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.

  • Review Article
  • Published:

The glutamate homeostasis hypothesis of addiction

Key Points

  • Addiction is associated with neuroplasticity in corticostriatal brain circuitry, notably in projections from the prefrontal cortex to the nucleus accumbens.

  • Repeated drug use impairs the capacity of prefrontal input to the nucleus accumbens to regulate well-established drug-seeking habits originating in motor corticostriatal circuitry.

  • One mechanism through which chronic drug use leads to the impaired regulation of drug seeking (relapse) is an enduring imbalance in how non-synaptic glial glutamate regulates synaptic glutamate transmission at prefrontal-to-accumbens synapses (that is, a loss of glutamate homeostasis).

  • Glutamate homeostasis refers to the homeostatic regulation of non-synaptic — primarily glial — extracellular glutamate by cystine–glutamate exchange and glutamate uptake, and the impact of this glutamate on pre- and postsynaptic metabotropic glutamate receptors in terms of regulating synaptic efficiency and plasticity.

  • The imbalance in glutamate homeostasis after chronic drug treatment arises in part from the down–regulation of both cystine–glutamate exchange and glial glutamate uptake.

  • The imbalance in glutamate homeostasis contributes to enduring drug-induced changes in the capacity to generate classic forms of synaptic plasticity, as well as changes in dendritic spine morphology in the nucleus accumbens.

  • Restoration of glutamate homeostasis by stimulating cystine–glutamate exchange with N-acetylcysteine restores the capacity to induce synaptic plasticity and reverses the drug-induced changes in spine morphology.

  • N-acetylcysteine also inhibits drug seeking in the reinstatement model of relapse, and the desire for cocaine and nicotine in addicts.

Abstract

Addiction is associated with neuroplasticity in the corticostriatal brain circuitry that is important for guiding adaptive behaviour. The hierarchy of corticostriatal information processing that normally permits the prefrontal cortex to regulate reinforcement-seeking behaviours is impaired by chronic drug use. A failure of the prefrontal cortex to control drug-seeking behaviours can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Corticostriatal circuits in addiction.
Figure 2: Neuroadaptations produced by the effects of chronic cocaine administration on protein content and function in excitatory synapses in the nucleus accumbens.
Figure 3: Changes in spine morphology and postsynaptic proteins produced by chronic cocaine and subsequent acute cocaine administration.

Similar content being viewed by others

References

  1. Berridge, K. & Robinson, T. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Rev. 28, 309–369 (1998).

    CAS  PubMed  Google Scholar 

  2. Kelley, A. E. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44, 161–179 (2004).

    CAS  PubMed  Google Scholar 

  3. Cardinal, R. N. & Everitt, B. J. Neural and psychological mechanisms underlying appetitive learning: links to drug addiction. Curr. Opin. Neurobiol. 14, 156–162 (2004).

    CAS  PubMed  Google Scholar 

  4. Di Chiara, G. Drug addiction as dopamine-dependent associative learning disorder. Eur. J. Pharmacol. 375, 13–30 (1999).

    CAS  PubMed  Google Scholar 

  5. Wise, R. A. Dopamine, learning and motivation. Nature Rev. Neurosci. 5, 483–494 (2004).

    CAS  Google Scholar 

  6. Barnes, T. D., Kubota, Y., Hu, D., Jin, D. Z. & Graybiel, A. M. Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories. Nature 437, 1158–1161 (2005).

    CAS  PubMed  Google Scholar 

  7. Yin, H. H. & Knowlton, B. J. The role of the basal ganglia in habit formation. Nature Rev. Neurosci. 7, 464–476 (2006). An outstanding review that integrates the neuroanatomy of the corticostriatal pathways with behaviour, especially in terms of the roles played by the prefrontal cortical projections in action–outcome contingencies and motor cortex projections in stimulus–response habits.

    CAS  Google Scholar 

  8. 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). A concise description of the underlying perspective in the field of addiction that drug seeking is progressively more habitual and guided by the motor subcircuit.

    CAS  PubMed  Google Scholar 

  9. Robbins, T. W. & Everitt, B. J. Limbic-striatal memory systems and drug addiction. Neurobiol. Learn. Mem. 78, 625–636 (2002).

    CAS  PubMed  Google Scholar 

  10. Everitt, B. J. et al. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 3125–3135 (2008).

    PubMed  PubMed Central  Google Scholar 

  11. Belin, D. & Everitt, B. J. Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57, 432–441 (2008).

    CAS  PubMed  Google Scholar 

  12. Haber, S. N. The primate basal ganglia: parallel and integrative networks. J. Chem. Neuroanat. 26, 317–330 (2003).

    PubMed  Google Scholar 

  13. Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381 (1986).

    CAS  PubMed  Google Scholar 

  14. Groenewegen, H. J., Wright, C. I. & Beijer, V. J. The nucleus accumbens: gateway for limbic structures to reach the motor system? Prog. Brain Res. 107, 485–551 (1996).

    CAS  PubMed  Google Scholar 

  15. Doya, K. Modulators of decision making. Nature Neurosci. 11, 410–416 (2008).

    CAS  PubMed  Google Scholar 

  16. Shaham, Y., Shalev, U., Lu, L., De Wit, H. & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl.) 168, 3–20 (2003).

    CAS  Google Scholar 

  17. Di Ciano, P., Robbins, T. W. & Everitt, B. J. Differential effects of nucleus accumbens core, shell, or dorsal striatal inactivations on the persistence, reacquisition, or reinstatement of responding for a drug-paired conditioned reinforcer. Neuropsychopharmacology 33, 1413–1425 (2008).

    CAS  PubMed  Google Scholar 

  18. Fuchs, R. A., Branham, R. K. & See, R. E. Different neural substrates mediate cocaine seeking after abstinence versus extinction training: a critical role for the dorsolateral caudate-putamen. J. Neurosci. 26, 3584–3588 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kantak, K. M., Black, Y., Valencia, E., Green-Jordan, K. & Eichenbaum, H. B. Stimulus-response functions of the lateral dorsal striatum and regulation of behavior studied in a cocaine maintenance/cue reinstatement model in rats. Psychopharmacology (Berl.) 161, 278–287 (2002).

    CAS  Google Scholar 

  20. Vanderschuren, L. J., Di Ciano, P. & Everitt, B. J. Involvement of the dorsal striatum in cue-controlled cocaine seeking. J. Neurosci. 25, 8665–8670 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Capriles, N., Rodaros, D., Sorge, R. E. & Stewart, J. A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl.) 168, 66–74 (2003).

    CAS  Google Scholar 

  22. Fuchs, R. A., Eaddy, J. L., Su, Z. I. & Bell, G. H. Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context-induced reinstatement of cocaine-seeking in rats. Eur. J. Neurosci. 26, 487–498 (2007).

    PubMed  Google Scholar 

  23. McFarland, K., Davidge, S. B., Lapish, C. C. & Kalivas, P. W. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J. Neurosci. 24, 1551–1560 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. McFarland, K. & Kalivas, P. W. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 21, 8655–8663 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. McLaughlin, J. & See, R. E. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl.) 168, 57–65 (2003).

    CAS  Google Scholar 

  26. Park, W. K. et al. Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J. Neurosci. 22, 2916–2925 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Peters, J., LaLumiere, R. T. & Kalivas, P. W. Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J. Neurosci. 28, 6046–6053 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. Porrino, L. J., Lyons, D., Smith, H. R., Daunais, J. B. & Nader, M. A. Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. J. Neurosci. 24, 3554–3562 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ito, R., Dalley, J. W., Howes, S. R., Robbins, T. W. & Everitt, B. J. Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J. Neurosci. 20, 7489–7495 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ito, R., Dalley, J. W., Robbins, T. W. & Everitt, B. J. Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue. J. Neurosci. 22, 6247–6253 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Pelloux, Y., Everitt, B. J. & Dickinson, A. Compulsive drug seeking by rats under punishment: effects of drug taking history. Psychopharmacology (Berl.) 194, 127–137 (2007).

