Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Opiate versus psychostimulant addiction: the differences do matter

Abstract

The publication of the psychomotor stimulant theory of addiction in 1987 and the finding that addictive drugs increase dopamine concentrations in the rat mesolimbic system in 1988 have led to a predominance of psychobiological theories that consider addiction to opiates and addiction to psychostimulants as essentially identical phenomena. Indeed, current theories of addiction — hedonic allostasis, incentive sensitization, aberrant learning and frontostriatal dysfunction — all argue for a unitary account of drug addiction. This view is challenged by behavioural, cognitive and neurobiological findings in laboratory animals and humans. Here, we argue that opiate addiction and psychostimulant addiction are behaviourally and neurobiologically distinct and that the differences have important implications for addiction treatment, addiction theories and future research.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dopamine receptor blockade or lesions of the mesolimbic dopamine system decrease cocaine reward but not heroin reward.
Figure 2: Morphine and cocaine have opposite effects on structural neuroplasticity in the NAc and mPFC.
Figure 3: Initiation of drug use and transition to compulsive drug use.
Figure 4: Similarities and differences in the brain sites controlling reinstatement of cocaine seeking and heroin seeking.
Figure 5: Setting differentially affects heroin and cocaine use in rats and humans.

Similar content being viewed by others

References

  1. Eddy, N. B. & Isbell, H. Addiction liability and narcotics control. Public Health Rep. 74, 755–763 (1959).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Collier, H. O. Supersensitivity and dependence. Nature 220, 228–231 (1968).

    Article  CAS  PubMed  Google Scholar 

  3. Collier, H. O. Supersensitivity and dependence on cocaine. Nature 220, 1327–1328 (1968).

    Article  CAS  PubMed  Google Scholar 

  4. Solomon, R. L. & Corbit, J. D. An opponent-process theory of motivation. II. Cigarette addiction. J. Abnorm. Psychol. 81, 158–171 (1973).

    Article  CAS  PubMed  Google Scholar 

  5. Olds, J. & Milner, P. M. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427 (1954).

    Article  CAS  PubMed  Google Scholar 

  6. Wise, R. A. Catecholamine theories of reward: a critical review. Brain Res. 152, 215–247 (1978).

    Article  CAS  PubMed  Google Scholar 

  7. Di Chiara, G. & Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl Acad. Sci. USA 85, 5274–5278 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Stewart, J., de Wit, H. & Eikelboom, R. Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol. Rev. 91, 251–268 (1984).

    Article  CAS  PubMed  Google Scholar 

  9. Robinson, T. E. & Becker, J. B. Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res. 396, 157–198 (1986).

    Article  CAS  PubMed  Google Scholar 

  10. Wise, R. A. & Bozarth, M. A. A psychomotor stimulant theory of addiction. Psychol. Rev. 94, 469–492 (1987).

    Article  CAS  PubMed  Google Scholar 

  11. Robinson, T. E. & Berridge, K. C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Rev. 18, 247–291 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Di Chiara, G. Drug addiction as dopamine-dependent associative learning disorder. Eur. J. Pharmacol. 375, 13–30 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Everitt, B. J. et al. Associative processes in addiction and reward. The role of amygdala–ventral striatal subsystems. Ann. NY Acad. Sci. 877, 412–438 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. White, N. M. Addictive drugs as reinforcers: multiple partial actions on memory systems. Addiction 91, 921–949 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Jentsch, J. D. & Taylor, J. R. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharamacology 146, 373–390 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Volkow, N. D. & Fowler, J. S. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb. Cortex 10, 318–325 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Association, Washington DC, 2000).

  20. Ettenberg, A., Pettit, H. O., Bloom, F. E. & Koob, G. F. Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology 78, 204–209 (1982).

    Article  CAS  PubMed  Google Scholar 

  21. Pettit, H. O., Ettenberg, A., Bloom, F. E. & Koob, G. F. Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration. Psychopharmacology 84, 167–173 (1984).

    Article  CAS  PubMed  Google Scholar 

  22. Bechara, A. Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective. Nature Neurosci. 8, 1458–1463 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Fu, L. P. et al. Impaired response inhibition function in abstinent heroin dependents: an fMRI study. Neurosci. Lett. 438, 322–326 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Fernandez-Serrano, M. J., Perez-Garcia, M., Schmidt Rio-Valle, J. & Verdejo-Garcia, A. Neuropsychological consequences of alcohol and drug abuse on different components of executive functions. J. Psychopharmacol. 24, 1317–1332 (2010).

    Article  PubMed  Google Scholar 

  25. Ornstein, T. J. et al. Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers. Neuropsychopharmacology 23, 113–126 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Muriach, M. et al. Cocaine causes memory and learning impairments in rats: involvement of nuclear factor κB and oxidative stress, and prevention by topiramate. J. Neurochem. 114, 675–684 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Tramullas, M., Martinez-Cue, C. & Hurle, M. A. Chronic administration of heroin to mice produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and memory. Neuropharmacology 54, 640–652 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Fole, A. et al. Effects of chronic cocaine administration on spatial learning and hippocampal spine density in two genetically different strains of rats. Neurobiol. Learn. Mem. 95, 491–497 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. McNamara, R., Dalley, J. W., Robbins, T. W., Everitt, B. J. & Belin, D. Trait-like impulsivity does not predict escalation of heroin self-administration in the rat. Psychopharmacology 212, 453–464 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Dalley, J. W. et al. Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin. Psychopharmacology 182, 579–587 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Dalley, J. W., Everitt, B. J. & Robbins, T. W. Impulsivity, compulsivity, and top-down cognitive control. Neuron 69, 680–694 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. de Wit, H. Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addiction Biol. 14, 22–31 (2009).

    Article  Google Scholar 

  33. Ersche, K. D., Clark, L., London, M., Robbins, T. W. & Sahakian, B. J. Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology 31, 1036–1047 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Ersche, K. D. et al. Abnormal frontal activations related to decision-making in current and former amphetamine and opiate dependent individuals. Psychopharmacology 180, 612–623 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ersche, K. D., Roiser, J. P., Robbins, T. W. & Sahakian, B. J. Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans. Psychopharmacology 197, 421–431 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. London, E. D. et al. Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers. Biol. Psychiatry 58, 770–778 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Lundqvist, T. Cognitive consequences of cannabis use: comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions. Pharmacol. Biochem. Behav. 81, 319–330 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Verdejo-Garcia, A., Perez-Garcia, M., Sanchez-Barrera, M., Rodriguez-Fernandez, A. & Gomez-Rio, M. Neuroimagen y drogodependencias: correlatos neuroanatómicos del consumo de cocaína, opiáceos, cannabis y éxtasis. Rev. Neurol. 44, 432–439 (2007) (in Spanish).

    CAS  PubMed  Google Scholar 

  39. Winstanley, C. A. et al. Increased impulsivity during withdrawal from cocaine self-administration: role for DeltaFosB in the orbitofrontal cortex. Cereb. Cortex 19, 435–444 (2009).

    Article  PubMed  Google Scholar 

  40. Liu, S., Heitz, R. P. & Bradberry, C. W. A touch screen based Stop Signal Response Task in rhesus monkeys for studying impulsivity associated with chronic cocaine self-administration. J. Neurosci. Meth. 177, 67–72 (2009).

    Article  Google Scholar 

  41. Fletcher, P. J., Rizos, Z., Noble, K. & Higgins, G. A. Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5HT(2C) receptor stimulation and 5HT(2A) receptor blockade. Neuropharmacology 61, 468–477 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Harty, S. C., Whaley, J. E., Halperin, J. M. & Ranaldi, R. Impulsive choice, as measured in a delay discounting paradigm, remains stable after chronic heroin administration. Pharmacol. Biochem. Behav. 98, 337–340 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Harris, J. E. & Baldessarini, R. J. Uptake of (3H)-catecholamines by homogenates of rat corpus striatum and cerebral cortex: effects of amphetamine analogues. Neuropharmacology 12, 669–679 (1973).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gysling, K. & Wang, R. Y. Morphine-induced activation of A10 dopamine neurons in the rat. Brain Res. 277, 119–127 (1983).

    Article  CAS  PubMed  Google Scholar 

  47. Johnson, S. W. & North, R. A. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 12, 483–488 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kalivas, P. W. & Volkow, N. D. The neural basis of addiction: a pathology of motivation and choice. Am. J. Psychiatry 162, 1403–1413 (2005).

    Article  PubMed  Google Scholar 

  49. Carelli, R. M., King, V. C., Hampson, R. E. & Deadwyler, S. A. Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Res. 626, 14–22 (1993).

    Article  CAS  PubMed  Google Scholar 

  50. Chang, J. Y., Zhang, L., Janak, P. H. & Woodward, D. J. Neuronal responses in prefrontal cortex and nucleus accumbens during heroin self-administration in freely moving rats. Brain Res. 754, 12–20 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Chang, J. Y., Janak, P. H. & Woodward, D. J. Comparison of mesocorticolimbic neuronal responses during cocaine and heroin self-administration in freely moving rats. J. Neurosci. 18, 3098–3115 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kalivas, P. W. & Stewart, J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res. Rev. 16, 223–244 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  55. Thomas, M. J., Kalivas, P. W. & Shaham, Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br. J. Pharmacol. 154, 327–342 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wolf, M. E., Sun, X., Mangiavacchi, S. & Chao, S. Z. Psychomotor stimulants and neuronal plasticity. Neuropharmacology 47, 61–79 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Girault, J. A., Valjent, E., Caboche, J. & Herve, D. ERK2: a logical AND gate critical for drug-induced plasticity? Curr. Opin. Pharmacol. 7, 77–85 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Bonci, A. & Williams, J. T. A common mechanism mediates long-term changes in synaptic transmission after chronic cocaine and morphine. Neuron 16, 631–639 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Bowers, M. S., Chen, B. T. & Bonci, A. AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future. Neuron 67, 11–24 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Francesconi, W. et al. Protracted withdrawal from alcohol and drugs of abuse impairs long-term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis. J. Neurosci. 29, 5389–5401 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vanderschuren, L. J. & Kalivas, P. W. Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151, 99–120 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Rossetti, Z. L., Hmaidan, Y. & Gessa, G. L. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. Eur. J. Pharmacol. 221, 227–234 (1992).

    Article  CAS  PubMed  Google Scholar 

  64. Dacher, M. & Nugent, F. S. Morphine-induced modulation of LTD at GABAergic synapses in the ventral tegmental area. Neuropharmacology 1 Dec 2010 (doi:10.1016/j.neuropharm.2010.11.012).

    Article  CAS  PubMed  Google Scholar 

  65. Niehaus, J. L., Murali, M. & Kauer, J. A. Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area. Eur. J. Neurosci. 32, 108–117 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Pan, B., Hillard, C. J. & Liu, Q. S. Endocannabinoid signaling mediates cocaine-induced inhibitory synaptic plasticity in midbrain dopamine neurons. J. Neurosci. 28, 1385–1397 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Huang, C. C., Lin, H. J. & Hsu, K. S. Repeated cocaine administration promotes long-term potentiation induction in rat medial prefrontal cortex. Cereb. Cortex 17, 1877–1888 (2007).

    Article  PubMed  Google Scholar 

  68. Lu, H., Cheng, P. L., Lim, B. K., Khoshnevisrad, N. & Poo, M. M. Elevated BDNF after cocaine withdrawal facilitates LTP in medial prefrontal cortex by suppressing GABA inhibition. Neuron 67, 821–833 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Van den Oever, M. C. et al. Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking. Nature Neurosci. 11, 1053–1058 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Robinson, T. E. & Kolb, B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J. Neurosci. 17, 8491–8497 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  72. Russo, S. J. et al. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 33, 267–276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gerfen, C. R. The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci. 15, 133–139 (1992).

    Article  CAS  PubMed  Google Scholar 

  74. Badiani, A. et al. Environmental modulation of amphetamine-induced cfos expression in D1 versus D2 striatal neurons. Behav. Brain Res. 103, 203–209 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Ferguson, S. M. & Robinson, T. E. Amphetamine-evoked gene expression in striatopallidal neurons: regulation by corticostriatal afferents and the ERK/MAPK signaling cascade. J. Neurochem. 91, 337–348 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Uslaner, J. et al. Amphetamine and cocaine induce different patterns of cfos mRNA expression in the striatum and subthalamic nucleus depending on environmental context. Eur. J. Neurosci. 13, 1977–1983 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Hope, B. T. et al. Induction of a long-lasting AP1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Maze, I. et al. Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327, 213–216 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lee, K. W. et al. Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens. Proc. Natl Acad. Sci. USA 103, 3399–3404 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Albertson, D. N., Schmidt, C. J., Kapatos, G. & Bannon, M. J. Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology 31, 2304–2312 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Warner, L. A., Kessler, R. C., Hughes, M., Anthony, J. C. & Nelson, C. B. Prevalence and correlates of drug use and dependence in the United States. Results from the National Comorbidity Survey. Arch. Gen. Psychiatry 52, 219–229 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Glantz, M. D. & Pickens, R. W. Vulnerability to Drug Abuse (American Psychological Association, Washington DC, 1992).

    Book  Google Scholar 

  83. Tsuang, M. T. et al. Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch. Gen. Psychiatry 55, 967–972 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Caprioli, D., Celentano, M., Paolone, G. & Badiani, A. Modeling the role of environment in addiction. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1639–1653 (2007).

    Article  PubMed  Google Scholar 

  85. Harding, W. M. & Zinberg, N. E. Controlling intoxicant use. J. Psychoactive Drugs 16, 101–106 (1984).

    Article  CAS  PubMed  Google Scholar 

  86. Robins, L. N., Davis, D. H. & Goodwin, D. W. Drug use by U. S. Army enlisted men in Vietnam: a follow-up on their return home. Am. J. Epidemiol. 99, 235–249 (1974).

    Article  CAS  PubMed  Google Scholar 

  87. Brady, J. V. Animal models for assessing drugs of abuse. Neurosci. Biobehav. Rev. 15, 35–43 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Schuster, C. R. & Thompson, T. Self administration of and behavioral dependence on drugs. Annu. Rev. Pharmacol. 9, 483–502 (1969).

    Article  CAS  PubMed  Google Scholar 

  89. Thomsen, M. & Caine, S. B. Intravenous drug self-administration in mice: practical considerations. Behav. Genet. 37, 101–118 (2007).

    Article  PubMed  Google Scholar 

  90. Carroll, M. E. & Meisch, M. E. in Advances in Behavioral Pharmacology (eds Thompson, T., Dews, P. B. & Barrett, J. E.) 47–88 (Academic Press, New York, 1984).

    Google Scholar 

  91. Lu, L., Shepard, J. D., Scott Hall, F. & Shaham, Y. Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci. Biobehav. Rev. 27, 457–491 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Piazza, P. V. & Le Moal, M. The role of stress in drug self-administration. Trends Pharmacol. Sci. 19, 67–74 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Lett, B. T. Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology 98, 357–362 (1989).

    Article  CAS  PubMed  Google Scholar 

  94. Shippenberg, T. S. & Elmer, G. I. The neurobiology of opiate reinforcement. Crit. Rev. Neurobiol. 12, 267–303 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Vezina, P. Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychostimulant drugs. Neurosci. Biobehav. Rev. 27, 827–839 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Carroll, M. E., Morgan, A. D., Lynch, W. J., Campbell, U. C. & Dess, N. K. Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology 161, 304–313 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Wills, T. A., Vaccaro, D. & McNamara, G. Novelty seeking, risk taking, and related constructs as predictors of adolescent substance use: an application of Cloninger's theory. J. Subst. Abuse 6, 1–20 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Piazza, P. V. & Le Moal, M. Pathophysiological basis of vulnerability to drug abuse: interaction between stress, glucocorticoids, and dopaminergic neurons. Ann. Rev. Pharmacol. Toxicol. 36, 359–378 (1996).

    Article  CAS  Google Scholar 

  99. Marinelli, M. & Piazza, P. V. Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur. J. Neurosci. 16, 387–394 (2002).

    Article  PubMed  Google Scholar 

  100. Marinelli, M., Aouizerat, B., Barrot, M., Le Moal, M. & Piazza, P. V. Dopamine-dependent responses to morphine depend on glucocorticoid receptors. Proc. Natl Acad. Sci. USA 95, 7742–7747 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ambroggi, F. et al. Stress and addiction: glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking. Nature Neurosci. 12, 247–249 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Ettenberg, A. Opponent process properties of self-administered cocaine. Neurosci. Biobehav. Rev. 27, 721–728 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Ettenberg, A. & Geist, T. D. Qualitative and quantitative differences in the operant runway behavior of rats working for cocaine and heroin reinforcement. Pharmacol. Biochem. Behav. 44, 191–198 (1993).

    Article  CAS  PubMed  Google Scholar 

  104. Ettenberg, A., Raven, M. A., Danluck, D. A. & Necessary, B. D. Evidence for opponent-process actions of intravenous cocaine. Pharmacol. Biochem. Behav. 64, 507–512 (1999).

    Article  CAS  PubMed  Google Scholar 

  105. Geist, T. D. & Ettenberg, A. Concurrent positive and negative goalbox events produce runway behaviors comparable to those of cocaine-reinforced rats. Pharmacol. Biochem. Behav. 57, 145–150 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Knackstedt, L. A., Samimi, M. M. & Ettenberg, A. Evidence for opponent-process actions of intravenous cocaine and cocaethylene. Pharmacol. Biochem. Behav. 72, 931–936 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Anthony, J. C., Tien, A. Y. & Petronis, K. R. Epidemiologic evidence on cocaine use and panic attacks. Am. J. Epidemiol. 129, 543–549 (1989).

    Article  CAS  PubMed  Google Scholar 

  108. Geracioti, T. D., Jr & Post, R. M. Onset of panic disorder associated with rare use of cocaine. Biol. Psychiatry 29, 403–406 (1991).

    Article  PubMed  Google Scholar 

  109. Breiter, H. C. et al. Acute effects of cocaine on human brain activity and emotion. Neuron 19, 591–611 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Becker, J. B. & Hu, M. Sex differences in drug abuse. Frontiers Neuroendocrinol. 29, 36–47 (2008).

    Article  CAS  Google Scholar 

  111. Roth, M. E., Cosgrove, K. P. & Carroll, M. E. Sex differences in the vulnerability to drug abuse: a review of preclinical studies. Neurosci. Biobehav. Rev. 28, 533–546 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Lynch, W. J. & Carroll, M. E. Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144, 77–82 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Stewart, J., Woodside, B. C. & Shaham, Y. Changes in ovarian hormones do not affect the initiation of intravenous self-administration of heroin in the female rat. Psychobiology 24, 154–159 (1996).

    CAS  Google Scholar 

  114. Stewart, J. & Rodaros, D. The effects of gonadal hormones on the development and expression of the stimulant effects of morphine in male and female rats. Behav. Brain Res. 102, 89–98 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Ahmed, S. H. Escalation of drug use. Neuromethods 53, 267–292 (2011).

    Article  CAS  Google Scholar 

  116. Ahmed, S. H. & Koob, G. F. Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function. