Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Contrasting forms of cocaine-evoked plasticity control components of relapse

Nature volume 509, pages 459–464 (2014)Cite this article

Subjects

Abstract

Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cue-associated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA (N-methyl-d-aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking, whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Withdrawal from cocaine self-administration evokes cell-type-specific modifications of excitatory synapses in the NAc.
Figure 2: Withdrawal from cocaine self-administration evokes input-specific plasticity in NAc D1R-MSNs.
Figure 3: Homosynaptic effects of optogenetic protocols applied ex vivo on D1R-MSN plasticity.
Figure 4: Heterosynaptic effects of optogenetic protocols applied ex vivo on D1R-MSN plasticity.
Figure 5: Linking cocaine-evoked plasticity at identified inputs to specific components of cue-associated cocaine seeking.

Similar content being viewed by others

References

  1. Robbins, T. W. & Everitt, B. J. Neurobehavioural mechanisms of reward and motivation. Curr. Opin. Neurobiol. 6, 228–236 (1996)

    CAS  PubMed  Google Scholar 

  2. Berridge, K. C. & Kringelbach, M. L. Neuroscience of affect: brain mechanisms of pleasure and displeasure. Curr. Opin. Neurobiol. 23, 294–303 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Humphries, M. D. & Prescott, T. J. The ventral basal ganglia, a selection mechanism at the crossroads of space, strategy, and reward. Prog. Neurobiol. 90, 385–417 (2010)

    PubMed  Google Scholar 

  4. Papp, E. et al. Glutamatergic input from specific sources influences the nucleus accumbens-ventral pallidum information flow. Brain Struct. Funct. 217, 37–48 (2012)

    CAS  PubMed  Google Scholar 

  5. Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neurosci. 8, 1481–1489 (2005)

    CAS  PubMed  Google Scholar 

  6. Kalivas, P. W. & Volkow, N. D. The neural basis of addiction: a pathology of motivation and choice. Am. J. Psychiatry 162, 1403–1413 (2005)

    PubMed  Google Scholar 

  7. Gangarossa, G. et al. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse nucleus accumbens. Front. Neural. Circuits 7, 22 (2013)

    PubMed  PubMed Central  Google Scholar 

  8. MacAskill, A. F., Little, J. P., Cassel, J. M. & Carter, A. G. Subcellular connectivity underlies pathway-specific signaling in the nucleus accumbens. Nature Neurosci. 15, 1624–1626 (2012)

    CAS  PubMed  Google Scholar 

  9. Smith, R. J., Lobo, M. K., Spencer, S. & Kalivas, P. W. Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways). Curr. Opin. Neurobiol. 23, 546–552 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Freund, T. F., Powell, J. F. & Smith, A. D. Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience 13, 1189–1215 (1984)

    CAS  PubMed  Google Scholar 

  11. Goto, Y. & Grace, A. A. Limbic and cortical information processing in the nucleus accumbens. Trends Neurosci. 31, 552–558 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cerovic, M., d’Isa, R., Tonini, R. & Brambilla, R. Molecular and cellular mechanisms of dopamine-mediated behavioral plasticity in the striatum. Neurobiol. Learn. Mem. 105, 63–80 (2013)

    CAS  PubMed  Google Scholar 

  13. Saddoris, M. P., Sugam, J. A., Cacciapaglia, F. & Carelli, R. M. Rapid dopamine dynamics in the accumbens core and shell: learning and action. Front. Biosci. (Elite Ed.) 5, 273–288 (2013)

    Google Scholar 

  14. Schultz, W. Potential vulnerabilities of neuronal reward, risk, and decision mechanisms to addictive drugs. Neuron 69, 603–617 (2011)

    CAS  PubMed  Google Scholar 

  15. Di Chiara, G. & Bassareo, V. Reward system and addiction: what dopamine does and doesn’t do. Curr. Opin. Pharmacol. 7, 69–76 (2007)