    CAS  Google Scholar 

  33. Vanderschuren, L. J. & Everitt, B. J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004).

    CAS  PubMed  Google Scholar 

  34. Herman, M. & Jahr, C. E. Extracellular glutamate concentration in hippocampal slice. J. Neurosci. 27, 9736–9741 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Diamond, J. S. & Jahr., C. E. Transporters buffer synaptically released glutamate on a submillisecond time scale. J. Neurosci. 17, 4672–4687 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Barbour, B. An evaluation of synapse independence. J. Neurosci. 21, 7969–7984 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Timmerman, W. & Westerink, B. H. Brain microdialysis of GABA and glutamate: what does it signify? Synapse 27, 242–261 (1997).

    CAS  PubMed  Google Scholar 

  38. Warr, O., Takahashi, M. & Attwell, D. Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange. J. Physiol. 514, 783–793 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Haydon, P. Glia: listening and talking to the synapse. Nature Neurosci. 2, 185–191 (2001).

    CAS  Google Scholar 

  40. Baker, D. A., Xi, Z. X., Shen, H., Swanson, C. J. & Kalivas, P. W. The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 22, 9134–9141 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. McBean, G. J. Cerebral cystine uptake: a tale of two transporters. Trends Pharmacol. Sci. 23, 299–302 (2002).

    CAS  PubMed  Google Scholar 

  42. Pendyam, S., Mohan, A., Kalivas, P. W. & Nair, S. S. Computational model of extracellular glutamate in the nucleus accumbens incorporates neuroadaptations by chronic cocaine. Neuroscience 158, 1266–1276 (2009).

    CAS  PubMed  Google Scholar 

  43. Knackstedt, L., LaRowe, S. D., Malcolm, R., Markou, A. & Kalivas, P. Nicotine self-administration reduces the cystine-glutamate exchanger, and exchanger activation decreases cigarette smoking. Biol. Psychiatry 65, 841–845 (2009).

    CAS  PubMed  Google Scholar 

  44. Knackstedt, L., Melendez, R. & Kalivas, P. W. Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol. Psychiatry. (in the press).

  45. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  47. Szumlinski, K. K. et al. Homer isoforms differentially regulate cocaine-induced neuroplasticity. Neuropsychopharmacology 31, 768–777 (2006).

    CAS  PubMed  Google Scholar 

  48. Xi, Z. X. et al. Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine. J. Pharmacol. Exp. Ther. 303, 608–615 (2002).

    CAS  PubMed  Google Scholar 

  49. Xi, Z. X. et al. Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J. Neurosci. 26, 8531–8536 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Madayag, A. et al. Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J. Neurosci. 27, 13968–13976 (2007). This excellent paper provides definitive evidence that the capacity of N -acetylcysteine to regulate drug-seeking behaviour results from actions on the cystine–glutamate exchanger and is associated with preventing the large release of glutamate in the accumbens during drug seeking.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Miguens, M. et al. Glutamate and aspartate levels in the nucleus accumbens during cocaine self-administration and extinction: a time course microdialysis study. Psychopharmacology (Berl.) 196, 303–313 (2008).

    CAS  Google Scholar 

  53. Danbolt, N. C. Glutamate uptake. Prog. Neurobiol. 65, 1–105 (2001).

    CAS  PubMed  Google Scholar 

  54. Schoepp, D. D. & True, R. A. 1S,3R-ACPD-sensitive (metabotropic) [3H]glutamate receptor binding in membranes. Neurosci. Lett. 145, 100–104 (1992).

    CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Alagarsamy, S., Sorensen, S. D. & Conn, P. J. Coordinate regulation of metabotropic glutamate receptors. Curr. Opin. Neurobiol. 11, 357–362 (2001).

    CAS  PubMed  Google Scholar 

  57. Mitrano, D. A., Arnold, C. & Smith, Y. Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the nucleus accumbens of cocaine-treated rats. Neuroscience 154, 653–666 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 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 (2007).

    PubMed  PubMed Central  Google Scholar 

  60. Moussawi, K. et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nature Neurosci. 12, 182–189 (2009).

    CAS  PubMed  Google Scholar 

  61. 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).

    CAS  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 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).

    CAS  PubMed  Google Scholar 

  64. Rothstein, J. D. et al. β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).

    CAS  PubMed  Google Scholar 

  65. Murphy, T. H., Miyamoto, M., Sastre, A., Schnaar, R. L. & Coyle, J. T. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2, 1547–1558 (1989).

    CAS  PubMed  Google Scholar 

  66. Bannai, S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J. Biol. Chem. 261, 2256–2263 (1986).

    CAS  PubMed  Google Scholar 

  67. Robinson, T. E. & Kolb, B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J. Neurosci. 17, 8491–8497 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Lee, K. W. et al. Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens. Proc. Natl Acad. Sci. USA 103, 3399–3404 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  70. Jedynak, J. P., Uslaner, J. M., Esteban, J. A. & Robinson, T. E. Methamphetamine-induced structural plasticity in the dorsal striatum. Eur. J. Neurosci. 25, 847–853 (2007).

    PubMed  Google Scholar 

  71. Shen, H. W. et al. Altered dendritic spine plasticity in cocaine-withdrawn rats. J. Neurosci. 29, 2876–2884 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006).

    CAS  PubMed  Google Scholar 

  73. Nestler, E. J. Is there a common molecular pathway for addiction? Nature Neurosci. 8, 1445–1449 (2005).

    CAS  PubMed  Google Scholar 

  74. Churchill, L., Swanson, C. J., Urbina, M. & Kalivas, P. W. Repeated cocaine alters glutamate receptor subunit levels in the nucleus accumbens and ventral tegmental area of rats that develop behavioral sensitization. J. Neurochem. 72, 2397–2403 (1999).

    CAS  PubMed  Google Scholar 

  75. Boudreau, A. C. & Wolf, M. E. Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens. J. Neurosci. 25, 9144–9151 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Conrad, K. L. et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454, 118–121 (2008). This paper clarifies the potential role of synaptic grading after chronic cocaine administration resulting in upregulated AMPA receptor signalling in the nucleus accumbens.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Anderson, S. M. et al. CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nature Neurosci. 11, 344–353 (2008). This paper demonstrates the rapid recruitment of AMPA receptors to the surface during cocaine seeking, and clarifies the manner in which D1 receptor signalling produces this effect.

    CAS  PubMed  Google Scholar 

  78. Backstrom, P. & Hyytia, P. Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl.) (2007).

  79. Cornish, J. & 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 

  80. Di Ciano, P. & Everitt, B. J. Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology 25, 341–360 (2001).

    CAS  PubMed  Google Scholar 

  81. Suto, N. et al. Previous exposure to psychostimulants enhances the reinstatement of cocaine seeking by nucleus accumbens AMPA. Neuropsychopharmacology 29, 2149–2159 (2004).

    CAS  PubMed  Google Scholar 

  82. Boudreau, A. C., Reimers, J. M., Milovanovic, M. & Wolf, M. E. Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases. J. Neurosci. 27, 10621–10635 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Liechti, M. E., Lhuillier, L., Kaupmann, K. & Markou, A. Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence. J. Neurosci. 27, 9077–9085 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bowers, M. S. et al. Activator of G-protein signaling 3: a gatekeeper of cocaine sensitization and drug-seeking. Neuron 42, 269–281 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Ghasemzadeh, M. B., Mueller, C. & Vasudevan, P. Behavioral sensitization to cocaine is associated with increased glutamate receptor trafficking to the postsynaptic density after extended withdrawal period. Neuroscience 159, 414–426 (2009).

    CAS  PubMed  Google Scholar 

  86. Takesono, A. et al. Receptor-independent activators of heterotrimeric G-protein signaling pathways. J. Biol. Chem. 274, 33202–33205 (1999).

    CAS  PubMed  Google Scholar 

  87. Yao, L. et al. Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proc. Natl Acad. Sci. USA 102, 8746–8751 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bowers, M. S. et al. Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ. Proc. Natl Acad. Sci. USA 105, 12533–12538 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Swanson, C., Baker, D., Carson, D., Worley, P. & Kalivas, P. W. Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: a potential role for Homer 1b/c. J. Neurosci. 21, 9043–9052 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Ary, A. W. & Szumlinski, K. K. Regional differences in the effects of withdrawal from repeated cocaine upon Homer and glutamate receptor expression: a two-species comparison. Brain Res. 1184, 295–305 (2007).

    CAS  PubMed  Google Scholar 

  91. Ghasemzadeh, M. B., Vasudevan, P., Mueller, C., Seubert, C. & Mantsch, J. R. Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration. Neurosci. Lett. 452, 167–171 (2009).

    CAS  PubMed  Google Scholar 

  92. Szumlinski, K. K. et al. Homer proteins regulate sensitivity to cocaine. Neuron 43, 401–413 (2004).

    CAS  PubMed  Google Scholar 

  93. Palmatier, M. I., Liu, X., Donny, E. C., Caggiula, A. R. & Sved, A. F. Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine. Neuropsychopharmacology 33, 2139–2147 (2008).

    CAS  PubMed  Google Scholar 

  94. Olive, M. F. et al. The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase Cε-dependent mechanism. Mol. Pharmacol. 67, 349–355 (2005).

    CAS  PubMed  Google Scholar 

  95. Tessari, M., Pilla, M., Andreoli, M., Hutcheson, D. M. & Heidbreder, C. A. Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur. J. Pharmacol. 499, 121–133 (2004).

    CAS  PubMed  Google Scholar 

  96. Ghasemzadeh, M. B., Permenter, L. K., Lake, R., Worley, P. F. & Kalivas, P. W. Homer1 proteins and AMPA receptors modulate cocaine-induced behavioural plasticity. Eur. J. Neurosci. 18, 1645–1651 (2003).

    PubMed  Google Scholar 

  97. Lee, B., Platt, D. M., Rowlett, J. K., Adewale, A. S. & Spealman, R. D. Attenuation of behavioral effects of cocaine by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine. J. Pharmacol. Exp. Ther. 312, 1232–1240 (2005).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  100. Paterson, N. E., Semenova, S., Gasparini, F. & Markou, A. The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology (Berl.) 167, 257–264 (2003).

    CAS  Google Scholar 

  101. Cingolani, L. & Goda, Y. Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nature Rev. Neurosci. 9, 344–356 (2008).

    CAS  Google Scholar 

  102. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Carpenter-Hyland, E. P. & Chandler, L. J. Homeostatic plasticity during alcohol exposure promotes enlargement of dendritic spines. Eur. J. Neurosci. 24, 3496–3506 (2006).

    PubMed  Google Scholar 

  104. Wheeler, R. A. & Carelli, R. M. Dissecting motivational circuitry to understand substance abuse. Neuropharmacology 56 (Suppl. 1), 149–159 (2008).

    PubMed  PubMed Central  Google Scholar 

  105. Kalivas, P. W. & Hu, X. T. Exciting inhibition in psychostimulant addiction. Trends Neurosci. 29, 610–616 (2006).

    CAS  PubMed  Google Scholar 

  106. Thomas, M. J., Kalivas, P. W. & Shaham, Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br. J. Pharmacol. 154, 327–342 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  110. Abraham, W. C. & Bear, M. F. Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 19, 126–130 (1996).

    CAS  PubMed  Google Scholar 

  111. 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 

  112. 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. Nature Neurosci. 9, 868–869 (2006). This paper describes the loss of capacity to induce LTD in accumbens slices after cocaine self-administration, and raises the possibility that cocaine-induced changes might dissociate synaptic grading from synaptic plasticity.

    CAS  PubMed  Google Scholar 

  113. 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).

    CAS  PubMed  Google Scholar 

  114. 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).

    CAS  PubMed  Google Scholar 

  115. 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 

  116. Yao, W. D. et al. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 41, 625–638 (2004).

    CAS  PubMed  Google Scholar 

  117. Li, Y. & Kauer, J. A. Repeated exposure to amphetamine disrupts dopaminergic modulation of excitatory synaptic plasticity and neurotransmission in nucleus accumbens. Synapse 51, 1–10 (2004).

    CAS  PubMed  Google Scholar 

  118. Lodge, D. J. & Grace, A. A. Amphetamine activation of hippocampal drive of mesolimbic dopamine neurons: a mechanism of behavioral sensitization. J. Neurosci. 28, 7876–7882 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Nelson, C. L., Milovanovic, M., Wetter, J. B., Ford, K. A. & Wolf, M. E. Behavioral sensitization to amphetamine is not accompanied by changes in glutamate receptor surface expression in the rat nucleus accumbens. J. Neurochem. 109, 35–51 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Lu, L. et al. Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nature Neurosci. 8, 212–219 (2005).

    CAS  PubMed  Google Scholar 

  121. Koob, G. & Kreek, M. J. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am. J. Psychiatry 164, 1149–1159 (2007).

    PubMed  PubMed Central  Google Scholar 

  122. Neisewander, J. L. et al. Fos protein expression and cocaine seeking behavior in rats after exposure to a cocaine self-administration environment. J. Neurosci. 20, 798–805 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Zavala, A. R., Biswas, S., Harlan, R. E. & Neisewander, J. L. Fos and glutamate AMPA receptor subunit coexpression associated with cue-elicited cocaine-seeking behavior in abstinent rats. Neuroscience 145, 438–452 (2007).

    CAS  PubMed  Google Scholar 

  124. Miller, C. A. & Marshall, J. F. Altered prelimbic cortex output during cue-elicited drug seeking. J. Neurosci. 24, 6889–6897 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Hearing, M. C., Miller, S. W., See, R. E. & McGinty, J. F. Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology (Berl.) 198, 77–91 (2008).

    CAS  Google Scholar 

  126. Goldstein, R. A. & 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).

    PubMed  PubMed Central  Google Scholar 

  127. Volkow, N. D. et al. Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction. J. Neurosci. 25, 3932–3939 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. George, M. S. et al. Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues. Arch. Gen. Psychiatry 58, 345–352 (2001).

    CAS  PubMed  Google Scholar 

  129. Franklin, T. R. et al. Limbic activation to cigarette smoking cues independent of nicotine withdrawal: a perfusion fMRI study. Neuropsychopharmacology 32, 2301–2309 (2007).

    CAS  PubMed  Google Scholar 

  130. Rogers, J. L., Ghee, S. & See, R. E. The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151, 579–588 (2008).

    CAS  PubMed  Google Scholar 

  131. Anderson, S. M., Schmidt, H. D. & Pierce, R. C. Administration of the D2 dopamine receptor antagonist sulpiride into the shell, but not the core, of the nucleus accumbens attenuates cocaine priming-induced reinstatement of drug seeking. Neuropsychopharmacology 31, 1452–1461 (2006).

