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Intrinsic plasticity: an emerging player in addiction

Abstract

Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability factors that are remote from the synapse). Accumulating evidence now suggests that intrinsic factors such as K+ channels are not only altered by cocaine but may also contribute to the shaping of the addiction phenotype.

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Figure 1: Compartmentalization of synaptic and intrinsic excitability factors within the cell.
Figure 2: Key reward-related neural circuits.
Figure 3: Drug-exposure procedures and animal behavioural models used to approximate human addiction.
Figure 4: Intrinsic-to-synaptic interaction hypotheses.

References

  1. Piazza, P. V. & Deroche-Gamonet, V. A multistep general theory of transition to addiction. Psychopharmacol. (Berl.) 229, 387–413 (2013).

    Article  CAS  Google Scholar 

  2. White, N. M. Addictive drugs as reinforcers: multiple partial actions on memory systems. Addiction 91, 921–949; discussion 951–965 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Siegel, S. Drug anticipation and the treatment of dependence. NIDA Res. Monogr. 84, 1–24 (1988).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Wolf, M. E. The Bermuda Triangle of cocaine-induced neuroadaptations. Trends Neurosci. 33, 391–398 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wolf, M. E. & Tseng, K. Y. Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why? Frontiers Mol. Neurosci. 5, 72 (2012).

    Article  CAS  Google Scholar 

  8. White, F. J. & Kalivas, P. W. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend. 51, 141–153 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Wolf, M. E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog. Neurobiol. 54, 679–720 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Lomazzi, M., Slesinger, P. A. & Luscher, C. Addictive drugs modulate GIRK-channel signaling by regulating RGS proteins. Trends Pharmacol. Sci. 29, 544–549 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Padgett, C. L. et al. Methamphetamine-evoked depression of GABAB receptor signaling in GABA neurons of the VTA. Neuron 73, 978–989 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hearing, M. et al. Repeated cocaine weakens GABAB–Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron 80, 159–170 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hearing, M. C., Zink, A. N. & Wickman, K. Cocaine-induced adaptations in metabotropic inhibitory signaling in the mesocorticolimbic system. Rev. Neurosci. 23, 325–351 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Luscher, C. & Slesinger, P. A. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nature Rev. Neurosci. 11, 301–315 (2010).

    Article  CAS  Google Scholar 

  15. Hille, B. Ionic Channels of Excitable Membranes 3rd edn (Sinauer Associates, 2001).

    Google Scholar 

  16. Roberts, E. GABAergic malfunction in the limbic system resulting from an aboriginal genetic defect in voltage-gated Na+-channel SCN5A is proposed to give rise to susceptibility to schizophrenia. Adv. Pharmacol. 54, 119–145 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Zou, X., Coyle, D., Wong-Lin, K. & Maguire, L. β-amyloid induced changes in A-type K+ current can alter hippocampo–septal network dynamics. J. Computat. Neurosci. 32, 465–477 (2012).

    Article  Google Scholar 

  18. Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Zhao, X. et al. A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nature Neurosci. 16, 1024–1031 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Beck, H. & Yaari, Y. Plasticity of intrinsic neuronal properties in CNS disorders. Nature Rev. Neurosci. 9, 357–369 (2008).

    Article  CAS  Google Scholar 

  21. Dong, Y. et al. CREB modulates excitability of nucleus accumbens neurons. Nature Neurosci. 9, 475–477 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Hu, X. T., Basu, S. & White, F. J. Repeated cocaine administration suppresses HVA–Ca2+ potentials and enhances activity of K+ channels in rat nucleus accumbens neurons. J. Neurophysiol. 92, 1597–1607 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Ishikawa, M. et al. Homeostatic synapse-driven membrane plasticity in nucleus accumbens neurons. J. Neurosci. 29, 5820–5831 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim, J., Park, B. H., Lee, J. H., Park, S. K. & Kim, J. H. Cell type-specific alterations in the nucleus accumbens by repeated exposures to cocaine. Biol. Psychiatry 69, 1026–1034 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Kourrich, S. et al. Dynamic interaction between σ1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell 152, 236–247 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kourrich, S. & Thomas, M. J. Similar neurons, opposite adaptations: psychostimulant experience differentially alters firing properties in accumbens core versus shell. J. Neurosci. 29, 12275–12283 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mu, P. et al. Exposure to cocaine dynamically regulates the intrinsic membrane excitability of nucleus accumbens neurons. J. Neurosci. 30, 3689–3699 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang, X. F., Cooper, D. C. & White, F. J. Repeated cocaine treatment decreases whole-cell calcium current in rat nucleus accumbens neurons. J. Pharmacol. Exp. Ther. 301, 1119–1125 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, X. F., Hu, X. T. & White, F. J. Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. J. Neurosci. 18, 488–498 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Robinson, T. E. & Berridge, K. C. Review. The incentive sensitization theory of addiction: some current issues. Phil. Trans. R. Soc. Lond. B 363, 3137–3146 (2008).

    Article  Google Scholar 

  31. Wise, R. A. & Bozarth, M. A. A psychomotor stimulant theory of addiction. Psychol. Rev. 94, 469–492 (1987).

    Article  CAS  PubMed  Google Scholar 

  32. Roberts, D. C., Koob, G. F., Klonoff, P. & Fibiger, H. C. Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol. Biochem. Behav. 12, 781–787 (1980).

    Article  CAS  PubMed  Google Scholar 

  33. Bossert, J. M., Marchant, N. J., Calu, D. J. & Shaham, Y. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology (Berl.) 229, 453–476 (2013).

    Article  CAS  Google Scholar 

  34. Stewart, J. Pathways to relapse: factors controlling the reinitiation of drug seeking after abstinence. Nebr Symp. Motiv. 50, 197–234 (2004).

    PubMed  Google Scholar 

  35. Stewart, J. Review. Psychological and neural mechanisms of relapse. Phil. Trans. R. Soc. B 363, 3147–3158 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hall, J., Parkinson, J. A., Connor, T. M., Dickinson, A. & Everitt, B. J. Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour. Eur. J. Neurosci. 13, 1984–1992 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Parkinson, J. A., Olmstead, M. C., Burns, L. H., Robbins, T. W. & Everitt, B. J. Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. J. Neurosci. 19, 2401–2411 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Corbit, L. H., Muir, J. L. & Balleine, B. W. The role of the nucleus accumbens in instrumental conditioning: Evidence of a functional dissociation between accumbens core and shell. J. Neurosci. 21, 3251–3260 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Parkinson, J. A., Willoughby, P. J., Robbins, T. W. & Everitt, B. J. Disconnection of the anterior cingulate cortex and nucleus accumbens core impairs Pavlovian approach behavior: further evidence for limbic cortical-ventral striatopallidal systems. Behav. Neurosci. 114, 42–63 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Floresco, S. B., McLaughlin, R. J. & Haluk, D. M. Opposing roles for the nucleus accumbens core and shell in cue-induced reinstatement of food-seeking behavior. Neuroscience 154, 877–884 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Ambroggi, F., Ghazizadeh, A., Nicola, S. M. & Fields, H. L. Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition. J. Neurosci. 31, 6820–6830 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ito, R., Robbins, T. W. & Everitt, B. J. Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nature Neurosci. 7, 389–397 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Fuchs, R. A., Evans, K. A., Parker, M. C. & See, R. E. Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacol. (Berl.) 176, 459–465 (2004).

    Article  CAS  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. Bossert, J. M., Poles, G. C., Wihbey, K. A., Koya, E. & Shaham, Y. Differential effects of blockade of dopamine D1-family receptors in nucleus accumbens core or shell on reinstatement of heroin seeking induced by contextual and discrete cues. J. Neurosci. 27, 12655–12663 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zahm, D. S. & Brog, J. S. On the significance of subterritories in the “accumbens” part of the rat ventral striatum. Neuroscience 50, 751–767 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Ghitza, U. E., Fabbricatore, A. T., Prokopenko, V. F. & West, M. O. Differences between accumbens core and shell neurons exhibiting phasic firing patterns related to drug-seeking behavior during a discriminative-stimulus task. J. Neurophysiol. 92, 1608–1614 (2004).

