Skip to main content
SpringerLink
Log in

Recent understanding in the mechanisms of addiction

  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

The rewarding effects of drugs of abuse have been linked to increases in dopamine transmission. However, changes in brain chemistry and morphology that are produced in addiction underlie the long-lasting vulnerability to relapse and are more closely linked with the adaptations in excitatory transmission. The drug-induced changes in excitatory transmission seem to be pathologic exacerbations of normal forms of brain plasticity, and they occur in the brain areas linked by neuroimaging studies in addicted patients to craving and relapse. This review describes the brain adaptations produced in excitatory transmission by addictive drugs and identifies new potential sites of pharmacotherapeutic intervention to ameliorate addiction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. O’Brien C: Drug addiction and drug abuse. In The Pharmacological Basis of Therapeutics. Edited by Hardman J, Limbird L, Gilman AG. New York: McGraw-Hill; 2001:621–642.

    Google Scholar 

  2. Wise RA, Rompre PP: Brain dopamine and reward. Annu Rev Psychol 1989, 40:191–215.

    Article  PubMed  CAS  Google Scholar 

  3. Koob G, LeMoal M: Drug addiction, dysregulation of reward and allostasis. Neuropsychopharmacology 2001, 24:97–129.

    Article  PubMed  CAS  Google Scholar 

  4. Robinson TE, Berridge KC: Addiction. Annu Rev Psychol 2003, 54:25–53.

    Article  PubMed  Google Scholar 

  5. Goldstein RZ, Volkow ND: Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 2002, 159:1642–1652. This review provides an excellent consensus of recent neuroimaging studies in the field of addiction, and endeavors to integrate those data into a model of relapse.

    Article  PubMed  Google Scholar 

  6. Groenewegen HJ, Wright CI, Beijer VJ: The nucleus accumbens: gateway for limbic structures to reach the motor system? Prog Brain Res 1996, 107:485–551.

    Article  PubMed  CAS  Google Scholar 

  7. Garavan H, Pankiewicz J, Bloom A, et al.: Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 2000, 157:1789–1798.

    Article  PubMed  CAS  Google Scholar 

  8. Carroll R, Beattie E, von Zastrow M, Malenka R: Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev Neurosci 2001, 2:315–324.

    Article  CAS  Google Scholar 

  9. Winder DG, Egli RE, Schramm NL, Matthews RT: Synaptic plasticity in drug reward circuitry. Curr Mol Med 2002, 2:667–676.

    Article  PubMed  CAS  Google Scholar 

  10. Wolf ME: The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 1998, 54:679–720.

    Article  PubMed  CAS  Google Scholar 

  11. Park WK, Bari AA, Jey AR, et al.: Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J Neurosci 2002, 22:2916–2925.

    PubMed  CAS  Google Scholar 

  12. Di Ciano P, Everitt BJ: Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology 2001, 25:341–360.

    Article  PubMed  Google Scholar 

  13. Cornish J, Kalivas P: Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 2000, 20:RC89.

    PubMed  CAS  Google Scholar 

  14. McFarland K, Lapish CC, Kalivas PW: Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 2003, 23:3531–3537.

    PubMed  CAS  Google Scholar 

  15. Nestler E: Molecular basis of long-term plasticity underlying addiction. Nature Rev 2001, 2:119–128.

    Article  CAS  Google Scholar 

  16. Kalivas PW, Toda S, Bowers MS, et al.: The temporal sequence of changes in gene expression by drugs of abuse. Methods Mol Med 2003, 79:3–11.

    PubMed  CAS  Google Scholar 

  17. McClung CA, Nestler EJ: Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat Neurosci 2003, 6:1208–1215. This study shows a remarkable parallel between the changes in gene expression produced by withdrawal from cocaine and changes elicited by long-term elevation of transcriptional regulators. This points strongly to a role by CREB and DeltaFosB in the transition from recreational drug use to addiction.

    Article  PubMed  CAS  Google Scholar 

  18. Swanson C, Baker D, Carson D, et al.: Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: A potential role for Homer 1b/c. J Neuroscience 2001, 21:9043–9052.

    CAS  Google Scholar 

  19. Lu L, Grimm JW, Shaham Y, et al.: 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 2003, 85:1604–1613.

    Article  PubMed  CAS  Google Scholar 

  20. Bowers MS, McFarland K, Lake RW, et al.: Activator of G-protein signaling 3: a gatekeeper of cocaine sensitization and drug-seeking. Neuron 2004, 42:269–281.

    Article  PubMed  CAS  Google Scholar 

  21. Jentsch K, Taylor J: Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacol 1999, 146:373–390.

    Article  CAS  Google Scholar 

  22. Berke J, Hyman S: Addiction, dopamine, and the molecular mechanisms of memory. Neuron 2000, 25:515–532.

    Article  PubMed  CAS  Google Scholar 

  23. Trantham H, Szumlinski K, McFarland K, et al.: Repeated cocaine administration alters the electrophysiological properties of prefrontal cortical neurons. Neuroscience 2002, 113:749.

    Article  PubMed  CAS  Google Scholar 

  24. White F, Hu X, Zhang X, Wolf M: Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J Pharmacol Exp Ther 1995, 273:445–454.

    PubMed  CAS  Google Scholar 

  25. Thomas MJ, Beurrier C, Bonci A, Malenka RC: Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nat Neurosci 2001, 4:1217–1223.

    Article  PubMed  CAS  Google Scholar 

  26. Szumlinski KK, Dehoff MH, Kang SH, et al.: Homer proteins regulate sensitivity to cocaine. Neuron 2004, In press.

  27. Toda S, Shen H-W, Cagles SE, Kalivas PW: The importance of LIMK-cofilin-actin cascade to cocaine-induced acute and chronic neuroplasticity. Soc Neurosci Abst 2004, In press.

  28. Yao WD, Gainetdinov RR, Arbuckle MI, et al.: Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 2004, 41:625–638.

    Article  PubMed  CAS  Google Scholar 

  29. Xi ZX, Ramamoorthy S, Baker DA, et al.: Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine. J Pharmacol Exp Ther 2002, 303:608–615.

    Article  PubMed  CAS  Google Scholar 

  30. Baker DA, McFarland K, Lake RW, et al.: Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 2003, 6:743–749. This article identifies a possible role for N-acetylcysteine as a novel treatment for relapse based on animal models.

    Article  PubMed  CAS  Google Scholar 

  31. Robinson TE, Kolb B: Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur J Neurosci 1999, 11:1598–1604.

    Article  PubMed  CAS  Google Scholar 

  32. Robinson TE, Gorny G, Mitton E, Kolb B: Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse 2001, 39:257–266.

    Article  PubMed  CAS  Google Scholar 

  33. McFarland K, Davidge SB, Lapish CC, Kalivas PW: Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci 2004, 24:1551–1560.

    Article  PubMed  CAS  Google Scholar 

  34. Baskys A, Malenka RC: Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus. J Physiol 1991, 444:687–701.

    PubMed  CAS  Google Scholar 

  35. Scannevin RH, Huganir RL: Postsynaptic organization and regulation of excitatory synapses. Nat Rev Neurosci 2000, 1:133–141.

    Article  PubMed  CAS  Google Scholar 

  36. Shih AY, Murphy TH: xCt cystine transporter expression in HEK293 cells: pharmacology and localization. Biochem Biophys Res Commun 2001, 282:1132–1137.

    Article  PubMed  CAS  Google Scholar 

  37. Moran M, Melendez R, Baker D, et al.: Cystine/glutamate antiporter regulation of vesicular glutamate release. Ann NY Acad Sci 2003, 1003:445–447.

    Article  PubMed  Google Scholar 

  38. Baptista MA, Martin-Fardon R, Weiss F: Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement comparison between cocaine and a potent conventional reinforcer. J Neurosci 2004, 24:4723–4727. This article identifies the potential utility of metabotropic glutamate receptor agonists in ameliorating craving and relapse.

    Article  PubMed  CAS  Google Scholar 

  39. Griffith OW: Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 1999, 27:922–935.

    Article  PubMed  CAS  Google Scholar 

  40. Blumer J, Lanier SM: Accessory proteins for G protein-signaling systems: activators of G protein signaling and other nonreceptor proteins influencing the activation state of G proteins. Receptors Channels 2003, 9:195–204.

    Article  PubMed  CAS  Google Scholar 

  41. Xiao B, Tu JC, Worley PF: Homer: a link between neural activity and glutamate receptor function. Curr Opin Neurobiol 2000, 10:370–374.

    Article  PubMed  CAS  Google Scholar 

  42. Ghasemzadeh MB, Permenter LK, Lake R, et al.: Homer1 proteins and AMPA receptors modulate cocaine-induced behavioural plasticity. Eur J Neurosci 2003, 18:1645–1651.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroscience, Medical University of South Carolina, 173 Ashley Avenue, 29464, Charleston, SC, USA

    Peter W. Kalivas PhD

Authors
  1. Peter W. Kalivas PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kalivas, P.W. Recent understanding in the mechanisms of addiction. Curr Psychiatry Rep 6, 347–351 (2004). https://doi.org/10.1007/s11920-004-0021-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-004-0021-0

Keywords

Search

Navigation