VTA GABAergic Plasticity: An Inhibitory Synaptic Model of Drug Addiction

  • Fereshteh S. Nugent


There is now compelling evidence suggesting that addiction is a pathological form of habit-based learning of the brain that involves drug-induced synaptic plasticity in addiction-related areas of the brain including the ventral tegmental area (VTA). Fortunately, over the last decade, tremendous progress has been made in the identification of neuroplastic changes in the relevant neural circuits involved in the development and maintenance of addiction using “synaptic plasticity models”. The current model of addiction supports the idea that the VTA is the major starting point of addiction-associated plasticity of the brain in response to drugs of abuse. While synaptic plasticity at excitatory synapses is well-studied and is correlated with addiction, the role of synaptic plasticity at inhibitory synapses is less well understood. However now there is a growing interest in characterizing and uncovering the underlying mechanisms of these forms of inhibitory plasticity and their link to different aspects of brain function, including the development of addictive behaviors. In this chapter, I will provide a brief synopsis of some forms of synaptic plasticity associated with addiction found at inhibitory GABAergic synapses in the VTA.


Synaptic Plasticity Ventral Tegmental Area Guanylate Cyclase Dorsal Striatum Gaba Release 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The opinions and assertions contained herein are the private opinions of the author and are not to be construed as official or reflecting the views of the Uniformed Services University of the Health Sciences or the Department of Defense or the Government of the United States. This work was supported by an R0 75OU grant from the Uniformed Services University (USUHS), and I also acknowledge past support (5F32 DA021973-02) from the National Institute of Drug Abuse. Thanks to Drs. Brian Cox, David Lovinger, Julie Kauer, and Suzanne Bausch for their helpful and constructive discussions for the present chapter.


  1. Adermark, L., G. Talani, and D.M. Lovinger, Endocannabinoid-dependent plasticity at GABAergic and glutamatergic synapses in the striatum is regulated by synaptic activity. Eur J Neurosci, 2009. 29(1): p. 32–41.PubMedGoogle Scholar
  2. Argilli, E., et al., Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area. J Neurosci, 2008. 28(37): p. 9092–100.PubMedGoogle Scholar
  3. Aston-Jones, G. and G.C. Harris, Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology, 2004. 47 Suppl 1: p. 167–79.Google Scholar
  4. Azad, S.C., et al., Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. J Neurosci, 2004. 24(44): p. 9953–61.PubMedGoogle Scholar
  5. Bear, M.F. and W.C. Abraham, Long-term depression in hippocampus. Annu Rev Neurosci, 1996. 19: p. 437–62.PubMedGoogle Scholar
  6. Bellone, C. and C. Luscher, mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors. Eur J Neurosci, 2005. 21(5): p. 1280–8.PubMedGoogle Scholar
  7. Bellone, C. and C. Luscher, Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci, 2006. 9(5): p. 636–41.PubMedGoogle Scholar
  8. Bellone, C., C. Luscher, and M. Mameli, Mechanisms of synaptic depression triggered by metabotropic glutamate receptors. Cell Mol Life Sci, 2008. 65(18): p. 2913–23.PubMedGoogle Scholar
  9. Betz, C., et al., Could a common biochemical mechanism underlie addictions? J Clin Pharm Ther, 2000. 25(1): p. 11–20.PubMedGoogle Scholar
  10. Bliss, T.V. and G.L. Collingridge, A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 1993. 361(6407): p. 31–9.PubMedGoogle Scholar
  11. Bonci, A. and R.C. Malenka, Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J Neurosci, 1999. 19(10): p. 3723–30.PubMedGoogle Scholar
  12. Bonci, A. and J.T. Williams, A common mechanism mediates long-term changes in synaptic transmission after chronic cocaine and morphine. Neuron, 1996. 16(3): p. 631–9.PubMedGoogle Scholar
  13. Borgland, S.L., et al., Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron, 2006. 49(4): p. 589–601.PubMedGoogle Scholar
  14. Borgland, S.L., R.C. Malenka, and A. Bonci, Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J Neurosci, 2004. 24(34): p. 7482–90.PubMedGoogle Scholar
  15. Bonci, A. and S. Borgland, Role of orexin/hypocretin and CRF in the formation of drug-dependent synaptic plasticity in the mesolimbic system. Neuropharmacology, 2008.Google Scholar
  16. Bonci, A. and J.T. Williams, Increased probability of GABA release during withdrawal from morphine. J Neurosci, 1997. 17(2): p. 796–803.PubMedGoogle Scholar
  17. Cameron, D.L. and J.T. Williams, Dopamine D1 receptors facilitate transmitter release. Nature, 1993. 366(6453): p. 344–7.PubMedGoogle Scholar
  18. Carr, D.B. and S.R. Sesack, Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci, 2000. 20(10): p. 3864–73.PubMedGoogle Scholar
  19. Chergui, K., et al., Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo. Eur J Neurosci, 1993. 5(2): p. 137–44.PubMedGoogle Scholar
  20. Chevaleyre, V. and P.E. Castillo, Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron, 2003. 38(3): p. 461–72.PubMedGoogle Scholar
  21. Chevaleyre, V., K.A. Takahashi, and P.E. Castillo, Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci, 2006. 29: p. 37–76.PubMedGoogle Scholar
  22. Chevaleyre, V., et al., Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha. Neuron, 2007. 54(5): p. 801–12.PubMedGoogle Scholar
  23. Chien, W.L., et al., Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole. Mol Pharmacol, 2003. 63(6): p. 1322–8.PubMedGoogle Scholar
  24. Churchill, L., R.P. Dilts, and P.W. Kalivas, Autoradiographic localization of gamma-aminobutyric acidA receptors within the ventral tegmental area. Neurochem Res, 1992. 17(1): p. 101–6.PubMedGoogle Scholar
  25. Christie, M.J., et al., Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area. Brain Res, 1985. 333(1): p. 169–72.PubMedGoogle Scholar
  26. De Vries, T.J. and T.S. Shippenberg, Neural systems underlying opiate addiction. J Neurosci, 2002. 22(9): p. 3321–5.PubMedGoogle Scholar
  27. Diana, M., et al., Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: electrophysiological and biochemical evidence. Proc Natl Acad Sci U S A, 1993. 90(17): p. 7966–9.PubMedGoogle Scholar
  28. Diana, M., et al., Mesolimbic dopaminergic reduction outlasts ethanol withdrawal syndrome: evidence of protracted abstinence. Neuroscience, 1996. 71(2): p. 411–5.PubMedGoogle Scholar
  29. Diana, M., et al., Marked decrease of A10 dopamine neuronal firing during ethanol withdrawal syndrome in rats. Eur J Pharmacol, 1992. 221(2–3): p. 403–4.PubMedGoogle Scholar
  30. Diana, M., et al., Profound decrease of mesolimbic dopaminergic neuronal activity in morphine withdrawn rats. J Pharmacol Exp Ther, 1995. 272(2): p. 781–5.PubMedGoogle Scholar
  31. Diana, M., et al., Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal. Eur J Neurosci, 1999. 11(3): p. 1037–41.PubMedGoogle Scholar
  32. Diana, M., et al., Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proc Natl Acad Sci U S A, 1998. 95(17): p. 10269–73.PubMedGoogle Scholar
  33. Di Chiara, G. and A. Imperato, Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A, 1988. 85(14): p. 5274–8.PubMedGoogle Scholar
  34. Dong, Y., et al., Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioral correlates in GluRA(/) mice. Proc Natl Acad Sci U S A, 2004. 101(39): p. 14282–7.PubMedGoogle Scholar
  35. Engblom, D., et al., Glutamate receptors on dopamine neurons control the persistence of cocaine seeking. Neuron, 2008. 59(3): p. 497–508.PubMedGoogle Scholar
  36. Faleiro, L.J., S. Jones, and J.A. Kauer, Rapid synaptic plasticity of glutamatergic synapses on dopamine neurons in the ventral tegmental area in response to acute amphetamine injection. Neuropsychopharmacology, 2004. 29(12): p. 2115–25.PubMedGoogle Scholar
  37. Fields, H.L., et al., Ventral Tegmental Area Neurons in Learned Appetitive Behavior and Positive Reinforcement. Annu Rev Neurosci, 2007.Google Scholar
  38. Fiorillo, C.D. and J.T. Williams, Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature, 1998. 394(6688): p. 78–82.PubMedGoogle Scholar
  39. Frenois, F., et al., A specific limbic circuit underlies opiate withdrawal memories. J Neurosci, 2005. 25(6): p. 1366–74.PubMedGoogle Scholar
  40. Frenois, F., et al., Neural correlates of the motivational and somatic components of naloxone-precipitated morphine withdrawal. Eur J Neurosci, 2002. 16(7): p. 1377–89.PubMedGoogle Scholar
  41. Garthwaite, J., Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci, 2008. 27(11): p. 2783–802.PubMedGoogle Scholar
  42. Garzon, M., et al., Cholinergic axon terminals in the ventral tegmental area target a subpopulation of neurons expressing low levels of the dopamine transporter. J Comp Neurol, 1999. 410(2): p. 197–210.PubMedGoogle Scholar
  43. Georges, F. and G. Aston-Jones, Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis. J Neurosci, 2001. 21(16): p. RC160.Google Scholar
  44. Gerdeman, G.L. and D.M. Lovinger, Emerging roles for endocannabinoids in long-term synaptic plasticity. Br J Pharmacol, 2003. 140(5): p. 781–9.PubMedGoogle Scholar
  45. Gerdeman, G.L., et al., It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci, 2003. 26(4): p. 184–92.PubMedGoogle Scholar
  46. Gerdeman, G.L., J. Ronesi, and D.M. Lovinger, Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci, 2002. 5(5): p. 446–51.PubMedGoogle Scholar
  47. Gutlerner, J.L., et al., Novel protein kinase A-dependent long-term depression of excitatory synapses. Neuron, 2002. 36(5): p. 921–31.PubMedGoogle Scholar
  48. Hahn, J., F.W. Hopf, and A. Bonci, Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons. J Neurosci, 2009. 29(20): p. 6535–44.PubMedGoogle Scholar
  49. Heifets, B.D. and P.E. Castillo, Endocannabinoid signaling and long-term synaptic plasticity. Annu Rev Physiol, 2009. 71: p. 283–306.PubMedGoogle Scholar
  50. Huang, C.C., S.H. Chan, and K.S. Hsu, cGMP/protein kinase G-dependent potentiation of glutamatergic transmission induced by nitric oxide in immature rat rostral ventrolateral medulla neurons in vitro. Mol Pharmacol, 2003. 64(2): p. 521–32.PubMedGoogle Scholar
  51. Hyman, S.E. and R.C. Malenka, Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci, 2001. 2(10): p. 695–703.PubMedGoogle Scholar
  52. Ikemoto, S., R.R. Kohl, and W.J. McBride, GABA(A) receptor blockade in the anterior ventral tegmental area increases extracellular levels of dopamine in the nucleus accumbens of rats. J Neurochem, 1997. 69(1): p. 137–43.PubMedGoogle Scholar
  53. Ikemoto, S., J.M. Murphy, and W.J. McBride, Self-infusion of GABA(A) antagonists directly into the ventral tegmental area and adjacent regions. Behav Neurosci, 1997. 111(2): p. 369–80.PubMedGoogle Scholar
  54. Jones, S., J.L. Kornblum, and J.A. Kauer, Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J Neurosci, 2000. 20(15): p. 5575–80.PubMedGoogle Scholar
  55. Jones, S. and J.A. Kauer, Amphetamine depresses excitatory synaptic transmission via serotonin receptors in the ventral tegmental area. J Neurosci, 1999. 19(22): p. 9780–7.PubMedGoogle Scholar
  56. Johnson, S.W., N.B. Mercuri, and R.A. North, 5-hydroxytryptamine1B receptors block the GABAB synaptic potential in rat dopamine neurons. J Neurosci, 1992. 12(5): p. 2000–6.PubMedGoogle Scholar
  57. Johnson, S.W., V. Seutin, and R.A. North, Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump. Science, 1992. 258(5082): p. 665–7.PubMedGoogle Scholar
  58. Johnson, S.W. and R.A. North, Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci, 1992. 12(2): p. 483–8.PubMedGoogle Scholar
  59. Kalivas, P.W. and C. O’Brien, Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology, 2008. 33(1): p. 166–80.PubMedGoogle Scholar
  60. Kalivas, P.W., et al., Glutamate transmission in addiction. Neuropharmacology, 2008.Google Scholar
  61. Kauer, J.A., Addictive drugs and stress trigger a common change at VTA synapses. Neuron, 2003. 37(4): p. 549–50.PubMedGoogle Scholar
  62. Kauer, J.A. and R.C. Malenka, Synaptic plasticity and addiction. Nat Rev Neurosci, 2007. 8(11): p. 844–58.PubMedGoogle Scholar
  63. Volkow, N. and T.K. Li, The neuroscience of addiction. Nat Neurosci, 2005. 8(11): p. 1429–30.PubMedGoogle Scholar
  64. Klitenick, M.A., P. DeWitte, and P.W. Kalivas, Regulation of somatodendritic dopamine release in the ventral tegmental area by opioids and GABA: an in vivo microdialysis study. J Neurosci, 1992. 12(7): p. 2623–32.PubMedGoogle Scholar
  65. Koob, G.F., T.L. Wall, and F.E. Bloom, Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal. Psychopharmacology (Berl), 1989. 98(4): p. 530–4.Google Scholar
  66. Koob, G.F., G. Kenneth Lloyd, and B.J. Mason, Development of pharmacotherapies for drug addiction: a Rosetta stone approach. Nat Rev Drug Discov, 2009. 8(6): p. 500–15.Google Scholar
  67. Koob, G.F., A role for brain stress systems in addiction. Neuron, 2008. 59(1): p. 11–34.PubMedGoogle Scholar
  68. Koob, G.F., Neural mechanisms of drug reinforcement. Ann N Y Acad Sci, 1992. 654: p. 171–91.PubMedGoogle Scholar
  69. Koob, G.F. and M. Le Moal, Drug abuse: hedonic homeostatic dysregulation. Science, 1997. 278(5335): p. 52–8.PubMedGoogle Scholar
  70. Koob, G.F. and M. Le Moal, Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci, 2005. 8(11): p. 1442–4.PubMedGoogle Scholar
  71. Koob, G.F. and N.D. Volkow, Neurocircuitry of Addiction. Neuropsychopharmacology, 2009.Google Scholar
  72. Koob, G.F. and M. Le Moal, Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology, 2001. 24(2): p. 97–129.PubMedGoogle Scholar
  73. Kreitzer, A.C. and R.C. Malenka, Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum. J Neurosci, 2005. 25(45): p. 10537–45.Google Scholar
  74. Kreitzer, A.C. and R.C. Malenka, Striatal plasticity and basal ganglia circuit function. Neuron, 2008. 60(4): p. 543–54.PubMedGoogle Scholar
  75. Kreitzer, A.C. and R.C. Malenka, Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature, 2007. 445(7128): p. 643–7.PubMedGoogle Scholar
  76. Lafourcade, M., et al., Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex. PLoS ONE, 2007. 2(1): p. e709.PubMedGoogle Scholar
  77. Liu, Z.H., R. Shin, and S. Ikemoto, Dual role of medial A10 dopamine neurons in affective encoding. Neuropsychopharmacology, 2008. 33(12): p. 3010–20.PubMedGoogle Scholar
  78. Liu, Q.S., L. Pu, and M.M. Poo, Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature, 2005. 437(7061): p. 1027–31.PubMedGoogle Scholar
  79. Liu, S., Y. Rao, and N. Daw, Roles of protein kinase A and protein kinase G in synaptic plasticity in the visual cortex. Cereb Cortex, 2003. 13(8): p. 864–9.PubMedGoogle Scholar
  80. Lovinger, D.M., Presynaptic modulation by endocannabinoids. Handb Exp Pharmacol, 2008(184): p. 435–77.Google Scholar
  81. Lovinger, D.M., J.G. Partridge, and K.C. Tang, Plastic control of striatal glutamatergic transmission by ensemble actions of several neurotransmitters and targets for drugs of abuse. Ann N Y Acad Sci, 2003. 1003: p. 226–40.PubMedGoogle Scholar
  82. Luscher, C. and C. Bellone, Cocaine-evoked synaptic plasticity: a key to addiction? Nat Neurosci, 2008. 11(7): p. 737–8.PubMedGoogle Scholar
  83. Lu, Y.F. and R.D. Hawkins, Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus. J Neurophysiol, 2002. 88(3): p. 1270–8.PubMedGoogle Scholar
  84. Lu, Y.F., E.R. Kandel, and R.D. Hawkins, Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci, 1999. 19(23): p. 10250–61.PubMedGoogle Scholar
  85. Mameli, M., et al., Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat Neurosci, 2009.Google Scholar
  86. Mameli, M., et al., Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science, 2007. 317(5837): p. 530–3.PubMedGoogle Scholar
  87. Mansvelder, H.D. and D.S. McGehee, Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron, 2000. 27(2): p. 349–57.PubMedGoogle Scholar
  88. Marsicano, G., et al., The endogenous cannabinoid system controls extinction of aversive memories. Nature, 2002. 418(6897): p. 530–4.PubMedGoogle Scholar
  89. Mato, S., et al., Role of the cyclic-AMP/PKA cascade and of P/Q-type Ca++ channels in endocannabinoid-mediated long-term depression in the nucleus accumbens. Neuropharmacology, 2008. 54(1): p. 87–94.PubMedGoogle Scholar
  90. McBain, C.J. and J.A. Kauer, Presynaptic plasticity: targeted control of inhibitory networks. Curr Opin Neurobiol, 2009.Google Scholar
  91. Melis, M., et al., Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure. J Neurosci, 2002. 22(6): p. 2074–82.PubMedGoogle Scholar
  92. Monfort, P., et al., Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. J Neurosci, 2002. 22(23): p. 10116–22.PubMedGoogle Scholar
  93. Monfort, P., et al., Sequential activation of soluble guanylate cyclase, protein kinase G and cGMP-degrading phosphodiesterase is necessary for proper induction of long-term potentiation in CA1 of hippocampus. Alterations in hyperammonemia. Neurochem Int, 2004. 45(6): p. 895–901.PubMedGoogle Scholar
  94. Murase, S., et al., Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo. Neurosci Lett, 1993. 157(1): p. 53–6.PubMedGoogle Scholar
  95. Nestler, E.J. and G.K. Aghajanian, Molecular and cellular basis of addiction. Science, 1997. 278(5335): p. 58–63.PubMedGoogle Scholar
  96. Nugent, F.S., J.L. Niehaus, and J.A. Kauer, PKG and PKA Signaling in LTP at GABAergic Synapses. Neuropsychopharmacology, 2009.PubMedGoogle Scholar
  97. Nugent, F.S., et al., High-frequency afferent stimulation induces long-term potentiation of field potentials in the ventral tegmental area. Neuropsychopharmacology, 2008. 33(7): p. 1704–12.PubMedGoogle Scholar
  98. Nugent, F.S., E.C. Penick, and J.A. Kauer, Opioids block long-term potentiation of inhibitory synapses. Nature, 2007. 446(7139): p. 1086–90.PubMedGoogle Scholar
  99. Nugent, F.S. and J.A. Kauer, LTP of GABAergic synapses in the ventral tegmental area and beyond. J Physiol, 2008. 586(6): p. 1487–93.PubMedGoogle Scholar
  100. Omelchenko, N. and S.R. Sesack, Ultrastructural analysis of local collaterals of rat ventral tegmental area neurons: GABA phenotype and synapses onto dopamine and GABA cells. Synapse, 2009. 63(10): p. 895–906.PubMedGoogle Scholar
  101. Pan, B., C.J. Hillard, and Q.S. Liu, Endocannabinoid signaling mediates cocaine-induced inhibitory synaptic plasticity in midbrain dopamine neurons. J Neurosci, 2008. 28(6): p. 1385–97.Google Scholar
  102. Pan, B., C.J. Hillard, and Q.S. Liu, D2 dopamine receptor activation facilitates endocannabinoid-mediated long-term synaptic depression of GABAergic synaptic transmission in midbrain dopamine neurons via cAMP-protein kinase A signaling. J Neurosci, 2008. 28(52): p. 14018–30.PubMedGoogle Scholar
  103. Robinson, T.E. and K.C. Berridge, The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev, 1993. 18(3): p. 247–91.Google Scholar
  104. Robinson, T.E. and K.C. Berridge, Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond B Biol Sci, 2008. 363(1507): p. 3137–46.PubMedGoogle Scholar
  105. Ronesi, J. and D.M. Lovinger, Induction of striatal long-term synaptic depression by moderate frequency activation of cortical afferents in rat. J Physiol, 2005. 562(Pt 1): p. 245–56.Google Scholar
  106. Saal, D., et al., Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron, 2003. 37(4): p. 577–82.PubMedGoogle Scholar
  107. Schultz, W., Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol, 1997. 7(2): p. 191–7.PubMedGoogle Scholar
  108. Sesack, S.R. and V.M. Pickel, Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol, 1992. 320(2): p. 145–60.PubMedGoogle Scholar
  109. Semba, K. and H.C. Fibiger, Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro- and antero-grade transport and immunohistochemical study. J Comp Neurol, 1992. 323(3): p. 387–410.PubMedGoogle Scholar
  110. Sjostrom, P.J., G.G. Turrigiano, and S.B. Nelson, Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron, 2003. 39(4): p. 641–54.PubMedGoogle Scholar
  111. Sjostrom, P.J., G.G. Turrigiano, and S.B. Nelson, Endocannabinoid-dependent neocortical layer-5 LTD in the absence of postsynaptic spiking. J Neurophysiol, 2004. 92(6): p. 3338–43.PubMedGoogle Scholar
  112. Spanagel, R., A. Herz, and T.S. Shippenberg, Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci U S A, 1992. 89(6): p. 2046–50.PubMedGoogle Scholar
  113. Sugita, S., S.W. Johnson, and R.A. North, Synaptic inputs to GABAA and GABAB receptors originate from discrete afferent neurons. Neurosci Lett, 1992. 134(2): p. 207–11.PubMedGoogle Scholar
  114. Thomas, M.J., et al., Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nat Neurosci, 2001. 4(12): p. 1217–23.Google Scholar
  115. Thomas, M.J. and R.C. Malenka, Synaptic plasticity in the mesolimbic dopamine system. Philos Trans R Soc Lond B Biol Sci, 2003. 358(1432): p. 815–9.PubMedGoogle Scholar
  116. Thomas, M.J., R.C. Malenka, and A. Bonci, Modulation of long-term depression by dopamine in the mesolimbic system. J Neurosci, 2000. 20(15): p. 5581–6.PubMedGoogle Scholar
  117. Ungless, M.A., P.J. Magill, and J.P. Bolam, Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science, 2004. 303(5666): p. 2040–2.PubMedGoogle Scholar
  118. Ungless, M.A., Dopamine: the salient issue. Trends Neurosci, 2004. 27(12): p. 702–6.PubMedGoogle Scholar
  119. Ungless, M.A., et al., Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature, 2001. 411(6837): p. 583–7.PubMedGoogle Scholar
  120. Wang, T. and E.D. French, Electrophysiological evidence for the existence of NMDA and non-NMDA receptors on rat ventral tegmental dopamine neurons. Synapse, 1993. 13(3): p. 270–7.PubMedGoogle Scholar
  121. Wang, T. and E.D. French, L-glutamate excitation of A10 dopamine neurons is preferentially mediated by activation of NMDA receptors: extra- and intracellular electrophysiological studies in brain slices. Brain Res, 1993. 627(2): p. 299–306.PubMedGoogle Scholar
  122. Weiss, F., et al., Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. J Neurosci, 1996. 16(10): p. 3474–85.PubMedGoogle Scholar
  123. Williams, J.T., M.J. Christie, and O. Manzoni, Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev, 2001. 81(1): p. 299–343.PubMedGoogle Scholar
  124. Wise, R.A., Brain reward circuitry: insights from unsensed incentives. Neuron, 2002. 36(2): p. 229–40.PubMedGoogle Scholar
  125. Wise, R.A., Roles for nigrostriatal-not just mesocorticolimbic-dopamine in reward and addiction. Trends Neurosci, 2009.Google Scholar
  126. Wolf, M.E., Addiction: making the connection between behavioral changes and neuronal plasticity in specific pathways. Mol Interv, 2002. 2(3): p. 146–57.PubMedGoogle Scholar
  127. Wolf, M.E., LTP may trigger addiction. Mol Interv, 2003. 3(5): p. 248–52.PubMedGoogle Scholar
  128. Wolf, M.E., The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol, 1998. 54(6): p. 679–720.PubMedGoogle Scholar
  129. Xi, Z.X. and E.A. Stein, Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors-an in vivo electrochemical study. Brain Res, 1998. 798(1–2): p. 156–65.PubMedGoogle Scholar
  130. Xi, Z.X. and E.A. Stein, GABAergic mechanisms of opiate reinforcement. Alcohol Alcohol, 2002. 37(5): p. 485–94.PubMedGoogle Scholar
  131. Xi, Z.X. and E.A. Stein, Increased mesolimbic GABA concentration blocks heroin self-administration in the rat. J Pharmacol Exp Ther, 2000. 294(2): p. 613–9.PubMedGoogle Scholar
  132. Xi, Z.X. and E.A. Stein, Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release. J Pharmacol Exp Ther, 1999. 290(3): p. 1369–74.PubMedGoogle Scholar
  133. Yasuda, H., Y. Huang, and T. Tsumoto, Regulation of excitability and plasticity by endocannabinoids and PKA in developing hippocampus. Proc Natl Acad Sci U S A, 2008. 105(8): p. 3106–11.Google Scholar
  134. Zweifel, L.S., et al., Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors. Neuron, 2008. 59(3): p. 486–96.PubMedGoogle Scholar
  135. Zhuo, M., et al., Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Nature, 1994. 368(6472): p. 635–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of PharmacologyUniformed Services University of the Health SciencesBethesdaUSA

Personalised recommendations