    Article  PubMed  Google Scholar 

  49. Stratford, T. R., Swanson, C. J. & Kelley, A. Specific changes in food intake elicited by blockade or activation of glutamate receptors in the nucleus accumbens shell. Behav. Brain Res. 93, 43–50 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Krause, M., German, P. W., Taha, S. A. & Fields, H. L. A pause in nucleus accumbens neuron firing is required to initiate and maintain feeding. J. Neurosci. 30, 4746–4756 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zahm, D. S. An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens. Neurosci. Biobehav. Rev. 24, 85–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Witten, I. B. et al. Cholinergic interneurons control local circuit activity and cocaine conditioning. Science 330, 1677–1681 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Khodorov, B. I., Vornovitskii, E. G., Ignat'eva, V. B., Mukumov, M. R. & Kitaigorodskaia, G. M. Mechanism of excitation and contraction uncoupling in frog and guinea pig myocardial fibers during block of slow sodium-calcium channels by compound D-600. Biofizika 21, 1024–1030 (in Russian) (1976).

    CAS  PubMed  Google Scholar 

  54. Weidmann, S. Effects of calcium ions and local anesthetics on electrical properties of Purkinje fibres. J. Physiol. 129, 568–582 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Crumb, W. J. Jr & Clarkson, C. W. Characterization of cocaine-induced block of cardiac sodium channels. Biophys. J. 57, 589–599 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Clarkson, C. W., Xu, Y. Q., Chang, C. & Follmer, C. H. Analysis of the ionic basis for cocaine's biphasic effect on action potential duration in guinea-pig ventricular myocytes. J. Mol. Cell. Cardiol. 28, 667–678 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Kimura, S., Bassett, A. L., Xi, H. & Myerburg, R. J. Early afterdepolarizations and triggered activity induced by cocaine. A possible mechanism of cocaine arrhythmogenesis. Circulation 85, 2227–2235 (1992).

    Article  CAS  PubMed  Google Scholar 

  58. Pettit, H. O., Pan, H. T., Parsons, L. H. & Justice, J. B. Jr. Extracellular concentrations of cocaine and dopamine are enhanced during chronic cocaine administration. J. Neurochem. 55, 798–804 (1990).

    Article  CAS  PubMed  Google Scholar 

  59. Badiani, A., Belin, D., Epstein, D., Calu, D. & Shaham, Y. Opiate versus psychostimulant addiction: the differences do matter. Nature Rev. Neurosci. 12, 685–700 (2011).

