Stress and tobacco smoking are risk factors for alcoholism, but the underlying neural mechanisms are not well understood. Although stress, nicotine, and alcohol have broad, individual effects in the brain, some of their actions converge onto the same mechanisms and circuits. Stress and nicotine augment alcohol-related behaviors, in part via modulation of alcohol-evoked neuronal plasticity and metaplasticity mechanisms. Stress modulates alcohol-evoked plasticity via the release of signaling molecules that influence synaptic transmission. Nicotine also activates some of the same signaling molecules, cells, and circuits, producing a convergence of both stress and nicotine onto common plasticity mechanisms that influence alcohol self-administration. We describe several forms of alcohol-induced plasticity, including classic Hebbian plasticity at glutamatergic synapses, and we highlight less appreciated forms, such as non-Hebbian and GABAergic synaptic plasticity. Risk factors such as stress and nicotine initiate lasting neural changes that modify subsequent alcohol-induced synaptic plasticity and increase the vulnerability to alcohol addiction.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. 1.  2004. Actual causes of death in the United States, 2000.. JAMA 291:1238–45 [Google Scholar]
  2. Dani JA, Harris RA. 2.  2005. Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat. Neurosci. 8:1465–70 [Google Scholar]
  3. Batel P, Pessione F, Maitre C, Rueff B. 3.  1995. Relationship between alcohol and tobacco dependencies among alcoholics who smoke. Addiction 90:977–80 [Google Scholar]
  4. Weitzman ER, Chen YY. 4.  2005. The co-occurrence of smoking and drinking among young adults in college: national survey results from the United States. Drug Alcohol Depend 80:377–86 [Google Scholar]
  5. Barrett SP, Tichauer M, Leyton M, Pihl RO. 5.  2006. Nicotine increases alcohol self-administration in non-dependent male smokers. Drug Alcohol Depend 81:197–204 [Google Scholar]
  6. Harrison EL, Desai RA, McKee SA. 6.  2008. Nondaily smoking and alcohol use, hazardous drinking, and alcohol diagnoses among young adults: findings from the NESARC. Alcohol. Clin. Exp. Res. 32:2081–87 [Google Scholar]
  7. Uhart M, Wand GS. 7.  2009. Stress, alcohol and drug interaction: an update of human research. Addict. Biol. 14:43–64 [Google Scholar]
  8. Ayer LA, Harder VS, Rose GL, Helzer JE. 8.  2011. Drinking and stress: an examination of sex and stressor differences using IVR-based daily data. Drug Alcohol Depend 115:205–12 [Google Scholar]
  9. Keyes KM, Hatzenbuehler ML, Grant BF, Hasin DS. 9.  2012. Stress and alcohol: epidemiologic evidence. Alcohol Res 34:391–400 [Google Scholar]
  10. Doyon WM, Dong Y, Ostroumov A, Thomas AM, Zhang TA, Dani JA. 10.  2013. Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones. Neuron 79:530–40 [Google Scholar]
  11. Ostroumov A, Thomas AM, Kimmey BA, Karsch JS, Doyon WM, Dani JA. 11.  2016. Stress increases ethanol self-administration via a shift toward excitatory GABA signaling in the ventral tegmental area. Neuron 92:493–504 [Google Scholar]
  12. Becker HC, Lopez MF, Doremus-Fitzwater TL. 12.  2011. Effects of stress on alcohol drinking: a review of animal studies. Psychopharmacology 218:131–56 [Google Scholar]
  13. Blomqvist O, Ericson M, Johnson DH, Engel JA, Soderpalm B. 13.  1996. Voluntary ethanol intake in the rat: effects of nicotinic acetylcholine receptor blockade or subchronic nicotine treatment. Eur. J. Pharmacol. 314:257–67 [Google Scholar]
  14. Skelly MJ, Chappell AE, Carter E, Weiner JL. 14.  2015. Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: possible role of disrupted noradrenergic signaling. Neuropharmacology 97:149–59 [Google Scholar]
  15. Noori HR, Helinski S, Spanagel R. 15.  2014. Cluster and meta-analyses on factors influencing stress-induced alcohol drinking and relapse in rodents. Addict. Biol. 19:225–32 [Google Scholar]