    CAS  PubMed  Google Scholar 

  16. Hyman, S. Addiction: a disease of learning and memory. Am. J. Psychol. 162, 1414–1422 (2005)

    Google Scholar 

  17. Lüscher, C. & Malenka, R. C. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69, 650–663 (2011)

    PubMed  PubMed Central  Google Scholar 

  18. Kourrich, S., Rothwell, P. E., Klug, J. R. & Thomas, M. J. Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J. Neurosci. 27, 7921–7928 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ortinski, P. I., Vassoler, F. M., Carlson, G. C. & Pierce, R. C. Temporally dependent changes in cocaine-induced synaptic plasticity in the nucleus accumbens shell are reversed by D1-like dopamine receptor stimulation. Neuropsychopharmacology 37, 1671–1682 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Cornish, J. L. & Kalivas, P. W. Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J. Neurosci. 20, RC89 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Conrad, K. L. et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454, 118–121 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ambroggi, F. et al. Stress and addiction: glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking. Nature Neurosci. 12, 247–249 (2009)

    CAS  PubMed  Google Scholar 

  23. Liu, S. J. & Zukin, R. S. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci. 30, 126–134 (2007)

    CAS  PubMed  Google Scholar 

  24. Britt, J. P. et al. Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron 76, 790–803 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. French, S. J. & Totterdell, S. Hippocampal and prefrontal cortical inputs monosynaptically converge with individual projection neurons of the nucleus accumbens. J. Comp. Neurol. 446, 151–165 (2002)

    PubMed  Google Scholar 

  26. French, S. J. & Totterdell, S. Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats. Neuroscience 119, 19–31 (2003)

    CAS  PubMed  Google Scholar 

  27. Goto, Y. & Grace, A. A. Dopamine-dependent interactions between limbic and prefrontal cortical plasticity in the nucleus accumbens: disruption by cocaine sensitization. Neuron 47, 255–266 (2005)

    CAS  PubMed  Google Scholar 

  28. Pascoli, V., Turiault, M. & Lüscher, C. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71–75 (2011)

    ADS  PubMed  Google Scholar 

  29. Robbe, D., Kopf, M., Remaury, A., Bockaert, J. & Manzoni, O. J. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc. Natl Acad. Sci. USA 99, 8384–8388 (2002)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kasanetz, F. et al. Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328, 1709–1712 (2010)

    ADS  CAS  PubMed  Google Scholar 

  31. Lüscher, C. & Huber, K. M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445–459 (2010)

    PubMed  PubMed Central  Google Scholar 

  32. Clem, R. L. & Huganir, R. L. Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science 330, 1108–1112 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. McCutcheon, J. E. et al. Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism. J. Neurosci. 31, 14536–14541 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bienenstock, E. L., Cooper, L. N. & Munro, P. W. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J. Neurosci. 2, 32–48 (1982)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lüscher, C. & Malenka, R. C. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb. Perspect. Biol. 4, a005710 (2012)

    PubMed  PubMed Central  Google Scholar 

  36. Counotte, D. S., Schiefer, C., Shaham, Y. & O’Donnell, P. Time-dependent decreases in nucleus accumbens AMPA/NMDA ratio and incubation of sucrose craving in adolescent and adult rats. Psychopharmacology 231, 1675–1684 (2013)

    PubMed  PubMed Central  Google Scholar 

  37. Smith, D. G. & Robbins, T. W. The neurobiological underpinnings of obesity and binge eating: a rationale for adopting the food addiction model. Biol. Psyc. 9, 804–810 (2013)

    Google Scholar 

  38. Bock, R. et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nature Neurosci. 16, 632–638 (2013)

    CAS  PubMed  Google Scholar 

  39. Lee, B. R. et al. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nature Neurosci. 16, 1644–1651 (2013)

    CAS  PubMed  Google Scholar 

  40. Kombian, S. B. & Malenka, R. C. Simultaneous LTP of non-NMDA- and LTD of NMDA-receptor-mediated responses in the nucleus accumbens. Nature 368, 242–246 (1994)

    ADS  CAS  PubMed  Google Scholar 

  41. Grueter, B. A., Brasnjo, G. & Malenka, R. C. Postsynaptic TRPV1 triggers cell type–specific long-term depression in the nucleus accumbens. Nature Neurosci. 13, 1519–1525 (2010)

    CAS  PubMed  Google Scholar 

  42. Bellone, C. & Lüscher, C. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nature Neurosci. 9, 636–641 (2006)

    CAS  PubMed  Google Scholar 

  43. Koya, E. et al. Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology 56 (suppl. 1). 177–185 (2009)

    CAS  PubMed  Google Scholar 

  44. Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd edn (Elsevier Academic Press, 2008)

    Google Scholar 

  45. Bertran-Gonzalez, J. et al. Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol. J. Neurosci. 28, 5671–5685 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ouimet, C. C. et al. DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J. Neurosci. 4, 111–124 (1984)

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Thomsen, M. & Caine, S. B. Intravenous drug self-administration in mice: practical considerations. Behav. Genet. 37, 101–118 (2006)

    PubMed  Google Scholar 

  48. Chistyakov, V. S. & Tsibulsky, V. L. How to achieve chronic intravenous drug self-administration in mice. J. Pharmacol. Toxicol. Methods 53, 117–127 (2006)

    CAS  PubMed  Google Scholar 

  49. Gipson, C. D. et al. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77, 867–872 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sparta, D. R. et al. Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits. Nature Protocols 7, 12–23 (2011)

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank D. Huber and M. Brown as well the members of the Lüscher laboratory for discussion and comments on the manuscript, and A. Hiver for assisting in animal surgery. This work was financed by a grant from the Swiss National Science Foundation, the National Center of Competence in Research (NCCR) ‘SYNAPSY - The Synaptic Bases of Mental Diseases’ of the Swiss National Science Foundation and a European Research Council advanced grant (MeSSI). J.T. is supported by an MD-PhD grant of the Swiss Confederation. The E.V. laboratory was supported by an Avenir grant (Inserm) and by the Agence Nationale de la Recherche.

Author information

Author notes

  1. Vincent Pascoli and Jean Terrier: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland,

    Vincent Pascoli, Jean Terrier, Eoin Cornelius O’Connor & Christian Lüscher

  2. INSERM, U661, Montpellier F-34094, France,

    Julie Espallergues & Emmanuel Valjent

  3. CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France,

    Julie Espallergues & Emmanuel Valjent

  4. Universités de Montpellier 1 & 2, UMR-5203, Montpellier F-34094, France,

    Julie Espallergues & Emmanuel Valjent

  5. Department of Clinical Neurosciences, Clinic of Neurology, Geneva University Hospital, CH-1211 Geneva, Switzerland,

    Christian Lüscher

Authors
  1. Vincent Pascoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean Terrier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julie Espallergues
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emmanuel Valjent
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eoin Cornelius O’Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christian Lüscher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

V.P. performed all the in vitro electrophysiological recordings. J.T. performed all surgery and behavioural experiments with the assistance of E.C.O’C. J.E. and E.V. performed the fluorescence immunohistochemical experiments. C.L., P.V., J.T. and E.C.O’C. designed the study, and C.L. wrote the manuscript with the help of all authors.

Corresponding author

Correspondence to Christian Lüscher.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Graphical abstract.

Top left: main excitatory afferents onto NAc shell D1R-MSNs (BLA: basolateral amygdala, vHipp: ventral subiculum of the hippocampus and mPFC: medial prefrontal cortex), which at baseline contain synapses that express NMDARs and GluA2-containing AMPARs. Top right: 1 month after withdrawal (WD) from cocaine self-administration (SA), mPFC synapses onto NAc shell D1R-MSNs express GluA2-lacking AMPARs whereas more GluA2-containing AMPARs are added at vHipp synapses. Effects of NMDAR- or mGluR1-dependent (1 or 13 Hz, respectively) light protocols applied at specific inputs (shown in green) on cocaine-evoked plasticity are illustrated, together with the consequence for cue-associated seeking behaviour.

Extended Data Figure 2 Identification and optogenetic targeting of excitatory inputs to the NAc shell.

a, Retrograde labelling with cholera toxin subunit B (AF594) injected into the NAc shell. Confocal images of injection sites (top) in the medio-dorsal (left) and medio-ventral (right) NAc shell are shown, regions where electrophysiology recordings were performed. b, Labelled cell bodies in corresponding projection areas (basolateral amygdala, ventral subiculum of the hippocampus and medial prefrontal cortex) are shown, with no discernable segregation between the medio-dorsal or medio-ventral NAc shell. For each projection area, the insert shows a complete hemisphere coronal section together with a zoomed image of the region of interest (indicated by yellow box). Il, infralimbic; CeL; central amygdala lateral; BLP, basolateral amydala posterior; BMP, basomedial amygdala posterior; PV, paraventricular thalamic nucleus; vHipp, central subiculum of the hippocampus; VIEnt, ventral intermediate entorhinal cortex; VTA, ventral tegmental area. c, Schematic of experiment (top) with light-evoked EPSCs recorded in D1R-MSNs of the NAc shell of mice infected with AAV1-ChR2–eYFP in the BLA (bottom left), vHipp (middle) or vmPFC (right) before and after bath application of glutamate receptor antagonists (NBQX 10 μM and AP5 50 μM for AMPAR and NMDAR, respectively). Scale bars, 20 ms, 50 pA.

Extended Data Figure 3 Individual MSNs receive inputs from multiple projection areas.

a, Confocal images of NAc from a mouse infected with AAV5-EF1–eYFP and AAV5-EF1–mCherry in the vHipp (left) and mPFC (right), respectively, at low magnification (first row). At higher magnification (second and third rows) eYFP from vHipp and mCherry from mPFC are present around MSNs stained by DARPP-32 (blue). aca, anterior commissure. Scale bar, 50 μm.

Extended Data Figure 4 Cocaine self-administration does not evoke input-specific plasticity in D2R-MSNs.

a, Top, schematic of whole-cell recordings of NAc shell D2R-MSNs of mice that 1 month previously self-administered saline (open points) or cocaine (filled points) and were infected with AAV1-ChR2–eYFP in the BLA (left), vHipp (middle) or mPFC (right). Bottom, after cocaine self-administration the mean amplitude of light-evoked EPSCs was not changed at any input onto D2R-MSNs (effect of group (saline/cocaine) and group × input (BLA/vHipp/mPFC) all not significant) (n = 10/14 for BLA (saline/cocaine), n = 10/20 for vHipp and n = 60/51 for mPFC). b, For each input, the rectification index (RI) was calculated. Example traces are shown (top), with the I/V plot (middle) and group mean rectification index data (bottom). Cocaine did not modify normalized AMPAR-EPSCs at +40 mV from BLA, vHipp or mPFC inputs (t12 = −0.20, P = 0.84, t18 = 0.44, P = 0.67 and t20 = 0.43, P = 067, respectively). The rectification index was also unchanged at D2R-MSN synapses from BLA, vHipp or mPFC inputs (t12 = −0.32, P = 0.75, t18 = −0.51, P = 0.62 and t20 = −0.67, P = 0.51 respectively). Scale bars, 20 ms, 20 pA. c, For the same cells as shown in b, the A/N ratio was calculated. For each input, example traces are shown (top), with group mean A/N ratios (bottom). Cocaine did not alter the A/N ratio at inputs onto D2R-MSNs from the BLA, vHipp or mPFC (t12 = −0.19, P = 0.85, t18 = 1.20, P = 0.25 and t20 = −0.04, P = 0.97, respectively). Scale bars, 20 ms, 20 pA. Error bars, s.e.m.

Extended Data Figure 5 mPFC and NAc recordings during 1 and 13 Hz optogenetic protocols and LTD in NAc D2R-MSNs induced by mPFC protocols applied after saline and cocaine self-administration.

a, Right, schematic of whole-cell recordings in the mPFC or NAc from mice infected with ChR2 in mPFC. Top, light-evoked action potentials recorded in current clamp of ChR2-infected mPFC neurons and EPSCs recorded in voltage-clamp of D1R-MSNs (bottom) during the beginning of the 1 Hz (left) or 13 Hz (right) stimulation protocols. Note that EPSCs fail to follow the 13 Hz protocol. b, Top left, schematic of experiment. Bottom, graph of normalized light-evoked EPSCs across time recorded in NAc D2R-MSNs from saline and mice that self-administered cocaine (each point represents mean of six sweeps), together with example traces (mean of 20 sweeps) before (1) and after (2) a 1 (left) or 13 Hz (right) light protocol was applied ex vivo (4 ms pulses at 1 or 13 Hz, 10 min). One month after saline or cocaine self-administration, the 1 Hz and 13 Hz protocols induced comparable LTDs in both groups (for 1 Hz: 50 ± 4.9% to 40 ± 2.6%, Student’s t-test t14 = −1.86, P = 0.080; n = 7–9 cells; for 13 Hz: 28 ± 3.7% to 33 ± 4.2%, Student’s t-test t18 = 1.41, P = 0.18; n = 11–9 cells). Error bars, s.e.m.

Extended Data Figure 6 Optogenetic protocols applied in vivo reverse cocaine evoked-plasticity at NAc D1R-MSNs.

a, Top, schematic of experiment. Mice were infected with ChR2 in the vHipp or mPFC and trained in saline or cocaine self-administration. Mice were then implanted with fibre optics targeting the NAc shell, and optogenetic protocols were applied in vivo 1 month after withdrawal. Four hours later, acute brain slices were prepared to assess the efficiency of optogenetic protocols applied in vivo to reverse cocaine-evoked plasticity at NAc D1R-MSNs. In brief, consistent with the ex vivo validation, the 1 Hz vHipp protocol applied in vivo normalized the A/N ratio, whereas the 13 Hz mPFC protocol normalized the I/V curve and rectification index in mice that self-administered cocaine. b, Left, schematic of experiment indicating that mice were infected with ChR2 in the vHipp. The rectification index and A/N ratio were determined with light-evoked EPSCs as described previously (see Fig. 2). The I/V plot is shown, together with group mean rectification index and A/N data. Cocaine did not alter normalized AMPAR-EPSCs recorded at +40 mV or the rectification index from vHipp inputs (same data as Fig. 3). The 1 Hz protocol applied in vivo was without effect on either of these measures in mice that self-administered saline or cocaine (effect of group (saline versus cocaine), protocol (control versus 1 Hz) and group × protocol, all not significant). The A/N ratio was increased at vHipp inputs in mice that self-administered cocaine (same data as Fig. 3), an effect that was reduced after the in vivo 1 Hz protocol (planned comparison, after ANOVA, by t-test, t26 = 4.97, oP < 0.001) (n = 13/15 for 1 Hz saline/cocaine group). c, As for b, except that mice were infected with ChR2 in the mPFC. Cocaine decreased AMPAR-EPSCs recorded at +40 mV and increased the rectification index from mPFC inputs (same data as Fig. 3). The 13 Hz protocol applied in vivo increased AMPAR-EPSCs at +40 mV in mice that self-administered cocaine (planned comparison with cocaine control group, after ANOVA, by t-test, t20 = 3.6, oP < 0.01) and decreased the rectification index in mice that self-administered cocaine (planned comparison with cocaine controls, after ANOVA, by t-test, t20 = 5.2, oP < 0.001). The A/N ratio was decreased at mPFC inputs in mice that self-administered cocaine (same data as Fig. 3), an effect that was normalized after the in vivo 13 Hz protocol (planned comparison with cocaine controls, after ANOVA, by t-test, t20 = 2.8, oP = 0.01) (n = 11/9 for 13 Hz saline/cocaine group). Error bars, s.e.m.

Extended Data Figure 7 Assessing effects of in vivo light stimulation on mEPSCs recorded in D2R- and D1R-MSNs.

a, Top, schematic of experiment. Mice were infected with ChR2 in the vHipp or mPFC and trained in saline or cocaine self-administration. Mice were then implanted with fibre optics targeting the NAc shell and optogenetic protocols applied in vivo 1 month after withdrawal. Four hours later, acute brain slices were prepared to assess the effect of optogenetic protocols applied in vivo on global excitatory transmission by recording mEPSCs at NAc D2R-MSNs. In brief, recordings from D2R-MSNs showed that mEPSCs were not affected by cocaine and not depressed by optogenetic LTD protocols applied in vivo. Note that although optogenetic protocols efficiently induced LTD at single inputs onto D2R-MSNs (Extended Data Fig. 5), this was not reflected by a decrease in mEPSC amplitudes. This may be accounted for by a presynaptic expression mechanism of LTD or that baseline amplitudes were already low such that a further depression only at a single input could not be measured by mEPSCs (that is, floor effect), which reflects synaptic transmission from multiple inputs. b, Example of mEPSCs recorded ex vivo in NAc shell D2R-MSNs in the presence of picrotoxin (100 μM) and tedrodotoxin (0.5 μM) (sample traces comprising six superimposed, 4 s traces). Scale bars, 20 pA, 500 ms. c, Histograms of group mean data of D2R-MSN mEPSC amplitudes (left) and frequency (right) are shown in control saline (sal) or cocaine (coc) conditions and after application of 1 Hz or 13 Hz light protocols at vHipp or mPFC synapses. Mean mEPSC amplitudes and frequencies were not changed by cocaine, and were not significantly decreased by protocols applied at either vHip or mPFC inputs (n = 5 to 13 cells per group). Error bars, s.e.m. d, e, As for a and b except in D1R-MSNs. In brief, the frequency of mEPCS was not affected by cocaine self-administration or laser protocols. In contrast, in mice that self-administered cocaine the amplitude of mEPSCs was significantly larger than controls, in line with a postsynaptic expression mechanism. Protocols that were most efficient at restoring the A/N ratio at vHipp synapses when assessed on slice, namely the 13 Hz mPFC and the 1 Hz vHipp protocol, were also most efficient at restoring baseline mEPSC amplitudes when applied in vivo. This suggests that cocaine-evoked plasticity at vHipp inputs largely accounts for the observed increase in mEPSC amplitudes. f, Mean mEPSC amplitudes were increased by cocaine self-administration (versus saline control, by t-test, t18 = 7.13, *P < 0.001). Protocols applied at vHipp terminals altered mEPSC amplitudes (one-way ANOVA comparing cocaine control, 1 and 13 Hz vHipp protocols: effect of protocol F2,28 = 5.7, P < 0.01). The 1 Hz but not the 13 Hz vHipp protocol reduced mEPSC amplitudes (versus cocaine control, for 1 Hz: t18 = 2.8, oP = 0.01), although amplitudes remained significantly higher than saline control mice after either protocol (all P < 0.01). Protocols applied at mPFC terminals also altered mEPSC amplitudes (effect of protocol, F2,29 = 13.1, P < 0.001), and the 13 Hz but not 1 Hz mPFC protocol reduced mEPSC amplitudes (versus cocaine control, for 1 Hz: t19 = 4.7, oP < 0.001). Moreover, amplitudes after the 13 Hz mPFC protocol did not differ from saline controls (P = 0.14). The frequencies of mEPSCs were not altered by cocaine or by protocols applied at either vHipp or mPFC inputs (n = 8–11 cells per group). All error bars, s.e.m.

Extended Data Figure 8 Optogenetic effect on cocaine seeking is persistent, and does not alter learning of a new response for food reward or food cue-associated seeking.

a, Schematic of experiment. Cocaine control and 13 Hz mPFC group mice were exposed to a second cocaine cue-associated seeking test 1 week after the first test (see Fig. 5), but without further optogenetic intervention. Two days after this second test, subgroups of mice from each condition were trained to nose-poke for sucrose pellets during once-daily 30 min sessions over 9 days. b, Raster plots of cue-associated seeking behaviour (active and inactive lever presses) during the second test are shown (left), together with group mean data showing active (a: filled boxes) and inactive (i: open boxes) lever presses. Seeking was present in cocaine control mice during the second test, but was absent in the 13 Hz mPFC group (effect of group, group and lever group, all P < 0.05; active versus inactive lever comparison by t-test, t43 = 6.13, #P < 0.001 for controls n = 44 and t9 = 0.97, P = 0.35 for 13 Hz mPFC, n = 10; active versus active lever comparison, o P < 0.01). c, For the acquisition of a new response test, group mean values are shown of active and inactive nose-pokes across training days. Responding was maintained by FR1, FR2 and FR3 schedules. ANOVA comparisons of nose-poke responding across 3 days at each fixed ratio schdule confirmed no difference between cocaine self-administration control (n = 15) and 13 Hz mPFC (n = 4) mice (effects of group and day × group × nose poke interactions, all not significant). d, Schematic of experiment. One month after food self-administration training, mice received the 13 Hz mPFC light protocol, 4 h before a 30 min test of seeking. e, Graph shows mean of active (a) and inactive (i) lever presses for sucrose pellets by new cohort of mice (n = 14) infected or not with ChR2 in the mPFC. Training parameters were identical to those used for the acquisition of cocaine self-administration, except that sessions lasted only 30 min. f, Raster plots of active and inactive lever presses during a cue-associated sucrose seeking session (left), together with group mean data of total active (a) and inactive (i) lever presses during the 30 min seeking test. Food seeking was robust in control mice and did not differ in the 13 Hz mPFC group (effect of lever, F1,12 = 163.7, P < 0.002; group and lever × group all non-significant; n = 6/8). Error bars, s.e.m.

Extended Data Figure 9 Position of fibre optic cannula placements for mice used in tests of cue-seeking.

Figure shows identified fibre optic cannula tip placements in controls (left) or mice that received different light protocols targeting either vHipp or mPFC to NAc synapses (right). Note that when mice were used for electrophysiology recordings, fibre optic placements were visually confirmed but not recorded.

Extended Data Table 1 ANOVA comparisons for (a) Figs 1–4 and (b) Fig. 5
Full size table

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pascoli, V., Terrier, J., Espallergues, J. et al. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509, 459–464 (2014). https://doi.org/10.1038/nature13257

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature13257

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing