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N-Acetylcysteine reverses cocaine-induced metaplasticity

Nature Neuroscience volume 12, pages 182–189 (2009)Cite this article

Abstract

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

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Figure 1: Characterization of nucleus accumbens field potentials evoked from the prefrontal cortex.
Figure 2: Field potentials in the NAcore reveal potentiation of the input-output curve in rats trained to self-administer cocaine.
Figure 3: LTP is impaired in rats trained to self-administer cocaine.
Figure 4: LTD is impaired after chronic cocaine but can be rescued using stronger LTD protocols.
Figure 5: NAC restores the capacity to induce both LTP and LTD.
Figure 6: Metabotropic glutamate receptors mediate NAC restoration of plasticity.
Figure 7: Regulation of drug-seeking by the mGluR5 antagonist MPEP and positive allosteric modulator CDPPB.

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References

  1. Mendelson, J.H. & Mello, N.K. Management of cocaine abuse and dependence. N. Engl. J. Med. 334, 965–972 (1996).

    Article  CAS  Google Scholar 

  2. Kalivas, P.W. & O'Brien, C. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33, 166–180 (2008).

    Article  CAS  Google Scholar 

  3. Robinson, T.E. & Kolb, B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47 Suppl 1: 33–46 (2004).

    Article  CAS  Google Scholar 

  4. Toda, S., Shen, H.W., Peters, J., Cagle, S. & Kalivas, P.W. Cocaine increases actin cycling: effects in the reinstatement model of drug seeking. J. Neurosci. 26, 1579–1587 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Martin, M., Chen, B.T., Hopf, F.W., Bowers, M.S. & Bonci, A. Cocaine self-administration selectively abolishes LTD in the core of the nucleus accumbens. Nat. Neurosci. 9, 868–869 (2006).

    Article  CAS  Google Scholar 

  7. Abraham, W.C. Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9, 387–399 (2008).

    Article  CAS  Google Scholar 

  8. Brebner, K. et al. Nucleus accumbens long-term depression and the expression of behavioral sensitization. Science 310, 1340–1343 (2005).

    Article  CAS  Google Scholar 

  9. Kauer, J.A. & Malenka, R.C. Synaptic plasticity and addiction. Nat. Rev. Neurosci. 8, 844–858 (2007).

    Article  CAS  Google Scholar 

  10. Bamford, N.S. et al. Repeated exposure to methamphetamine causes long-lasting presynaptic corticostriatal depression that is renormalized with drug readministration. Neuron 58, 89–103 (2008).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. Madayag, A. et al. Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J. Neurosci. 27, 13968–13976 (2007).

    Article  CAS  Google Scholar 

  13. Zhou, W. & Kalivas, P.W. N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol. Psychiatry 63, 338–340 (2008).

    Article  CAS  Google Scholar 

  14. Moran, M.M., McFarland, K., Melendez, R.I., Kalivas, P.W. & Seamans, J.K. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J. Neurosci. 25, 6389–6393 (2005).

    Article  CAS  Google Scholar 

  15. Baker, D.A. et al. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat. Neurosci. 6, 743–749 (2003).

    Article  CAS  Google Scholar 

  16. LaRowe, S.D. et al. Is cocaine desire reduced by N-acetylcysteine? Am. J. Psychiatry 164, 1115–1117 (2007).

    Article  Google Scholar 

  17. Goldstein, R.Z. & Volkow, N.D. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am. J. Psychiatry 159, 1642–1652 (2002).

    Article  Google Scholar 

  18. van Dongen, Y.C., Mailly, P., Thierry, A.M., Groenewegen, H.J. & Deniau, J.M. Three-dimensional organization of dendrites and local axon collaterals of shell and core medium-sized spiny projection neurons of the rat nucleus accumbens. Brain Struct. Funct. 213, 129–147 (2008).

    Article  Google Scholar 

  19. Sesack, S.R., Deutch, A.Y., Roth, R.H. & Bunney, B.S. Topographical organization of the efferent projections of the medial prefrontal cortex in rat: An anterograde tract-tracing study with Phaseolus vulgais leucoagglutinin. J. Comp. Neurol. 290, 213–242 (1989).