  16. Phillips TJ, Roberts AJ, Lessov CN. 16.  1997. Behavioral sensitization to ethanol: genetics and the effects of stress. Pharmacol. Biochem. Behav. 57:487–93 [Google Scholar]
  17. Whitaker LR, Degoulet M, Morikawa H. 17.  2013. Social deprivation enhances VTA synaptic plasticity and drug-induced contextual learning. Neuron 77:335–45 [Google Scholar]
  18. Gubner NR, Phillips TJ. 18.  2015. Effects of nicotine on ethanol-induced locomotor sensitization: a model of neuroadaptation. Behav. Brain Res. 288:26–32 [Google Scholar]
  19. Maddux JN, Chaudhri N. 19.  2017. Nicotine-induced enhancement of Pavlovian alcohol-seeking behavior in rats. Psychopharmacology 234:727–38 [Google Scholar]
  20. Kauer JA, Malenka RC. 20.  2007. Synaptic plasticity and addiction. Nat. Rev. Neurosci. 8:844–58 [Google Scholar]
  21. Luscher C. 21.  2016. The emergence of a circuit model for addiction. Annu. Rev. Neurosci. 39:257–76 [Google Scholar]
  22. Hyman SE, Malenka RC, Nestler EJ. 22.  2006. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29:565–98 [Google Scholar]
  23. Armario A. 23.  2010. Activation of the hypothalamic-pituitary-adrenal axis by addictive drugs: different pathways, common outcome. Trends Pharmacol. Sci. 31:318–25 [Google Scholar]
  24. Doyon WM, Thomas AM, Ostroumov A, Dong Y, Dani JA. 24.  2013. Potential substrates for nicotine and alcohol interactions: a focus on the mesocorticolimbic dopamine system. Biochem. Pharmacol. 86:1181–93 [Google Scholar]
  25. Polter AM, Kauer JA. 25.  2014. Stress and VTA synapses: implications for addiction and depression. Eur. J. Neurosci. 39:1179–88 [Google Scholar]
  26. Francis TC, Lobo MK. 26.  2017. Emerging role for nucleus accumbens medium spiny neuron subtypes in depression. Biol. Psychiatry 81:645–53 [Google Scholar]
  27. Marinelli M, Piazza PV. 27.  2002. Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur. J. Neurosci. 16:387–94 [Google Scholar]
  28. Pastor R, Reed C, Meyer PJ, McKinnon C, Ryabinin AE, Phillips TJ. 28.  2012. Role of corticotropin-releasing factor and corticosterone in behavioral sensitization to ethanol. J. Pharmacol. Exp. Ther. 341:455–63 [Google Scholar]
  29. Dani JA, Bertrand D. 29.  2007. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu. Rev. Pharmacol. Toxicol. 47:699–729 [Google Scholar]
  30. Leao RM, Cruz FC, Vendruscolo LF, de Guglielmo G, Logrip ML. 30.  et al. 2015. Chronic nicotine activates stress/reward-related brain regions and facilitates the transition to compulsive alcohol drinking. J. Neurosci. 35:6241–53 [Google Scholar]
  31. Porcu P, Sogliano C, Cinus M, Purdy RH, Biggio G, Concas A. 31.  2003. Nicotine-induced changes in cerebrocortical neuroactive steroids and plasma corticosterone concentrations in the rat. Pharmacol. Biochem. Behav. 74:683–90 [Google Scholar]
  32. De Biasi M, Dani JA. 32.  2011. Reward, addiction, withdrawal to nicotine. Annu. Rev. Neurosci. 34:105–30 [Google Scholar]
  33. Abraham WC. 33.  2008. Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9:387 [Google Scholar]
  34. Turrigiano GG. 34.  2008. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135:422–35 [Google Scholar]
  35. Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ. 35.  et al. 2004. Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci. Biobehav. Rev. 27:739–49 [Google Scholar]
  36. DiFranza JR, Wellman RJ. 36.  2005. A sensitization-homeostasis model of nicotine craving, withdrawal, and tolerance: integrating the clinical and basic science literature. Nicot. Tob. Res. 7:9–26 [Google Scholar]
  37. Hebb DO. 37.  1949. The Organization of Behavior: A Neuropsychological Theory New York: Wiley
  38. Caporale N, Dan Y. 38.  2008. Spike timing-dependent plasticity: a Hebbian learning rule. Annu. Rev. Neurosci. 31:25–46 [Google Scholar]
  39. Citri A, Malenka RC. 39.  2008. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33:18–41 [Google Scholar]
  40. Luscher C, Malenka RC. 40.  2012. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb. Perspect. Biol. 4:a005710 [Google Scholar]
