Is there a common molecular pathway for addiction?


Drugs of abuse have very different acute mechanisms of action but converge on the brain's reward pathways by producing a series of common functional effects after both acute and chronic administration. Some similar actions occur for natural rewards as well. Researchers are making progress in understanding the molecular and cellular basis of these common effects. A major goal for future research is to determine whether such common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders.

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Figure 1: Highly simplified scheme of converging acute actions of drugs of abuse on the VTA-NAc.
Figure 2: Highly simplified scheme of some common, chronic actions of drugs of abuse on the VTA-NAc.

Ann Thomson


  1. 1

    Koob, G.F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Nestler, E.J. Molecular basis of long-term plasticity underlying addiction. Nat. Rev. Neurosci. 2, 119–128 (2001).

    CAS  Article  Google Scholar 

  3. 3

    Di Chiara, G. et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47 (suppl.) 227–241 (2004).

    CAS  Article  Google Scholar 

  4. 4

    Volkow, N.D., Fowler, J.S., Wang, G.J. & Swanson, J.M. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol. Psychiatry 9, 557–569 (2004).

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

    Boehm, S.L., II et al. gamma-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions. Biochem. Pharmacol. 68, 1581–1602 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Dani, J.A., Ji, D. & Zhou, F.M. Synaptic plasticity and nicotine addiction. Neuron 31, 349–352 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Howlett, A.C. et al. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47 (suppl.) 345–358 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Everitt, B.J. & Wolf, M.E. Psychomotor stimulant addiction: a neural systems perspective. J. Neurosci. 22, 3312–3320 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Robinson, T.E. & Berridge, K.C. Addiction. Annu. Rev. Psychol. 54, 25–53 (2003).

    Article  Google Scholar 

  11. 11

    Hyman, S.E. & Malenka, R.C. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat. Rev. Neurosci. 2, 695–703 (2001).

    CAS  Article  Google Scholar 

  12. 12

    Everitt, B.J., Cardinal, R.N., Parkinson, J.A. & Robbins, T.W. Appetitive behavior: impact of amygdala-dependent mechanisms of emotional learning. Ann. NY Acad. Sci. 985, 233–250 (2003).

    Article  Google Scholar 

  13. 13

    Kalivas, P.W. Glutamate systems in cocaine addiction. Curr. Opin. Pharmacol. 4, 23–29 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Kelley, A.E. & Berridge, K.C. The neuroscience of natural rewards: relevance to addictive drugs. J. Neurosci. 22, 3306–3311 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Tobler, P.N., Fiorillo, C.D. & Schultz, W. Adaptive coding of reward value by dopamine neurons. Science 307, 1642–1645 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Avena, N.M. & Hoebel, B.G. A diet promoting sugar dependency causes behavioral cross-sensitization to a low dose of amphetamine. Neuroscience 122, 17–20 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Heinrichs, S.C. & Koob, G.F. Corticotropin-releasing factor in brain: a role in activation, arousal and affect regulation. J. Pharmacol. Exp. Ther. 311, 427–440 (2004).

    CAS  Article  Google Scholar 

  18. 18

    Kalivas, P.W., Volkow, N. & Seamans, J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45, 647–650 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Saal, D., Dong, Y., Bonci, A. & Malenka, R.C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37, 577–582 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Borgland, S.L., Malenka, R.C. & Bonci, A. Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J. Neurosci. 24, 7482–7490 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Thomas, M.J. & Malenka, R.C. Synaptic plasticity in the mesolimbic dopamine system. Phil. Trans. R. Soc. Lond. B Biol. Sci. 358, 815–819 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Kauer, J.A. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu. Rev. Physiol. 66, 447–475 (2004).

    CAS  Article  Google Scholar 

  23. 23

    Carlezon, W.A., Jr. & Nestler, E.J. Elevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse? Trends Neurosci. 25, 610–615 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Bonci, A. & Williams, J.T. Increased probability of GABA release during withdrawal from morphine. J. Neurosci. 17, 796–803 (1997).

    CAS  Article  Google Scholar 

  25. 25

    Nestler, E.J. Molecular mechanisms of drug addiction. J. Neurosci. 12, 2439–2450 (1992).

    CAS  Article  Google Scholar 

  26. 26

    Lu, L., Grimm, J.W., Shaham, Y. & Hope, B.T. Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats. J. Neurochem. 85, 1604–1613 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Olson, V.G. et al. Regulation of drug reward by CREB: Evidence for two functionally distinct subregions of the ventral tegmental area. J. Neurosci. 25, 5553–5562 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Walters, C.L., Godfrey, M., Li, X. & Blendy, J.A. Alterations in morphine-induced reward, locomotor activity, and thermoregulation in CREB-deficient mice. Brain Res. 1032, 193–199 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Walters, C.L., Cleck, J.N., Kuo, Y.C. & Blendy, J.A. mu-Opioid receptor and CREB activation are required for nicotine reward. Neuron 46, 933–943 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Bolanos, C.A. & Nestler, E.J. Neurotrophic mechanisms in drug addiction. Neuromol. Med. 5, 69–83 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Pierce, R.C. & Bari, A.A. The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity. Rev. Neurosci. 12, 95–110 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Lu, L. et al. A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J. Neurosci. 24, 1604–1611 (2004).

    CAS  Article  Google Scholar 

  33. 33

    Hall, F.S., Drgonova, J., Goeb, M. & Uhl, G.R. Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuropsychopharmacology 28, 1485–1490 (2003).

    CAS  Article  Google Scholar 

  34. 34

    Nestler, E.J., Barrot, M. & Self, D.W. ΔFosB: A molecular switch for addiction. Proc. Natl. Acad. Sci. USA 98, 11042–11046 (2001).

    CAS  Article  Google Scholar 

  35. 35

    McClung, C.A. et al. ΔFosB: A molecular switch for long-term adaptation. Mol. Brain Res. 132, 146–154 (2004).

    CAS  Article  Google Scholar 

  36. 36

    McClung, C.A. & Nestler, E.J. Regulation of gene expression and cocaine reward by CREB and ΔFosB. Nat. Neurosci. 6, 1208–1215 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Shaw-Lutchman, T.Z. et al. Regional and cellular mapping of CRE-mediated transcription during naltrexone-precipitated morphine withdrawal. J. Neurosci. 22, 3663–3672 (2002).

    CAS  Article  Google Scholar 

  38. 38

    Shaw-Lutchman, T.Z., Impey, S., Storm, D. & Nestler, E.J. Regulation of CRE-mediated transcription in mouse brain by amphetamine. Synapse 48, 10–17 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Barrot, M. et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc. Natl. Acad. Sci. USA 99, 11435–11440 (2002).

    CAS  Article  Google Scholar 

  40. 40

    Brunzell, D.H., Russell, D.S. & Picciotto, M.R. In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. J. Neurochem. 84, 1431–1441 (2003).

    CAS  Article  Google Scholar 

  41. 41

    Pandey, S.C., Roy, A., Zhang, H. & Xu, T. Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors. J. Neurosci. 24, 5022–5030 (2004).

    CAS  Article  Google Scholar 

  42. 42

    Constantinescu, A., Wu, M., Asher, O. & Diamond, I. CAMP-dependent protein kinase type I regulates ethanol-induced cAMP response element-mediated gene expression via activation of CREB-binding protein and inhibition of MAPK. J. Biol. Chem. 279, 43321–43329 (2004).

    CAS  Article  Google Scholar 

  43. 43

    Walters, C.L. & Blendy, J.A. Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J. Neurosci. 21, 9438–9444 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Carlezon, W.A., Jr., Duman, R.S. & Nestler, E.J. The many faces of CREB. Trends Neurosci. 28, 436–445 (2005).

    CAS  Article  Google Scholar 

  45. 45

    Self, D.W. et al. Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior. J. Neurosci. 18, 1848–1859 (1998).

    CAS  Article  Google Scholar 

  46. 46

    Kreek, M.J. Drug addictions. Molecular and cellular endpoints. Ann. NY Acad. Sci. 937, 27–49 (2001).

    CAS  Article  Google Scholar 

  47. 47

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

    CAS  Article  Google Scholar 

  48. 48

    Eisch, A.J. Adult neurogenesis: implications for psychiatry. Prog. Brain Res. 138, 315–342 (2002).

    Article  Google Scholar 

  49. 49

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

    CAS  Article  Google Scholar 

  50. 50

    Littleton, J. & Zieglgansberger, W. Pharmacological mechanisms of naltrexone and acamprosate in the prevention of relapse in alcohol dependence. Am. J. Addict. 12 (suppl.) S3–S11 (2003).

    Article  Google Scholar 

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Preparation of this review was supported by the National Institute on Drug Abuse.

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

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