    Article  CAS  Google Scholar 

  20. Nicola, S.M., Kombian, S.B. & Malenka, R.C. Psychostimulants depress excitatory synaptic transmission in the nucleus accumbens via presynaptic D1-like dopamine receptors. J. Neurosci. 16, 1591–1604 (1996).

    Article  CAS  Google Scholar 

  21. Pennartz, C.M., Boeijinga, P.H. & Lopes da Silva, F.H. Locally evoked potentials in slices of the rat nucleus accumbens: NMDA and non-NMDA receptor–mediated components and modulation by GABA. Brain Res. 529, 30–41 (1990).

    Article  CAS  Google Scholar 

  22. Montaron, M.F., Deniau, J.M., Menetrey, A., Glowinski, J. & Thierry, A.M. Prefrontal cortex inputs of the nucleus accumbens-nigro-thalamic circuit. Neuroscience 71, 371–382 (1996).

    Article  CAS  Google Scholar 

  23. Finch, D.M. Neurophysiology of converging synaptic inputs from the rat prefrontal cortex, amygdala, midline thalamus, and hippocampal formation onto single neurons of the caudate/putamen and nucleus accumbens. Hippocampus 6, 495–512 (1996).

    Article  CAS  Google Scholar 

  24. Pierce, R.C., Bell, K., Duffy, P. & Kalivas, P.W. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J. Neurosci. 16, 1550–1560 (1996).

    Article  CAS  Google Scholar 

  25. Rozas, C. et al. Developmental inhibitory gate controls the relay of activity to the superficial layers of the visual cortex. J. Neurosci. 21, 6791–6801 (2001).

    Article  CAS  Google Scholar 

  26. Pennartz, C.M.A., Ameerun, R.F., Groenewegen, H.J. & Lopes da Silva, F.H. Synaptic plasticity in an in vitro slice preparation of the rat nucleus accumbens. Eur. J. Neurosci. 5, 107–117 (1993).

    Article  CAS  Google Scholar 

  27. Malenka, R.C. & Bear, M.F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Fourgeaud, L. et al. A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens. J. Neurosci. 24, 6939–6945 (2004).

    Article  CAS  Google Scholar 

  30. Kau, K.S. et al. Blunted cystine-glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking. Neuroscience 155, 530–537 (2008).

    Article  CAS  Google Scholar 

  31. Baptista, M.A., Martin-Fardon, R. & Weiss, F. Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer. J. Neurosci. 24, 4723–4727 (2004).

    Article  CAS  Google Scholar 

  32. Peters, J. & Kalivas, P.W. The group II metabotropic glutamate receptor agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats. Psychopharmacology (Berl.) 186, 143–149 (2006).

    Article  CAS  Google Scholar 

  33. Bossert, J.M., Gray, S.M., Lu, L. & Shaham, Y. Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Neuropsychopharmacology 31, 2197–2209 (2006).

    Article  CAS  Google Scholar 

  34. McFarland, K., Lapish, C.C. & Kalivas, P.W. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 23, 3531–3537 (2003).

    Article  CAS  Google Scholar 

  35. Grueter, B.A. & Winder, D.G. Group II and III metabotropic glutamate receptors suppress excitatory synaptic transmission in the dorsolateral bed nucleus of the stria terminalis. Neuropsychopharmacology 30, 1302–1311 (2005).

    Article  CAS  Google Scholar 

  36. Losonczy, A., Somogyi, P. & Nusser, Z. Reduction of excitatory postsynaptic responses by persistently active metabotropic glutamate receptors in the hippocampus. J. Neurophysiol. 89, 1910–1919 (2003).

    Article  CAS  Google Scholar 

  37. Wu, J., Rowan, M.J. & Anwyl, R. An NMDAR-independent LTP mediated by group II metabotropic glutamate receptors and p42/44 MAP kinase in the dentate gyrus in vitro. Neuropharmacology 46, 311–317 (2004).