  41. Saal D, Dong Y, Bonci A, Malenka RC. 41.  2003. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–82 [Google Scholar]
  42. Heikkinen AE, Moykkynen TP, Korpi ER. 42.  2009. Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology 34:290–98 [Google Scholar]
  43. Wanat MJ, Sparta DR, Hopf FW, Bowers MS, Melis M, Bonci A. 43.  2009. Strain specific synaptic modifications on ventral tegmental area dopamine neurons after ethanol exposure. Biol. Psychiatry 65:646–53 [Google Scholar]
  44. Stuber GD, Hopf FW, Hahn J, Cho SL, Guillory A, Bonci A. 44.  2008. Voluntary ethanol intake enhances excitatory synaptic strength in the ventral tegmental area. Alcohol. Clin. Exp. Res. 32:1714–20 [Google Scholar]
  45. Engle SE, McIntosh JM, Drenan RM. 45.  2015. Nicotine and ethanol cooperate to enhance ventral tegmental area AMPA receptor function via α6-containing nicotinic receptors. Neuropharmacology 91:13–22 [Google Scholar]
  46. Yuan T, Mameli M, O'Connor EC, Dey PN, Verpelli C. 46.  et al. 2013. Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 80:1025–38 [Google Scholar]
  47. Mameli M, Bellone C, Brown MT, Luscher C. 47.  2011. Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area. Nat. Neurosci. 14:414–16 [Google Scholar]
  48. Fitzgerald LW, Ortiz J, Hamedani AG, Nestler EJ. 48.  1996. Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents. J. Neurosci. 16:274–82 [Google Scholar]
  49. Ortiz J, Fitzgerald LW, Charlton M, Lane S, Trevisan L. 49.  et al. 1995. Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. Synapse 21:289–98 [Google Scholar]
  50. Dong Y, Saal D, Thomas M, Faust R, Bonci A. 50.  et al. 2004. Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioral correlates in GluRA−/− mice. PNAS 101:14282–87 [Google Scholar]
  51. Daftary SS, Panksepp J, Dong Y, Saal DB. 51.  2009. Stress-induced, glucocorticoid-dependent strengthening of glutamatergic synaptic transmission in midbrain dopamine neurons. Neurosci. Lett. 452:273–76 [Google Scholar]
  52. Covington HE III, Tropea TF, Rajadhyaksha AM, Kosofsky BE, Miczek KA. 52.  2008. NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking. Psychopharmacology 197:203–16 [Google Scholar]
  53. Ford CP, Mark GP, Williams JT. 53.  2006. Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location. J. Neurosci. 26:2788–97 [Google Scholar]
  54. Lammel S, Hetzel A, Hackel O, Jones I, Liss B, Roeper J. 54.  2008. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57:760–73 [Google Scholar]
  55. Lammel S, Ion DI, Roeper J, Malenka RC. 55.  2011. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70:855–62 [Google Scholar]
  56. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L. 56.  et al. 2004. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47:Suppl. 1227–41 [Google Scholar]
  57. Robbins TW, Ersche KD, Everitt BJ. 57.  2008. Drug addiction and the memory systems of the brain. Ann. N. Y. Acad. Sci. 1141:1–21 [Google Scholar]
  58. Kalivas PW, McFarland K. 58.  2003. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology 168:44–56 [Google Scholar]
  59. Lobo MK, Covington HE III, Chaudhury D, Friedman AK, Sun H. 59.  et al. 2010. Cell type–specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330:385–90 [Google Scholar]
  60. Soares-Cunha C, Coimbra B, David-Pereira A, Borges S, Pinto L. 60.  et al. 2016. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation. Nat. Commun. 7:11829 [Google Scholar]
  61. Trifilieff P, Feng B, Urizar E, Winiger V, Ward RD. 61.  et al. 2013. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol. Psychiatry 18:1025–33 [Google Scholar]
  62. Beckley JT, Laguesse S, Phamluong K, Morisot N, Wegner SA, Ron D. 62.  2016. The first alcohol drink triggers mTORC1-dependent synaptic plasticity in nucleus accumbens dopamine D1 receptor neurons. J. Neurosci. 36:701–13 [Google Scholar]
  63. Buffington SA, Huang W, Costa-Mattioli M. 63.  2014. Translational control in synaptic plasticity and cognitive dysfunction. Annu. Rev. Neurosci. 37:17–38 [Google Scholar]
  64. Abrahao KP, Ariwodola OJ, Butler TR, Rau AR, Skelly MJ. 64.  et al. 2013. Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration. J. Neurosci. 33:4834–42 [Google Scholar]
  65. Campioni MR, Xu M, McGehee DS. 65.  2009. Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J. Neurophysiol. 101:3192–98 [Google Scholar]
  66. Garcia-Keller C, Kupchik YM, Gipson CD, Brown RM, Spencer S. 66.  et al. 2016. Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Mol. Psychiatry 21:1063–69 [Google Scholar]
  67. Garcia-Keller C, Martinez SA, Esparza MA, Bollati F, Kalivas PW, Cancela LM. 67.  2013. Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens. Eur. J. Neurosci. 37:982–95 [Google Scholar]
  68. Day JJ, Carelli RM. 68.  2007. The nucleus accumbens and Pavlovian reward learning. Neuroscientist 13:148–59 [Google Scholar]
  69. De Giovanni LN, Guzman AS, Virgolini MB, Cancela LM. 69.  2016. NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats. Behav. Brain Res. 315:150–59 [Google Scholar]
  70. Childs E, O'Connor S, de Wit H. 70.  2011. Bidirectional interactions between acute psychosocial stress and acute intravenous alcohol in healthy men. Alcohol. Clin. Exp. Res. 35:1794–803 [Google Scholar]
  71. de Wit H, Soderpalm AH, Nikolayev L, Young E. 71.  2003. Effects of acute social stress on alcohol consumption in healthy subjects. Alcohol. Clin. Exp. Res. 27:1270–77 [Google Scholar]
  72. Besheer J, Fisher KR, Jaramillo AA, Frisbee S, Cannady R. 72.  2014. Stress hormone exposure reduces mGluR5 expression in the nucleus accumbens: functional implications for interoceptive sensitivity to alcohol. Neuropsychopharmacology 39:2376–86 [Google Scholar]
  73. Brown MT, Bellone C, Mameli M, Labouebe G, Bocklisch C. 73.  et al. 2010. Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation. PLOS ONE 5:e15870 [Google Scholar]
  74. Melis M, Camarini R, Ungless MA, Bonci A. 74.  2002. Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure. J. Neurosci. 22:2074–82 [Google Scholar]
  75. Xiao C, Shao XM, Olive MF, Griffin WC III, Li KY. 75.  et al. 2009. Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area. Neuropsychopharmacology 34:307–18 [Google Scholar]
  76. Lovinger DM, White G, Weight FF. 76.  1989. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–24 [Google Scholar]
  77. Yaka R, Phamluong K, Ron D. 77.  2003. Scaffolding of Fyn kinase to the NMDA receptor determines brain region sensitivity to ethanol. J. Neurosci. 23:3623–32 [Google Scholar]
  78. Ron D, Wang J. 78.  2009. The NMDA receptor and alcohol addiction. Biology of the NMDA Receptor AM Van Dongen 59–78 Boca Raton, FL: CRC Press [Google Scholar]
  79. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM. 79.  et al. 2010. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–64 [Google Scholar]
  80. Brischoux F, Chakraborty S, Brierley DI, Ungless MA. 80.  2009. Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. PNAS 106:4894–99 [Google Scholar]
  81. Imperato A, Puglisi-Allegra S, Casolini P, Zocchi A, Angelucci L. 81.  1989. Stress-induced enhancement of dopamine and acetylcholine release in limbic structures: role of corticosterone. Eur. J. Pharmacol. 165:337–38 [Google Scholar]
  82. Anstrom KK, Woodward DJ. 82.  2005. Restraint increases dopaminergic burst firing in awake rats. Neuropsychopharmacology 30:1832–40 [Google Scholar]
  83. Tidey JW, Miczek KA. 83.  1996. Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study. Brain Res 721:140–49 [Google Scholar]
  84. Dong Y, Zhang T, Li W, Doyon WM, Dani JA. 84.  2010. Route of nicotine administration influences in vivo dopamine neuron activity: habituation, needle injection, and cannula infusion. J. Mol. Neurosci. 40:164–71 [Google Scholar]
  85. Korotkova TM, Brown RE, Sergeeva OA, Ponomarenko AA, Haas HL. 85.  2006. Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat. Eur. J. Neurosci. 23:2677–85 [Google Scholar]
  86. Wanat MJ, Hopf FW, Stuber GD, Phillips PEM, Bonci A. 86.  2008. Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. J. Physiol. 586:2157–70 [Google Scholar]
  87. Riegel AC, Williams JT. 87.  2008. CRF facilitates calcium release from intracellular stores in midbrain dopamine neurons. Neuron 57:559–70 [Google Scholar]
  88. Ungless MA, Singh V, Crowder TL, Yaka R, Ron D, Bonci A. 88.  2003. Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. Neuron 39:401–7 [Google Scholar]
  89. Bonci A, Borgland S. 89.  2009. Role of orexin/hypocretin and CRF in the formation of drug-dependent synaptic plasticity in the mesolimbic system. Neuropharmacology 56:Suppl. 1107–11 [Google Scholar]
  90. Berridge CW, Espana RA, Vittoz NM. 90.  2010. Hypocretin/orexin in arousal and stress. Brain Res 1314:91–102 [Google Scholar]
  91. Overton PG, Tong ZY, Brain PF, Clark D. 91.  1996. Preferential occupation of mineralocorticoid receptors by corticosterone enhances glutamate-induced burst firing in rat midbrain dopaminergic neurons. Brain Res 737:146–54 [Google Scholar]
  92. Cho K, Little HJ. 92.  1999. Effects of corticosterone on excitatory amino acid responses in dopamine-sensitive neurons in the ventral tegmental area. Neuroscience 88:837–45 [Google Scholar]
  93. Harnett MT, Bernier BE, Ahn KC, Morikawa H. 93.  2009. Burst-timing-dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons. Neuron 62:826–38 [Google Scholar]
  94. Bernier BE, Whitaker LR, Morikawa H. 94.  2011. Previous ethanol experience enhances synaptic plasticity of NMDA receptors in the ventral tegmental area. J. Neurosci. 31:5205–12 [Google Scholar]
  95. Stelly CE, Pomrenze MB, Cook JB, Morikawa H. 95.  2016. Repeated social defeat stress enhances glutamatergic synaptic plasticity in the VTA and cocaine place conditioning. eLife 5:e15448 [Google Scholar]
  96. Ahn KC, Bernier BE, Harnett MT, Morikawa H. 96.  2010. IP3 receptor sensitization during in vivo amphetamine experience enhances NMDA receptor plasticity in dopamine neurons of the ventral tegmental area. J. Neurosci. 30:6689–99 [Google Scholar]
  97. Moghaddam B, Bolinao ML. 97.  1994. Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens. Neurosci. Lett. 178:99–102 [Google Scholar]
  98. Melendez RI, Hicks MP, Cagle SS, Kalivas PW. 98.  2005. Ethanol exposure decreases glutamate uptake in the nucleus accumbens. Alcohol. Clin. Exp. Res. 29:326–33 [Google Scholar]
  99. Pati D, Kelly K, Stennett B, Frazier CJ, Knackstedt LA. 99.  2016. Alcohol consumption increases basal extracellular glutamate in the nucleus accumbens core of Sprague-Dawley rats without increasing spontaneous glutamate release. Eur. J. Neurosci. 44:1896–905 [Google Scholar]
  100. Griffin WC III, Haun HL, Hazelbaker CL, Ramachandra VS, Becker HC. 100.  2014. Increased extracellular glutamate in the nucleus accumbens promotes excessive ethanol drinking in ethanol dependent mice. Neuropsychopharmacology 39:707–17 [Google Scholar]
  101. Ding ZM, Rodd ZA, Engleman EA, Bailey JA, Lahiri DK, McBride WJ. 101.  2013. Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol-preferring (P) rats. Addict. Biol. 18:297–306 [Google Scholar]
  102. Renteria R, Maier EY, Buske TR, Morrisett RA. 102.  2017. Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure. Neuropharmacology 112:164–71 [Google Scholar]
  103. Jeanes ZM, Buske TR, Morrisett RA. 103.  2011. In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell. J. Pharmacol. Exp. Ther. 336:155–64 [Google Scholar]
  104. Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M. 104.  et al. 2010. Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328:1709–12 [Google Scholar]
  105. Jiang B, Wang W, Wang F, Hu ZL, Xiao JL. 105.  et al. 2013. The stability of NR2B in the nucleus accumbens controls behavioral and synaptic adaptations to chronic stress. Biol. Psychiatry 74:145–55 [Google Scholar]
  106. Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. 106.  2012. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487:183–89 [Google Scholar]
  107. Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G. 107.  et al. 2015. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol. Psychiatry 77:212–22 [Google Scholar]
  108. Bagot RC, Parise EM, Pena CJ, Zhang HX, Maze I. 108.  et al. 2015. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat. Commun. 6:7062 [Google Scholar]
  109. Khibnik LA, Beaumont M, Doyle M, Heshmati M, Slesinger PA. 109.  et al. 2016. Stress and cocaine trigger divergent and cell type-specific regulation of synaptic transmission at single spines in nucleus accumbens. Biol. Psychiatry 79:898–905 [Google Scholar]
  110. Xin W, Edwards N, Bonci A. 110.  2016. VTA dopamine neuron plasticity: the unusual suspects. Eur. J. Neurosci. 44:2975–83 [Google Scholar]
  111. Maguire J. 111.  2014. Stress-induced plasticity of GABAergic inhibition. Front. Cell Neurosci. 8:157 [Google Scholar]
  112. Graziane NM, Polter AM, Briand LA, Pierce RC, Kauer JA. 112.  2013. Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron 77:942–54 [Google Scholar]
  113. Creed MC, Ntamati NR, Tan KR. 113.  2014. VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems. Front. Behav. Neurosci. 8:8 [Google Scholar]
  114. Nugent FS, Penick EC, Kauer JA. 114.  2007. Opioids block long-term potentiation of inhibitory synapses. Nature 446:1086–90 [Google Scholar]
  115. Kodangattil JN, Dacher M, Authement ME, Nugent FS. 115.  2013. Spike timing-dependent plasticity at GABAergic synapses in the ventral tegmental area. J. Physiol. 591:4699–710 [Google Scholar]
  116. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H. 116.  et al. 1999. The K+/Cl co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–55 [Google Scholar]
  117. De Koninck Y. 117.  2007. Altered chloride homeostasis in neurological disorders: a new target. Curr. Opin. Pharmacol. 7:93–99 [Google Scholar]
  118. Ben-Ari Y. 118.  2002. Excitatory actions of GABA during development: the nature of the nurture. Nat. Rev. Neurosci. 3:728–39 [Google Scholar]
  119. Hewitt SA, Wamsteeker JI, Kurz EU, Bains JS. 119.  2009. Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis. Nat. Neurosci. 12:438–43 [Google Scholar]
  120. Coull JAM, Boudreau D, Bachand K, Prescott SA, Nault F. 120.  et al. 2003. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–42 [Google Scholar]
  121. Woodin MA, Ganguly K, Poo MM. 121.  2003. Coincident pre- and postsynaptic activity modifies GABAergic synapses by postsynaptic changes in Cl transporter activity. Neuron 39:807–20 [Google Scholar]
  122. Fiumelli H, Cancedda L, Poo MM. 122.  2005. Modulation of GABAergic transmission by activity via postsynaptic Ca2+-dependent regulation of KCC2 function. Neuron 48:773–86 [Google Scholar]
  123. Hubner CA, Holthoff K. 123.  2013. Anion transport and GABA signaling. Front. Cell Neurosci. 7:177 [Google Scholar]
  124. Lee HH, Deeb TZ, Walker JA, Davies PA, Moss SJ. 124.  2011. NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents. Nat. Neurosci. 14:736–43 [Google Scholar]
  125. Staley KJ, Soldo BL, Proctor WR. 125.  1995. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 269:977–81 [Google Scholar]
  126. Gagnon M, Bergeron MJ, Lavertu G, Castonguay A, Tripathy S. 126.  et al. 2013. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med. 19:1524–28 [Google Scholar]
  127. Theile JW, Morikawa H, Gonzales RA, Morrisett RA. 127.  2008. Ethanol enhances GABAergic transmission onto dopamine neurons in the ventral tegmental area of the rat. Alcohol. Clin. Exp. Res. 32:1040–48 [Google Scholar]
  128. Xiao C, Ye JH. 128.  2008. Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: role of μ-opioid receptors. Neuroscience 153:240–48 [Google Scholar]
  129. Taylor AM, Castonguay A, Ghogha A, Vayssiere P, Pradhan AA. 129.  et al. 2016. Neuroimmune regulation of GABAergic neurons within the ventral tegmental area during withdrawal from chronic morphine. Neuropsychopharmacology 41:949–59 [Google Scholar]
