1932

Abstract

Addiction is a disease of altered behavior. Addicts use drugs compulsively and will continue to do so despite negative consequences. Even after prolonged periods of abstinence, addicts are at risk of relapse, particularly when cues evoke memories that are associated with drug use. Rodent models mimic many of the core components of addiction, from the initial drug reinforcement to cue-associated relapse and continued drug intake despite negative consequences. Rodent models have also enabled unprecedented mechanistic insight into addiction, revealing plasticity of glutamatergic synaptic transmission evoked by the strong activation of mesolimbic dopamine—a defining feature of all addictive drugs—as a neural substrate for these drug-adaptive behaviors. Cell type–specific optogenetic manipulations have allowed both identification of the relevant circuits and design of protocols to reverse drug-evoked plasticity and to establish links of causality with drug-adaptive behaviors. The emergence of a circuit model for addiction will open the door for novel therapies, such as deep brain stimulation.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-neuro-070815-013920
2016-07-08
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/neuro/39/1/annurev-neuro-070815-013920.html?itemId=/content/journals/10.1146/annurev-neuro-070815-013920&mimeType=html&fmt=ahah

Literature Cited

  1. Adamantidis AR, Tsai H-C, Boutrel B, Zhang F, Stuber GD. et al. 2011. Optogenetic interrogation of dopaminergic modulation of the multiple phases of reward-seeking behavior. J. Neurosci. 31:3010829–35 [Google Scholar]
  2. Am. Soc. Addict. Med 2011. Public policy statement: definition of addiction. Am. Soc. Addict. Med., Chevy Chase, MD. http://www.asam.org/for-the-public/definition-of-addiction
  3. Baimel C, Bartlett SE, Chiou L-C, Lawrence AJ, Muschamp JW. et al. 2015. Orexin/hypocretin role in reward: implications for opioid and other addictions. Br. J. Pharmacol. 172:2334–48 [Google Scholar]
  4. Bechara A, van der Kooy D. 1992. Lesions of the tegmental pedunculopontine nucleus: effects on the locomotor activity induced by morphine and amphetamine. Pharmacol. Biochem. Behav. 42:19–18 [Google Scholar]
  5. Bellone C, Lüscher C. 2006. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat. Neurosci. 9:5636–41 [Google Scholar]
  6. Bocklisch C, Pascoli V, Wong JCY, House DRC, Yvon C. et al. 2013. Cocaine disinhibits dopamine neurons by potentiation of GABA transmission in the ventral tegmental area. Science 341:61531521–25 [Google Scholar]
  7. Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A. 2006. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49:4589–601 [Google Scholar]
  8. Boudreau AC, Reimers JM, Milovanovic M, Wolf ME. 2007. 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. 27:3910621–35 [Google Scholar]
  9. Brown MTC, Bellone C, Mameli M, Labouèbe G, Bocklisch C. et al. 2010. Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation. PLOS ONE 5:12e15870 [Google Scholar]
  10. Brown TE, Lee BR, Mu P, Ferguson D, Dietz D. et al. 2011. A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J. Neurosci. 31:228163–74 [Google Scholar]
  11. Buchta WC, Riegel AC. 2015. Chronic cocaine disrupts mesocortical learning mechanisms. Brain Res. 1628:Part A88–103 [Google Scholar]
  12. Chen BT, Yau H-J, Hatch C, Kusumoto-Yoshida I, Cho SL. et al. 2013. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496:7445359–62 [Google Scholar]
  13. Chen R, Tilley MR, Wei H, Zhou F, Zhou F-M. et al. 2006. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. PNAS 103:249333–38 [Google Scholar]
  14. Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. 2012. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482:738385–88 [Google Scholar]
  15. Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng L-J. et al. 2008. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454:7200118–21 [Google Scholar]
  16. Creed MC, Lüscher C. 2013. Drug-evoked synaptic plasticity: beyond metaplasticity. Curr. Opin. Neurobiol. 23:4553–58 [Google Scholar]
  17. Creed MC, Pascoli V, Lüscher C. 2015. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science 347:6222659–64 [Google Scholar]
  18. Cruz HG, Ivanova T, Lunn M-L, Stoffel M, Slesinger PA, Lüscher C. 2004. Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system. Nat. Neurosci. 7:2153–59 [Google Scholar]
  19. Di Chiara G, Imperato A. 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. PNAS 85:145274–78 [Google Scholar]
  20. Engblom D, Bilbao A, Sanchis-Segura C, Dahan L, Perreau-Lenz S. et al. 2008. Glutamate receptors on dopamine neurons control the persistence of cocaine seeking. Neuron 59:3497–508 [Google Scholar]
  21. Everitt BJ, Robbins TW. 2013. From the ventral to the dorsal striatum: devolving views of their roles in drug addiction. Neurosci. Biobehav. Rev. 37:9 Part A1946–54 [Google Scholar]
  22. Gessa GL, Muntoni F, Collu M, Vargiu L, Mereu G. 1985. Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area. Brain Res. 348:1201–3 [Google Scholar]
  23. Good CH, Lupica CR. 2010. Afferent-specific AMPA receptor subunit composition and regulation of synaptic plasticity in midbrain dopamine neurons by abused drugs. J. Neurosci. 30:237900–9 [Google Scholar]
  24. Gremel CM, Costa RM. 2013a. Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Nat. Commun. 4:2264 [Google Scholar]
  25. Gremel CM, Costa RM. 2013b. Premotor cortex is critical for goal-directed actions. Front. Comput. Neurosci. 7:110 [Google Scholar]
  26. Hearing MC, Jedynak J, Ebner SR, Ingebretson A, Asp AJ. et al. 2016. Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement. PNAS 113:3757–62 [Google Scholar]
  27. Heikkinen AE, Möykkynen TP, Korpi ER. 2009. Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology 34:2290–98 [Google Scholar]
  28. Hnasko TS, Sotak BN, Palmiter RD. 2005. Morphine reward in dopamine-deficient mice. Nature 438:7069854–57 [Google Scholar]
  29. Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC. 2009. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61:5786–800 [Google Scholar]
  30. Jhou TC, Good CH, Rowley CS, Xu S-P, Wang H. et al. 2013. Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways. J. Neurosci. 33:177501–12 [Google Scholar]
  31. Johnson SW, North RA. 1992. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 12:2483–88 [Google Scholar]
  32. Kalivas PW, Volkow N, Seamans J. 2005. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45:5647–50 [Google Scholar]
  33. Kasanetz F, Lafourcade M, Deroche-Gamonet V, Revest J-M, Berson N. et al. 2012. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol. Psychiatr. 18:6729–37 [Google Scholar]
  34. Keiflin R, Janak PH. 2015. Dopamine prediction errors in reward learning and addiction: from theory to neural circuitry. Neuron 88:2247–63 [Google Scholar]
  35. Kenny PJ. 2014. Epigenetics, microRNA, and addiction. Dialogues Clin. Neurosci. 16:3335–44 [Google Scholar]
  36. Kessler RC, Berglund P, Chiu WT, Demler O, Heeringa S. et al. 2004. The US National Comorbidity Survey Replication (NCS-R): design and field procedures. Int. J. Methods Psychiatr. Res. 13:269–92 [Google Scholar]
  37. Koob GF. 2009. Brain stress systems in the amygdala and addiction. Brain Res. 1293:61–75 [Google Scholar]
  38. Kourrich S, Rothwell PE, Klug JR, Thomas MJ. 2007. Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J. Neurosci. 27:307921–28 [Google Scholar]
  39. Labouèbe G, Lomazzi M, Cruz HG, Creton C, Luján R. et al. 2007. RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nat. Neurosci. 10:121559–68 [Google Scholar]
  40. Lammel S, Lim BK, Malenka RC. 2014. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76:Part B351–59 [Google Scholar]
  41. Lammel S, Lim BK, Ran C, Huang KW, Betley MJ. et al. 2012. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491:7423212–17 [Google Scholar]
  42. Laviolette SR, Nader K, van der Kooy D. 2002. Motivational state determines the functional role of the mesolimbic dopamine system in the mediation of opiate reward processes. Behav. Brain Res. 129:1–217–29 [Google Scholar]
  43. Lee BR, Ma Y-Y, Huang YH, Wang X, Otaka M. et al. 2013. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci. 16:111644–51 [Google Scholar]
  44. Liu Q-S, Pu L, Poo M-M. 2005. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437:70611027–31 [Google Scholar]
  45. Liu SJ, Zukin RS. 2007. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci. 30:3126–34 [Google Scholar]
  46. Loweth JA, Scheyer AF, Milovanovic M, LaCrosse AL, Flores-Barrera E. et al. 2014. Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. Nat. Neurosci. 17:173–80 [Google Scholar]
  47. Lüscher C. 2013. Drug-evoked synaptic plasticity causing addictive behavior. J. Neurosci. 33:4517641–46 [Google Scholar]
  48. Lüscher C, Huber KM. 2010. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65:4445–59 [Google Scholar]
  49. Lüscher C, Jan LY, Stoffel M, Malenka RC, Nicoll RA. 1997. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron 19:3687–95 [Google Scholar]
  50. Lüscher C, Malenka RC. 2011. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69:4650–63 [Google Scholar]
  51. Lüscher C, Ungless MA. 2006. The mechanistic classification of addictive drugs. PLOS Med. 3:11e437 [Google Scholar]
  52. Lüthi A, Lüscher C. 2014. Pathological circuit function underlying addiction and anxiety disorders. Nat. Neurosci. 17:121635–43 [Google Scholar]
  53. Ma Y-Y, Lee BR, Wang X, Guo C, Liu L. et al. 2014. Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83:61453–67 [Google Scholar]
  54. Mameli M, Balland B, Luján R, Lüscher C. 2007. Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science 317:5837530–33 [Google Scholar]
  55. Mameli M, Bellone C, Brown MTC, Lüscher C. 2011. Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area. Nat. Neurosci. 14:4414–16 [Google Scholar]
  56. Mameli M, Halbout B, Creton C, Engblom D, Parkitna JR. et al. 2009. Cocaine-evoked synaptic plasticity: Persistence in the VTA triggers adaptations in the NAc. Nat. Neurosci. 12:81036–41 [Google Scholar]
  57. Maroteaux M, Mameli M. 2012. Cocaine evokes projection-specific synaptic plasticity of lateral habenula neurons. J. Neurosci. 32:3612641–46 [Google Scholar]
  58. Matsumoto M, Hikosaka O. 2009. Representation of negative motivational value in the primate lateral habenula. Nat. Neurosci. 12:177–84 [Google Scholar]
  59. McCutcheon JE, Wang X, Tseng KY, Wolf ME, Marinelli M. 2011. Calcium-permeable AMPA receptors are present in nucleus accumbens synapses after prolonged withdrawal from cocaine self-administration but not experimenter-administered cocaine. J. Neurosci. 31:155737–43 [Google Scholar]
  60. Melis M, Spiga S, Diana M. 2005. The dopamine hypothesis of drug addiction: hypodopaminergic state. Int. Rev. Neurobiol. 63:101–54 [Google Scholar]
  61. Meye FJ, Valentinova K, Lecca S, Marion-Poll L, Maroteaux MJ. et al. 2015. Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula. Nat. Neurosci. 18:3376–78 [Google Scholar]
  62. Nugent FS, Kauer JA. 2008. LTP of GABAergic synapses in the ventral tegmental area and beyond. J. Physiol. 586:61487–93 [Google Scholar]
  63. Nutt DJ, Lingford-Hughes A, Erritzoe D, Stokes PRA. 2015. The dopamine theory of addiction: 40 years of highs and lows. Nat. Rev. Neurosci. 16:5305–12 [Google Scholar]
  64. Padgett CL, Lalive AL, Tan KR, Terunuma M, Munoz MB. et al. 2012. Methamphetamine-evoked depression of GABAB receptor signaling in GABA neurons of the VTA. Neuron 73:5978–89 [Google Scholar]
  65. Paoletti P, Bellone C, Zhou Q. 2013. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14:6383–400 [Google Scholar]
  66. Pascoli V, Besnard A, Hervé D, Pagès C, Heck N. et al. 2011. Cyclic adenosine monophosphate–independent tyrosine phosphorylation of NR2B mediates cocaine-induced extracellular signal-regulated kinase activation. Biol. Psychiatr. 69:3218–27 [Google Scholar]
  67. Pascoli V, Terrier J, Espallergues J, Valjent E, O'Connor EC, Lüscher C. 2014. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509:7501459–64 [Google Scholar]
  68. Pascoli V, Terrier J, Hiver A, Lüscher C. 2015. Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction. Neuron 88:51054–66 [Google Scholar]
  69. Pascoli V, Turiault M, Lüscher C. 2012. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481:737971–75 [Google Scholar]
  70. Pérez-Otaño I, Schulteis CT, Contractor A, Lipton SA, Trimmer JS. et al. 2001. Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J. Neurosci. 21:41228–37 [Google Scholar]
  71. Peters J, LaLumiere RT, Kalivas PW. 2008. Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J. Neurosci. 28:236046–53 [Google Scholar]
  72. Piazza PV, Deroche-Gamonet V. 2014. A general theory of transition to addiction it was and a general theory of transition to addiction it is. Psychopharmacology 231:193929–37 [Google Scholar]
  73. Proulx CD, Hikosaka O, Malinow R. 2014. Reward processing by the lateral habenula in normal and depressive behaviors. Nat. Neurosci. 17:91146–52 [Google Scholar]
  74. Rehm J, Anderson P, Barry J, Dimitrov P, Elekes Z. et al. 2015. Prevalence of and potential influencing factors for alcohol dependence in Europe. Eur. Addict. Res. 21:16–18 [Google Scholar]
  75. Roberts DC, Corcoran ME, Fibiger HC. 1977. On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol. Biochem. Behav. 6:6615–20 [Google Scholar]
  76. Robison AJ, Nestler EJ. 2011. Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. 12:11623–37 [Google Scholar]
  77. Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R. et al. 1998. Cocaine self-administration in dopamine-transporter knockout mice. Nat. Neurosci. 1:2132–37 [Google Scholar]
  78. Rudd RA, Aleshire N, Zibbell JE, Gladden RM. 2016. Increases in drug and opioid overdose deaths—United States, 2000–2014. Morb. Mortal. Wkly. Rep. 64:50–511378–82 [Google Scholar]
  79. Saal D, Dong Y, Bonci A, Malenka RC. 2003. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:4577–82 [Google Scholar]
  80. Scheyer AF, Wolf ME, Tseng KY. 2014. A protein synthesis-dependent mechanism sustains calcium-permeable AMPA receptor transmission in nucleus accumbens synapses during withdrawal from cocaine self-administration. J. Neurosci. 34:83095–100 [Google Scholar]
  81. Schultz W. 2011. Potential vulnerabilities of neuronal reward, risk, and decision mechanisms to addictive drugs. Neuron 69:4603–17 [Google Scholar]
  82. Schultz W, Dayan P, Montague PR. 1997. A neural substrate of prediction and reward. Science 275:53061593–99 [Google Scholar]
  83. Shen W, Flajolet M, Greengard P, Surmeier DJ. 2008. Dichotomous dopaminergic control of striatal synaptic plasticity. Science 321:5890848–51 [Google Scholar]
  84. Sora I, Hall FS, Andrews AM, Itokawa M, Li XF. et al. 2001. Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. PNAS 98:95300–5 [Google Scholar]
  85. Tan KR, Brown M, Labouèbe G, Yvon C, Creton C. et al. 2010. Neural bases for addictive properties of benzodiazepines. Nature 463:7282769–74 [Google Scholar]
  86. Terraneo A, Leggio L, Saladini M, Ermani M, Bonci A, Gallimberti L. 2015. Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: a pilot study. Eur. Neuropsychopharmacol. 26:137–44 [Google Scholar]
  87. Terrier J, Lüscher C, Pascoli V. 2015. Cell-type specific insertion of GluA2-lacking AMPARs in cocaine sensitization, cue-associated seeking and incubation of craving. Neuropsychopharmacology. In press. doi: 10.1038/npp.2015.345
  88. Thomas MJ, Beurrier C, Bonci A, Malenka RC. 2001. Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nat. Neurosci. 4:121217–23 [Google Scholar]
  89. Threlfell S, Cragg SJ. 2011. Dopamine signaling in dorsal versus ventral striatum: the dynamic role of cholinergic interneurons. Front. Syst. Neurosci. 5:11 [Google Scholar]
  90. Tsai H-C, Zhang F, Adamantidis A, Stuber GD, Bonci A. et al. 2009. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324:59301080–84 [Google Scholar]
  91. Ungless MA, Whistler JL, Malenka RC, Bonci A. 2001. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:6837583–87 [Google Scholar]
  92. Volkow ND. 2014. Drugs, brains, and behavior: the science of addiction NIH Pub No. 14-5605, Natl. Inst. Drug Abuse, Bethesda, MD. https://www.drugabuse.gov/sites/default/files/soa_2014.pdf
  93. Volkow ND, Wang G-J, Ma Y, Fowler JS, Wong C. et al. 2005. Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction. J. Neurosci. 25:153932–39 [Google Scholar]
  94. Wagner FA, Anthony JC. 2002. From first drug use to drug dependence: developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology 26:4479–88 [Google Scholar]
  95. Waung MW, Pfeiffer BE, Nosyreva ED, Ronesi JA, Huber KM. 2008. Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59:184–97 [Google Scholar]
  96. Wise RA. 2004. Dopamine, learning and motivation. Nat. Rev. Neurosci. 5:6483–94 [Google Scholar]
  97. Wolf ME, Ferrario CR. 2010. AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine. Neurosci. Biobehav. Rev. 35:2185–211 [Google Scholar]
  98. Wolf ME, Tseng KY. 2012. Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: When, how, and why?. Front. Mol. Neurosci. 5:72 [Google Scholar]
  99. World Health Organ 2010. ATLAS on substance use (2010): resources for the prevention and treatment of substance use disorders World Health Organ., Geneva. http://www.who.int/substance_abuse/activities/msbatlasfrontncont.pdf?ua=1
  100. Yang Y, Lee P, Sternson SM. 2015. Cell type-specific pharmacology of NMDA receptors using masked MK801. eLife 4:e10206 [Google Scholar]
  101. Yuan T, Mameli M, O'Connor EC, Dey PN, Verpelli C. et al. 2013. Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 80:41025–38 [Google Scholar]
  102. Zhu Y, Wienecke CF, Nachtrab G, Chen X. 2016. A thalamic input to the nucleus accumbens mediates opiate dependence. Nature 530:7589219–22 [Google Scholar]
  103. Zinberg NE. 1986. Drug, Set, and Setting: The Basis for Controlled Intoxicant Use New Haven, CT: Yale University Press
/content/journals/10.1146/annurev-neuro-070815-013920
Loading
/content/journals/10.1146/annurev-neuro-070815-013920
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error