MA, Betuing S, Boudier T, Vanhoutte P, Caboche J, Heck N (2017) Rapid Synaptogenesis in the nucleus accumbens is induced by a single cocaine administration and stabilized by mitogen-activated protein kinase interacting kinase-1 activity. Biol Psychiatry 82:806–818. CrossRefPubMedGoogle Scholar
  15. Ehlers MD, Heine M, Groc L, Lee MC, Choquet D (2007) Diffusional trapping of GluR1 AMPA receptors by input-specific synaptic activity. Neuron 54:447–460. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Giannotti G, Barry SM, Siemsen BM, Peters J, McGinty JF (2018) Divergent prelimbic cortical pathways control BDNF-dependent vs. independent suppression of cocaine seeking. J Neurosci 38:8956–8966CrossRefPubMedGoogle Scholar
  17. Gipson CD, Kupchik YM, Shen H, Reissner KJ, Thomas CA, Kalivas PW (2013) Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77:867–872. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Go BS, Barry SM, McGinty JF (2016) Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking. Eur Neuropsychopharmacol 26:1989–1999. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Han JH, Kushner SA, Yiu AP, Cole CJ, Matynia A, Brown RA, Neve RL, Guzowski JF, Silva AJ, Josselyn SA (2007) Neuronal competition and selection during memory formation. Science 316:457–460. CrossRefPubMedGoogle Scholar
  20. Hu H, Real E, Takamiya K, Kang MG, Ledoux J, Huganir RL, Malinow R (2007) Emotion enhances learning via norepinephrine regulation of AMPA-receptor trafficking. Cell 131:160–173. CrossRefPubMedGoogle Scholar
  21. Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572. CrossRefPubMedGoogle Scholar
  22. Kalivas PW, Volkow N, Seamans J (2005) Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45:647–650. CrossRefPubMedGoogle Scholar
  23. Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H (2003) Structure-stability-function relationships of dendritic spines. Trends Neurosci 26:360–368. CrossRefPubMedGoogle Scholar
  24. Lambe EK, Aghajanian GK (2003) Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron 40:139–150CrossRefPubMedGoogle Scholar
  25. Lambe EK, Picciotto MR, Aghajanian GK (2003) Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 28:216–225. CrossRefPubMedGoogle Scholar
  26. Larkum ME, Nevian T, Sandler M, Polsky A, Schiller J (2009) Synaptic integration in tuft dendrites of layer 5 pyramidal neurons: a new unifying principle. Science 325:756–760. CrossRefPubMedGoogle Scholar
  27. Lisman J, Cooper K, Sehgal M, Silva AJ (2018) Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat Neurosci 21:309–314. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Liu RJ, Aghajanian GK (2008) Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci USA 105:359–364. CrossRefPubMedGoogle Scholar
  29. Liu RJ, Ota KT, Dutheil S, Duman RS, Aghajanian GK (2015) Ketamine strengthens CRF-activated amygdala inputs to basal dendrites in mPFC layer V pyramidal cells in the prelimbic but not infralimbic subregion, a key suppressor of stress responses. Neuropsychopharmacology 40:2066–2075. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Matsuo N, Reijmers L, Mayford M (2008) Spine-type-specific recruitment of newly synthesized AMPA receptors with learning. Science 319:1104–1107. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H (2001) Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci 4:1086–1092. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H (2004) Structural basis of long-term potentiation in single dendritic spines. Nature 429:761–766. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Middei S, Spalloni A, Longone P, Pittenger C, O’Mara SM, Marie H, Ammassari-Teule M (2012) CREB selectively controls learning-induced structural remodeling of neurons. Learn Mem 19:330–336. CrossRefPubMedGoogle Scholar
  34. Middei S, Houeland G, Cavallucci V, Ammassari-Teule M, D’Amelio M, Marie H (2013) CREB is necessary for synaptic maintenance and learning-induced changes of the AMPA receptor GluA1 subunit. Hippocampus 23:488–499. CrossRefPubMedGoogle Scholar
  35. Otis JM, Mueller D (2017) Reversal of cocaine-associated synaptic plasticity in medial prefrontal cortex parallels elimination of memory retrieval. Neuropsychopharmacology 42:2000–2010. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Otis JM, Namboodiri VM, Matan AM, Voets ES, Mohorn EP, Kosyk O, McHenry JA, Robinson JE, Resendez SL, Rossi MA, Stuber GD (2017) Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature 543:103–107. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Parrilla-Carrero J, Buchta WC, Goswamee P, Culver O, McKendrick G, Harlan B, Moutal A, Penrod R, Lauer A, Ramakrishnan V, Khanna R, Kalivas P, Riegel AC (2018) Restoration of Kv7 channel-mediated inhibition reduces cued-reinstatement of cocaine seeking. J Neurosci 38:4212–4229. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Passafaro M, Nakagawa T, Sala C, Sheng M (2003) Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature 424:677–681. CrossRefPubMedGoogle Scholar
  39. Pignataro A, Borreca A, Ammassari-Teule M, Middei S (2015) CREB regulates experience-dependent spine formation and enlargement in mouse barrel cortex. Neural Plast 2015:651469. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Prithviraj R, Kelly KM, Espinoza-Lewis R, Hexom T, Clark AB, Inglis FM (2008) Differential regulation of dendrite complexity by AMPA receptor subunits GluR1 and GluR2 in motor neurons. Dev Neurobiol 68:247–264. CrossRefPubMedGoogle Scholar