  130. Gulacsi A, Lee CR, Sik A, Viitanen T, Kaila K. 130.  et al. 2003. Cell type-specific differences in chloride-regulatory mechanisms and GABAA receptor-mediated inhibition in rat substantia nigra. J. Neurosci. 23:8237–46 [Google Scholar]
  131. Nieh EH, Vander Weele CM, Matthews GA, Presbrey KN, Wichmann R. 131.  et al. 2016. Inhibitory input from the lateral hypothalamus to the ventral tegmental area disinhibits dopamine neurons and promotes behavioral activation. Neuron 90:1286–98 [Google Scholar]
  132. Xia Y, Driscoll JR, Wilbrecht L, Margolis EB, Fields HL, Hjelmstad GO. 132.  2011. Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area. J. Neurosci. 31:7811–16 [Google Scholar]
  133. Laviolette SR, Gallegos RA, Henriksen SJ, van der Kooy D. 133.  2004. Opiate state controls bi-directional reward signaling via GABAA receptors in the ventral tegmental area. Nat. Neurosci. 7:160–69 [Google Scholar]
  134. Gubellini P, Ben-Ari Y, Gaiarsa JL. 134.  2001. Activity- and age-dependent GABAergic synaptic plasticity in the developing rat hippocampus. Eur. J. Neurosci. 14:1937–46 [Google Scholar]
  135. McLean HA, Caillard O, Ben-Ari Y, Gaiarsa JL. 135.  1996. Bidirectional plasticity expressed by GABAergic synapses in the neonatal rat hippocampus. J. Physiol. 496:2471–77 [Google Scholar]
  136. Chevy Q, Heubl M, Goutierre M, Backer S, Moutkine I. 136.  et al. 2015. KCC2 gates activity-driven AMPA receptor traffic through cofilin phosphorylation. J. Neurosci. 35:15772–86 [Google Scholar]
  137. Li H, Khirug S, Cai C, Ludwig A, Blaesse P. 137.  et al. 2007. KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56:1019–33 [Google Scholar]
  138. Guan YZ, Ye JH. 138.  2010. Ethanol blocks long-term potentiation of GABAergic synapses in the ventral tegmental area involving μ-opioid receptors. Neuropsychopharmacology 35:1841–49 [Google Scholar]
  139. Authement ME, Langlois LD, Kassis H, Gouty S, Dacher M. 139.  et al. 2016. Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition. J. Neurophysiol. 116:1093–103 [Google Scholar]
  140. Nylander I, Roman E. 140.  2013. Is the rodent maternal separation model a valid and effective model for studies on the early-life impact on ethanol consumption?. Psychopharmacology 229:555–69 [Google Scholar]
  141. Ikemoto S. 141.  2007. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res. Rev. 56:27–78 [Google Scholar]
  142. Haber SN, Fudge JL, McFarland NR. 142.  2000. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J. Neurosci. 20:2369–82 [Google Scholar]
  143. Edwards NJ, Tejeda HA, Pignatelli M, Zhang S, McDevitt RA. 143.  et al. 2017. Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior. Nat. Neurosci. 20:438–48 [Google Scholar]
  144. Belin D, Everitt BJ. 144.  2008. Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57:432–41 [Google Scholar]
  145. Everitt BJ, Robbins TW. 145.  2005. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8:1481–89 [Google Scholar]
  146. Grueter BA, Rothwell PE, Malenka RC. 146.  2012. Integrating synaptic plasticity and striatal circuit function in addiction. Curr. Opin. Neurobiol. 22:545–51 [Google Scholar]
  147. Luscher C, Bellone C. 147.  2008. Cocaine-evoked synaptic plasticity: a key to addiction?. Nat. Neurosci. 11:737–38 [Google Scholar]
  148. Barker JM, Taylor JR. 148.  2014. Habitual alcohol seeking: modeling the transition from casual drinking to addiction. Neurosci. Biobehav. Rev. 47:281–94 [Google Scholar]
  149. Gourley SL, Swanson AM, Jacobs AM, Howell JL, Mo M. 149.  et al. 2012. Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding. PNAS 109:20714–19 [Google Scholar]
  150. Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR. 150.  et al. 2009. Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325:621–25 [Google Scholar]
  151. Schwabe L, Wolf OT. 151.  2009. Stress prompts habit behavior in humans. J. Neurosci. 29:7191–98 [Google Scholar]

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