    CAS  PubMed  Google Scholar 

  132. Di Ciano, P. & Everitt, B. J. Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats. J. Neurosci. 24, 7167–7173 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Sun, W. & Rebec, G. V. Repeated cocaine self-administration alters processing of cocaine-related information in rat prefrontal cortex. J. Neurosci. 26, 8004–8008 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Thomas, M. J., Beurrier, C., Bonci, A. & Malenka, R. C. Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nature Neurosci. 4, 1217–1223 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  136. Vocci, F. & Ling, W. Medications development: successes and challenges. Pharmacol. Ther. 108, 94–108 (2005).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  138. Yin, H. H. et al. Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill. Nature Neurosci. 12, 333–341 (2009).

    CAS  PubMed  Google Scholar 

  139. Balleine, B. W., Liljeholm, M. & Ostlund, S. B. The integrative function of the basal ganglia in instrumental conditioning. Behav. Brain Res. 199, 43–52 (2009).

    PubMed  Google Scholar 

  140. Yin, H. H., Ostlund, S. B. & Balleine, B. W. Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks. Eur. J. Neurosci. 28, 1437–1448 (2008).

    Google Scholar 

  141. Robinson, T. E. & Berridge, K. C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Rev. 18, 247–291 (1993).

    CAS  PubMed  Google Scholar 

  142. Tzschentke, T. M. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict. Biol. 12, 227–462 (2007).

    CAS  PubMed  Google Scholar 

  143. Epstein, D. H., Preston, K. L., Stewart, J. & Shaham, Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl.) 189, 1–16 (2006).

    CAS  Google Scholar 

  144. Everitt, B. J. & Robbins, T. W. Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology (Berl.) 153, 17–30 (2000).

    CAS  Google Scholar 

  145. Flanagan, R. J. & Meredith, T. J. Use of N-acetylcysteine in clinical toxicology. Am. J. Med. 91, 131S–139S (1991).

    CAS  PubMed  Google Scholar 

  146. Ono, S. Regulation of actin filament dynamics by actin depolymerizing factor/cofilin and actin-interacting protein 1: new blades for twisted filaments. Biochemistry 42, 13363–13370 (2003).

    CAS  PubMed  Google Scholar 

  147. May, R. C. The Arp2/3 complex: a central regulator of the actin cytoskeleton. Cell. Mol. Life Sci. 58, 1607–1626 (2001).

    CAS  PubMed  Google Scholar 

  148. Krause, M., Dent, E. W., Bear, J. E., Loureiro, J. J. & Gertler, F. B. Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration. Annu. Rev. Cell Dev. Biol. 19, 541–564 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I thank the members of my laboratory who made helpful editorial comments, including P. Hurt, R. LaLumiere, L. Knackstedt, K. Moussawi, A. Rocha, H. Shen, J. Uys and A. Wiggins. Much of the research incorporated into this Review was supported by NIDA (DA 015,369, DA 015,851, DA 012,513 and DA 003,906).

Author information

Authors and Affiliations

Authors

Related links

Related links

FURTHER INFORMATION

Peter W. Kalivas's homepage

Glossary

Operant task

A behavioural act with a consequence. In the context of addiction, this is most often a lever press to deliver an addictive drug.

Ceftriaxone

A cephalosporin antibiotic in the β-lactam family that is used to treat pneumonia and bacterial meningitis. It was recently shown to also promote the synthesis and expression of the glial glutamate transporter.

Prime-induced reinstatement of drug seeking behaviour

Stimulating the reinstatement of lever pressing by an external stimulus. Examples of such a stimulus include presentation of a cue previously paired with the delivery of an addictive drug, presentation of an acute stressor, or acute administration of the addictive drug.

Synaptic grading

The capacity of synapses to potentiate and depotentiate the efficiency of communication between the pre- and postsynaptic components. It includes enduring plasticity in synaptic efficiency, such as long-term potentiation and long-term depression.

Tetanic stimulation

A train of stimuli in which afferent axons are briefly activated at high frequency. In LTP experiments, a 1 s train of pulses delivered at a frequency of 100 Hz is commonly used to potentiate transmission.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kalivas, P. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10, 561–572 (2009). https://doi.org/10.1038/nrn2515

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2515

This article is cited by

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