    Article  CAS  Google Scholar 

  38. Grover, L.M. & Yan, C. Evidence for involvement of group II/III metabotropic glutamate receptors in NMDA receptor–independent long-term potentiation in area CA1 of rat hippocampus. J. Neurophysiol. 82, 2956–2969 (1999).

    Article  CAS  Google Scholar 

  39. Backstrom, P. & Hyytia, P. Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking. Neuropsychopharmacology 31, 778–786 (2006).

    Article  Google Scholar 

  40. McGeehan, A.J. & Olive, M.F. The mGluR5 antagonist MPEP reduces the conditioned rewarding effects of cocaine but not other drugs of abuse. Synapse 47, 240–242 (2003).

    Article  CAS  Google Scholar 

  41. Lindsley, C.W. et al. Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J. Med. Chem. 47, 5825–5828 (2004).

    Article  CAS  Google Scholar 

  42. Yin, H.H., Knowlton, B.J. & Balleine, B.W. Inactivation of dorsolateral striatum enhances sensitivity to changes in the action-outcome contingency in instrumental conditioning. Behav. Brain Res. 166, 189–196 (2006).

    Article  Google Scholar 

  43. Suto, N., Tanabe, L.M., Austin, J.D., Creekmore, E. & Vezina, P. Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor–dependent manner. Neuropsychopharmacology 28, 629–639 (2003).

    Article  CAS  Google Scholar 

  44. LaLumiere, R.T. & Kalivas, P.W. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J. Neurosci. 28, 3170–3177 (2008).

    Article  CAS  Google Scholar 

  45. Mitrano, D.A. & Smith, Y. Comparative analysis of the subcellular and subsynaptic localization of mGluR1a and mGluR5 metabotropic glutamate receptors in the shell and core of the nucleus accumbens in rat and monkey. J. Comp. Neurol. 500, 788–806 (2007).

    Article  CAS  Google Scholar 

  46. Chiamulera, C. et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat. Neurosci. 4, 873–874 (2001).

    Article  CAS  Google Scholar 

  47. De Roo, M., Klauser, P., Garcia, P.M., Poglia, L. & Muller, D. Spine dynamics and synapse remodeling during LTP and memory processes. Prog. Brain Res. 169, 199–207 (2008).

    Article  CAS  Google Scholar 

  48. Lavin, A. et al. Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling. J. Neurosci. 25, 5013–5023 (2005).

    Article  CAS  Google Scholar 

  49. 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).

    Article  CAS  Google Scholar 

  50. West, A.R., Moore, H. & Grace, A.A. Direct examination of local regulation of membrane activity in striatal and prefrontal cortical neurons in vivo using simultaneous intracellular recording and microdialysis. J. Pharmacol. Exp. Ther. 301, 867–877 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank F. Thiels (University of Pittsburgh) for invaluable advice on field recording. This research was supported by US Public Health Service grants DA03906, DA12513, DA015369 and DA024355.

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Authors and Affiliations

  1. Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue BSB410, Charleston, South Carolina, USA

    Khaled Moussawi, Alejandra Pacchioni, Megan Moran, Antonieta Lavin & Peter W Kalivas

  2. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 173 Ashley Avenue BSB410, Charleston, South Carolina, USA

    M Foster Olive & Justin T Gass

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  1. Khaled Moussawi
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Contributions

K.M. was primary in conducting the study. A.P. assisted in conducting the microdialysis experiments. M.M. collected the initial preliminary data indicating that NAC would reverse the cocaine-induced loss of LTP. A.L. provided training and technical advice for the in vivo recordings. M.F.O. and J.T.G. assisted in the behavioral pharmacology experiments. K.M. and P.W.K. developed the experimental design and made the primary contributions in writing the manuscript and preparing the figures.

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Correspondence to Peter W Kalivas.

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Moussawi, K., Pacchioni, A., Moran, M. et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci 12, 182–189 (2009). https://doi.org/10.1038/nn.2250

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