  41. Radley JJ, Anderson RM, Cosme CV, Glanz RM, Miller MC, Romig-Martin SA, LaLumiere RT (2015) The contingency of cocaine administration accounts for structural and functional medial prefrontal deficits and increased adrenocortical activation. J Neurosci 35:11897–11910. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 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:e102524. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 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 39:257–266.;2-1 CrossRefPubMedGoogle Scholar
  44. Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ (2010) The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci 33:267–276. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Saglietti L, Dequidt C, Kamieniarz K, Rousset MC, Valnegri P, Thoumine O, Beretta F, Fagni L, Choquet D, Sala C, Sheng M, Passafaro M (2007) Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron 54:461–477. CrossRefPubMedGoogle Scholar
  46. Scofield MD, Li H, Siemsen BM, Healey KL, Tran PK, Woronoff N, Boger HA, Kalivas PW, Reissner KJ (2016) Cocaine self-administration and extinction leads to reduced glial fibrillary acidic protein expression and morphometric features of astrocytes in the nucleus accumbens core. Biol Psychiatry 80:207–215. CrossRefPubMedGoogle Scholar
  47. Sepulveda-Orengo MT, Healey KL, Kim R, Auriemma AC, Rojas J, Woronoff N, Hyppolite R, Reissner KJ (2017) Riluzole impairs cocaine reinstatement and restores adaptations in intrinsic excitability and GLT-1 expression. Neuropsychopharmacology. PubMedGoogle Scholar
  48. Shepherd JD, Huganir RL (2007) The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 23:613–643. CrossRefPubMedGoogle Scholar
  49. Siemsen BM, Lombroso PJ, McGinty JF (2018) Intra-prelimbic cortical inhibition of striatal-enriched tyrosine phosphatase suppresses cocaine seeking in rats. Addict Biol 23:219–229. CrossRefPubMedGoogle Scholar
  50. Spencer S, Garcia-Keller C, Roberts-Wolfe D, Heinsbroek JA, Mulvaney M, Sorrell A, Kalivas PW (2017) Cocaine use reverses striatal plasticity produced during cocaine seeking. Biol Psychiatry 81:616–624. CrossRefPubMedGoogle Scholar
  51. Stefanik MT, Kupchik YM, Kalivas PW (2016) Optogenetic inhibition of cortical afferents in the nucleus accumbens simultaneously prevents cue-induced transient synaptic potentiation and cocaine-seeking behavior. Brain Struct Funct 221:1681–1689. CrossRefPubMedGoogle Scholar
  52. Sun X, Zhao Y, Wolf ME (2005) Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons. J Neurosci 25:7342–7351. CrossRefPubMedGoogle Scholar
  53. Sun WL, Zelek-Molik A, McGinty JF (2013) Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex. Psychopharmacology 229:603–613. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Sun WL, Coleman NT, Zelek-Molik A, Barry SM, Whitfield TW Jr, McGinty JF (2014a) Relapse to cocaine-seeking after abstinence is regulated by cAMP-dependent protein kinase A in the prefrontal cortex. Addict Biol 19:77–86. CrossRefPubMedGoogle Scholar
  55. Sun WL, Eisenstein SA, Zelek-Molik A, McGinty JF (2014b) A single brain-derived neurotrophic factor infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal. Int J Neuropsychopharmacol. PubMedCentralGoogle Scholar
  56. Szepesi Z, Hosy E, Ruszczycki B, Bijata M, Pyskaty M, Bikbaev A, Heine M, Choquet D, Kaczmarek L, Wlodarczyk J (2014) Synaptically released matrix metalloproteinase activity in control of structural plasticity and the cell surface distribution of GluA1-AMPA receptors. PLoS One 9:e98274. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683–1687. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Toda S, Shen H, Kalivas PW (2010) Inhibition of actin polymerization prevents cocaine-induced changes in spine morphology in the nucleus accumbens. Neurotox Res 18:410–415. CrossRefPubMedGoogle Scholar
  59. Trantham-Davidson H, Centanni SW, Garr SC, New NN, Mulholland PJ, Gass JT, Glover EJ, Floresco SB, Crews FT, Krishnan HR, Pandey SC, Chandler LJ (2017) Binge-like alcohol exposure during adolescence disrupts dopaminergic neurotransmission in the adult prelimbic cortex. Neuropsychopharmacology 42:1024–1036. CrossRefPubMedGoogle Scholar
  60. Vissavajjhala P, Janssen WG, Hu Y, Gazzaley AH, Moran T, Hof PR, Morrison JH (1996) Synaptic distribution of the AMPA-GluR2 subunit and its colocalization with calcium-binding proteins in rat cerebral cortex: an immunohistochemical study using a GluR2-specific monoclonal antibody. Exp Neurol 142:296–312. CrossRefPubMedGoogle Scholar
  61. Whitfield TW Jr, Shi X, Sun WL, McGinty JF (2011) The suppressive effect of an intra-prefrontal cortical infusion of BDNF on cocaine-seeking is Trk receptor and extracellular signal-regulated protein kinase mitogen-activated protein kinase dependent. J Neurosci 31:834–842. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Yiu AP, Mercaldo V, Yan C, Richards B, Rashid AJ, Hsiang HL, Pressey J, Mahadevan V, Tran MM, Kushner SA, Woodin MA, Frankland PW, Josselyn SA (2014) Neurons are recruited to a memory trace based on relative neuronal excitability immediately before training. Neuron 83:722–735. CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of NeuroscienceMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Anesthesiology and Perioperative MedicineMedical University of South CarolinaCharlestonUSA

Personalised recommendations