    Article  CAS  Google Scholar 

  60. Uslaner, J. et al. Amphetamine and cocaine induce different patterns of c-fos mRNA expression in the striatum and subthalamic nucleus depending on environmental context. Eur. J. Neurosci. 13, 1977–1983 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Di Chiara, G. & Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl Acad. Sci. USA 85, 5274–5278 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kourrich, S., Klug, J. R., Mayford, M. & Thomas, M. J. AMPAR-independent effect of striatal αCaMKII promotes the sensitization of cocaine reward. J. Neurosci. 32, 6578–6586 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sergeant, G. P. et al. Regulation of Kv4.3 currents by Ca2+/calmodulin-dependent protein kinase II. Am. J. Physiol. Cell Physiol. 288, C304–C313 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Varga, A. W. et al. Calcium-calmodulin-dependent kinase II modulates K-4.2 channel expression and upregulates neuronal A-type potassium currents. J. Neurosci. 24, 3643–3654 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yao, W. D. & Wu, C. F. Distinct roles of CaMKII and PKA in regulation of firing patterns and K+ currents in Drosophila neurons. J. Neurophysiol. 85, 1384–1394 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Hayashi, T. & Su, T. P. σ1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131, 596–610 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Hayashi, T. & Su, T. P. σ1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18, 269–284 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Kourrich, S., Su, T. P., Fujimoto, M. & Bonci, A. The σ1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 35, 762–771 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Maurice, T. & Su, T. P. The pharmacology of σ1 receptors. Pharmacol. Ther. 124, 195–206 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hayashi, T. & Su, T. P. Intracellular dynamics of σ1 receptors (σ1 binding sites) in NG108-15 cells. J. Pharmacol. Exp. Ther. 306, 726–733 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Su, T. P., Hayashi, T., Maurice, T., Buch, S. & Ruoho, A. E. The σ1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol. Sci. 31, 557–566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chen, Y., Hajipour, A. R., Sievert, M. K., Arbabian, M. & Ruoho, A. E. Characterization of the cocaine binding site on the σ1 receptor. Biochemistry 46, 3532–3542 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Kahoun, J. R. & Ruoho, A. E. (125I)iodoazidococaine, a photoaffinity label for the haloperidol-sensitive σ receptor. Proc. Natl Acad. Sci. USA 89, 1393–1397 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Paradis, S., Sweeney, S. T. & Davis, G. W. Homeostatic control of presynaptic release is triggered by postsynaptic membrane depolarization. Neuron 30, 737–749 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Benavides, D. R. et al. Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability. J. Neurosci. 27, 12967–12976 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fabbricatore, A. T., Ghitza, U. E., Prokopenko, V. F. & West, M. O. Electrophysiological evidence of mediolateral functional dichotomy in the rat accumbens during cocaine self-administration: tonic firing patterns. Eur. J. Neurosci. 30, 2387–2400 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ghitza, U. E., Prokopenko, V. F., West, M. O. & Fabbricatore, A. T. Higher magnitude accumbal phasic firing changes among core neurons exhibiting tonic firing increases during cocaine self-administration. Neuroscience 137, 1075–1085 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Hollander, J. A. & Carelli, R. M. Abstinence from cocaine self-administration heightens neural encoding of goal-directed behaviors in the accumbens. Neuropsychopharmacology 30, 1464–1474 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Hollander, J. A. & Carelli, R. M. Cocaine-associated stimuli increase cocaine seeking and activate accumbens core neurons after abstinence. J. Neurosci. 27, 3535–3539 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. O'Brien, C. P., Childress, A. R., McLellan, A. T. & Ehrman, R. Classical conditioning in drug-dependent humans. Ann. NY Acad. Sci. 654, 400–415 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Peoples, L. L., Uzwiak, A. J., Guyette, F. X. & West, M. O. Tonic inhibition of single nucleus accumbens neurons in the rat: a predominant but not exclusive firing pattern induced by cocaine self-administration sessions. Neuroscience 86, 13–22 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Peoples, L. L., Uzwiak, A. J., Gee, F. & West, M. O. Tonic firing of rat nucleus accumbens neurons: changes during the first 2 weeks of daily cocaine self-administration sessions. Brain Res. 822, 231–236 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Peoples, L. L. & Cavanaugh, D. Differential changes in signal and background firing of accumbal neurons during cocaine self-administration. J. Neurophysiol. 90, 993–1010 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Peoples, L. L., Kravitz, A. V. & Guillem, K. The role of accumbal hypoactivity in cocaine addiction. ScientificWorldJournal 7, 22–45 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Guillem, K., Ahmed, S. H. & Peoples, L. L. Escalation of cocaine intake and incubation of cocaine seeking are correlated with dissociable neuronal processes in different accumbens subregions. Biol. Psychiatry 76, 31–39 (2013).

    Article  PubMed  CAS  Google Scholar 

  86. Grimm, J. W., Hope, B. T., Wise, R. A. & Shaham, Y. Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412, 141–142 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Otaka, M. et al. Exposure to cocaine regulates inhibitory synaptic transmission in the nucleus accumbens. J. Neurosci. 33, 6753–6758 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Basso, A. M. & Kelley, A. E. Feeding induced by GABAA receptor stimulation within the nucleus accumbens shell: regional mapping and characterization of macronutrient and taste preference. Behav. Neurosci. 113, 324–336 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Maldonado-Irizarry, C. S., Swanson, C. J. & Kelley, A. E. Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus. J. Neurosci. 15, 6779–6788 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Reynolds, S. M. & Berridge, K. C. Fear and feeding in the nucleus accumbens shell: rostrocaudal segregation of GABA-elicited defensive behavior versus eating behavior. J. Neurosci. 21, 3261–3270 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stratford, T. R. & Kelley, A. E. GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior. J. Neurosci. 17, 4434–4440 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Stratford, T. R. & Kelley, A. E. Evidence of a functional relationship between the nucleus accumbens shell and lateral hypothalamus subserving the control of feeding behavior. J. Neurosci. 19, 11040–11048 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kelley, A. E., Baldo, B. A., Pratt, W. E. & Will, M. J. Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. Physiol. Behav. 86, 773–795 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Baldo, B. A. & Kelley, A. E. Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding. Psychopharmacol. (Berl.) 191, 439–459 (2007).

    Article  CAS  Google Scholar 

  95. Harris, G. C., Wimmer, M. & Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Marchant, N. J. et al. A critical role of lateral hypothalamus in context-induced relapse to alcohol seeking after punishment-imposed abstinence. J. Neurosci. 34, 7447–7457 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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  PubMed  PubMed Central  Google Scholar 

  100. Pascoli, V. et al. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509, 459–464 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pascoli, V., Turiault, M. & Luscher, C. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71–75 (2012).

    Article  CAS  Google Scholar 

  103. Suska, A., Lee, B. R., Huang, Y. H., Dong, Y. & Schluter, O. M. Selective presynaptic enhancement of the prefrontal cortex to nucleus accumbens pathway by cocaine. Proc. Natl Acad. Sci. USA 110, 713–718 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Ma, Y. Y. et al. Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83, 1453–1467 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Turrigiano, G. Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb. Perspect. Biol. 4, a005736 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Ibata, K., Sun, Q. & Turrigiano, G. G. Rapid synaptic scaling induced by changes in postsynaptic firing. Neuron 57, 819–826 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Keck, T. et al. Synaptic scaling and homeostatic plasticity in the mouse visual cortex in vivo. Neuron 80, 327–334 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Bachtell, R. K. et al. Role of GluR1 expression in nucleus accumbens neurons in cocaine sensitization and cocaine-seeking behavior. Eur. J. Neurosci. 27, 2229–2240 (2008).

    Article  PubMed  Google Scholar 

  109. Kelz, M. B. et al. Expression of the transcription factor δFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Anderson, S. M. et al. CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nature Neurosci. 11, 344–353 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. 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  PubMed  PubMed Central  Google Scholar 

  112. Bachtell, R. K. & Self, D. W. Renewed cocaine exposure produces transient alterations in nucleus accumbens AMPA receptor-mediated behavior. J. Neurosci. 28, 12808–12814 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ferrario, C. R. et al. The role of glutamate receptor redistribution in locomotor sensitization to cocaine. Neuropsychopharmacology 35, 818–833 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Sutton, M. A. et al. Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature 421, 70–75 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Wang, X. et al. Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization. J. Neurosci. 33, 11012–11022 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  117. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Disterhoft, J. F. & Oh, M. M. Learning, aging and intrinsic neuronal plasticity. Trends Neurosci. 29, 587–599 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Moyer, J. R. Jr, Thompson, L. T. & Disterhoft, J. F. Trace eyeblink conditioning increases CA1 excitability in a transient and learning-specific manner. J. Neurosci. 16, 5536–5546 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Thompson, L. T., Moyer, J. R. Jr & Disterhoft, J. F. Transient changes in excitability of rabbit CA3 neurons with a time course appropriate to support memory consolidation. J. Neurophysiol. 76, 1836–1849 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, W. & Linden, D. J. The other side of the engram: experience-driven changes in neuronal intrinsic excitability. Nature Rev. Neurosci. 4, 885–900 (2003).

    Article  CAS  Google Scholar 

  123. Debanne, D. & Poo, M. M. Spike-timing dependent plasticity beyond synapse – pre- and post-synaptic plasticity of intrinsic neuronal excitability. Frontiers Synapt. Neurosci. 2, 21 (2010).

    Google Scholar 

  124. Haber, S. N., Fudge, J. L. & McFarland, N. R. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J. Neurosci. 20, 2369–2382 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Carlezon, W. A. Jr & Thomas, M. J. Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacology 56 (Suppl. 1), 122–132 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Wikler, A. Dynamics of drug dependence. Implications of a conditioning theory for research and treatment. Arch. General Psychiatry 28, 611–616 (1973).

    Article  CAS  Google Scholar 

  127. Nestler, E. J. Common molecular and cellular substrates of addiction and memory. Neurobiol. Learn. Mem. 78, 637–647 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Gasque, G., Labarca, P., Delgado, R. & Darszon, A. Bridging behavior and physiology: ion-channel perspective on mushroom body-dependent olfactory learning and memory in Drosophila. J. Cell. Physiol. 209, 1046–1053 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Deschaux, O. & Bizot, J. C. Effect of apamin, a selective blocker of Ca2+-activated K+-channel, on habituation and passive avoidance responses in rats. Neurosci. Lett. 227, 57–60 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Deschaux, O. & Bizot, J. C. Apamin produces selective improvements of learning in rats. Neurosci. Lett. 386, 5–8 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Fournier, C., Kourrich, S., Soumireu-Mourat, B. & Mourre, C. Apamin improves reference memory but not procedural memory in rats by blocking small conductance Ca2+-activated K+ channels in an olfactory discrimination task. Behav. Brain Res. 121, 81–93 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Kourrich, S., Mourre, C. & Soumireu-Mourat, B. Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improves associative learning in rats. Behav. Brain Res. 120, 35–46 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Kourrich, S., Manrique, C., Salin, P. & Mourre, C. Transient hippocampal down-regulation of Kv1.1 subunit mRNA during associative learning in rats. Learn. Mem. 12, 511–519 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Kourrich, S., Masmejean, F., Martin-Eauclaire, M. F., Soumireu-Mourat, B. & Mourre, C. Inwardly rectifying Kir3.1 subunit knockdown impairs learning and memory in an olfactory associative task in rat. Brain Res. Mol. Brain Res. 113, 97–106 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Chaudhury, D. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Nusser, Z. Variability in the subcellular distribution of ion channels increases neuronal diversity. Trends Neurosci. 32, 267–274 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Grienberger, C. & Konnerth, A. Imaging calcium in neurons. Neuron 73, 862–885 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Fortin, D. L., Dunn, T. W. & Kramer, R. H. Engineering light-regulated ion channels. Cold Spring Harbor Protoc. 2011, 579–585 (2011).

    Article  Google Scholar 

  140. Fortin, D. L. et al. Optogenetic photochemical control of designer K+ channels in mammalian neurons. J. Neurophysiol. 106, 488–496 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Chambers, J. J., Banghart, M. R., Trauner, D. & Kramer, R. H. Light-induced depolarization of neurons using a modified Shaker K+ channel and a molecular photoswitch. J. Neurophysiol. 96, 2792–2796 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Fortin, D. L. et al. Photochemical control of endogenous ion channels and cellular excitability. Nature Methods 5, 331–338 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Chambers, J. J. & Kramer, R. H. Light-activated ion channels for remote control of neural activity. Methods Cell Biol. 90, 217–232 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kramer, R. H., Mourot, A. & Adesnik, H. Optogenetic pharmacology for control of native neuronal signaling proteins. Nature Neurosci. 16, 816–823 (2013).

    Article  PubMed  Google Scholar 

  145. Mourot, A., Tochitsky, I. & Kramer, R. H. Light at the end of the channel: optical manipulation of intrinsic neuronal excitability with chemical photoswitches. Frontiers Mol. Neurosci. 6, 5 (2013).

    Article  CAS  Google Scholar 

  146. Mourot, A., Fehrentz, T. & Kramer, R. H. Photochromic potassium channel blockers: design and electrophysiological characterization. Methods Mol. Biol. 995, 89–105 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. MacLean, J. N., Zhang, Y., Johnson, B. R. & Harris-Warrick, R. M. Activity-independent homeostasis in rhythmically active neurons. Neuron 37, 109–120 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Bergquist, S., Dickman, D. K. & Davis, G. W. A hierarchy of cell intrinsic and target-derived homeostatic signaling. Neuron 66, 220–234 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Turrigiano, G. Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Annu. Rev. Neurosci. 34, 89–103 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Marder, E. & Goaillard, J. M. Variability, compensation and homeostasis in neuron and network function. Nature Rev. Neurosci. 7, 563–574 (2006).

    Article  CAS  Google Scholar 

  151. Lujan, R. Organisation of potassium channels on the neuronal surface. J. Chem. Neuroanat 40, 1–20 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Vacher, H., Mohapatra, D. P. & Trimmer, J. S. Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Physiol. Rev. 88, 1407–1447 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Wolf, J. A. et al. NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron. J. Neurosci. 25, 9080–9095 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Shen, W., Hernandez-Lopez, S., Tkatch, T., Held, J. E. & Surmeier, D. J. Kv1.2-containing K+ channels regulate subthreshold excitability of striatal medium spiny neurons. J. Neurophysiol. 91, 1337–1349 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. Steephen, J. E. & Manchanda, R. Differences in biophysical properties of nucleus accumbens medium spiny neurons emerging from inactivation of inward rectifying potassium currents. J. Computat. Neurosci. 27, 453–470 (2009).

    Article  Google Scholar 

  156. John, J. & Manchanda, R. Modulation of synaptic potentials and cell excitability by dendritic KIR and KAs channels in nucleus accumbens medium spiny neurons: a computational study. J. Biosciences 36, 309–328 (2011).

    Article  Google Scholar 

  157. Rescorla, R. A. & Wagner, A. R. in Classical Conditioning II: Current Research and Theory (eds Black, A. H. & Prokasy, W. F.) 64–99 (Appleton-Century-Crofts, 1972).

    Google Scholar 

  158. Sutton, R. S. & Barto, A. Reinforcement Learning: An Introduction (MIT Press, 1998).

    Google Scholar 

  159. Sutton, R. S. Learning to predict by the method of temporal diferences. Machine Learn. 3, 9–44 (1988).

    Google Scholar 

  160. Suri, R. E., Bargas, J. & Arbib, M. A. Modeling functions of striatal dopamine modulation in learning and planning. Neuroscience 103, 65–85 (2001).

    Article  CAS  PubMed  Google Scholar 

  161. Joel, D., Niv, Y. & Ruppin, E. Actor-critic models of the basal ganglia: new anatomical and computational perspectives. Neural Netw. 15, 535–547 (2002).

    Article  PubMed  Google Scholar 

  162. Atallah, H. E., Lopez-Paniagua, D., Rudy, J. W. & O'Reilly, R. C. Separate neural substrates for skill learning and performance in the ventral and dorsal striatum. Nature Neurosci. 10, 126–131 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Doya, K. What are the computations of the cerebellum, the basal ganglia and the cerebral cortex? Neural Netw. 12, 961–974 (1999).

    Article  CAS  PubMed  Google Scholar 

  164. Pessiglione, M., Seymour, B., Flandin, G., Dolan, R. J. & Frith, C. D. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 442, 1042–1045 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Dezfouli, A. & Balleine, B. W. Habits, action sequences and reinforcement learning. Eur. J. Neurosci. 35, 1036–1051 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Dayan, P. & Balleine, B. W. Reward, motivation, and reinforcement learning. Neuron 36, 285–298 (2002).

    Article  CAS  PubMed  Google Scholar 

  167. O'Doherty, J. et al. Dissociable roles of ventral and dorsal striatum in instrumental conditioning. Science 304, 452–454 (2004).

    Article  CAS  PubMed  Google Scholar 

  168. Montague, P. R., Hyman, S. E. & Cohen, J. D. Computational roles for dopamine in behavioural control. Nature 431, 760–767 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. Takahashi, Y., Schoenbaum, G. & Niv, Y. Silencing the critics: understanding the effects of cocaine sensitization on dorsolateral and ventral striatum in the context of an actor/critic model. Frontiers Neurosci. 2, 86–99 (2008).

    Article  Google Scholar 

  170. Dezfouli, A. et al. A neurocomputational model for cocaine addiction. Neural Comput. 21, 2869–2893 (2009).

    Article  PubMed  Google Scholar 

  171. Redish, A. D. Addiction as a computational process gone awry. Science 306, 1944–1947 (2004).

    Article  CAS  PubMed  Google Scholar 

  172. Redish, A. D., Jensen, S. & Johnson, A. A unified framework for addiction: vulnerabilities in the decision process. Behav. Brain Sci. 31, 415–437; discussion 437–487 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Redish, A. D., Jensen, S., Johnson, A. & Kurth-Nelson, Z. Reconciling reinforcement learning models with behavioral extinction and renewal: implications for addiction, relapse, and problem gambling. Psychol. Rev. 114, 784–805 (2007).

    Article  PubMed  Google Scholar 

  174. Piray, P., Keramati, M. M., Dezfouli, A., Lucas, C. & Mokri, A. Individual differences in nucleus accumbens dopamine receptors predict development of addiction-like behavior: a computational approach. Neural Comput. 22, 2334–2368 (2010).

    Article  PubMed  Google Scholar 

  175. Gutkin, B. S., Dehaene, S. & Changeux, J. P. A neurocomputational hypothesis for nicotine addiction. Proc. Natl Acad. Sci. USA 103, 1106–1111 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Saddoris, M. P. & Carelli, R. M. Cocaine self-administration abolishes associative neural encoding in the nucleus accumbens necessary for higher-order learning. Biol. Psychiatry 75, 156–164 (2014).

    Article  CAS  PubMed  Google Scholar 

  177. Saddoris, M. P., Stamatakis, A. & Carelli, R. M. Neural correlates of Pavlovian-to-instrumental transfer in the nucleus accumbens shell are selectively potentiated following cocaine self-administration. Eur. J. Neurosci. 33, 2274–2287 (2011).

    Article  PubMed  Google Scholar 

  178. Takahashi, Y., Roesch, M. R., Stalnaker, T. A. & Schoenbaum, G. Cocaine exposure shifts the balance of associative encoding from ventral to dorsolateral striatum. Front. Integr. Neurosci. 1, 11 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Cameron, C. M. & Carelli, R. M. Cocaine abstinence alters nucleus accumbens firing dynamics during goal-directed behaviors for cocaine and sucrose. Eur. J. Neurosci. 35, 940–951 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Kourrich, S. & Bonci, A. Neurobiology of Mental Illness 4th edn Ch.5 (eds Charney, D. S., Buxbaum, J. D., Sklar, P. & Nestler, E. J.) (Oxford Univ. Press, 2013).

    Google Scholar 

  181. Yamaguchi, T., Wang, H. L., Li, X., Ng, T. H. & Morales, M. Mesocorticolimbic glutamatergic pathway. J. Neurosci. 31, 8476–8490 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Tecuapetla, F. et al. Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens. J. Neurosci. 30, 7105–7110 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Stuber, G. D., Hnasko, T. S., Britt, J. P., Edwards, R. H. & Bonci, A. Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J. Neurosci. 30, 8229–8233 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Y. Shaham, B. C. Finger and G. Schoenbaum for reading an early version of this manuscript.

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Glossary

Abstinence

A period of no drug use usually occurring after a period of repeated drug use. This term is used to describe both human abstinence, in which subjects voluntarily (rehabilitation) or involuntarily (incarceration) abstain from drug use, and also in animal models of drug relapse, in which abstinence is experimentally imposed (forced) by removing the animals from the drug self-administration environment.

A-type K+ current

A transient K+ current that is activated at subthreshold voltage and therefore plays an important part in the generation of the first action potential. A-type K+ currents were originally subdivided in two subtypes: As (also known as ID), which are mediated by Kv1 channels; and Af (also known as IA), which can be mediated by members from Kv1, Kv3 and Kv4 subfamilies. As currents are slowly inactivating (hundreds of milliseconds) K+ currents, whereas Af are fast-inactivating (tens of milliseconds) K+ currents.

Conditioned place preference

A Pavlovian (classical) conditioning model in which one distinct context is paired with drug injections, whereas another context is paired with vehicle injections during the training phase. In the subsequent testing phase (which is drug-free), the animal's preference for either context is determined by allowing the animal to move between the two contexts. An increase in preference for the drug-associated context serves as a measure of the drug's Pavlovian rewarding effects.

Contingent cocaine injections

Intravenous cocaine injections that are delivered as a consequence of the animal's conditioned responding (commonly a lever press or nose poke) during self- administration procedures. These injections are frequently paired with cues (such as a tone or light) that become associated with drug injections.

Incubation of cocaine craving

A hypothetical process of time-dependent increases in cue-induced cocaine seeking after withdrawal from cocaine self-administration in rats.

Non-contingent cocaine injections

Cocaine injections that are delivered independently of the animal's conditioned response; that is, non-voluntary cocaine injections. In psychomotor sensitization, non-contingent intraperitoneal cocaine injections are commonly administered by the experimenter. Self-administration procedures sometimes use control animals that receive non-contingent intravenous injections that equivalent to linked to the conditioned responding of an actively self-administering animal.

Psychomotor sensitization

A progressive increase in locomotor activity or other activity-related measure (stereotypy) that occurs after repeated injections of cocaine and related drugs.

Reinstatement

The recovery of a learned response (for example, lever-pressing) that occurs when a subject is exposed non-contingently to the unconditioned stimulus (for example, food) after extinction. In studies of reinstatement of drug seeking, reinstatement typically refers to the resumption of drug seeking after extinction following exposure to drugs, drug cues or stressors.

Self-administration

In the context of animal models of drug use and addiction, self-administration refers to a behavioural procedure in which animals perform an operant conditioned response (lever press or nose poke) to receive intravenous drug (that is, cocaine) injections. This procedure allows the animal to control its own drug intake voluntarily and thus more closely models the human condition.

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Kourrich, S., Calu, D. & Bonci, A. Intrinsic plasticity: an emerging player in addiction. Nat Rev Neurosci 16, 173–184 (2015). https://doi.org/10.1038/nrn3877

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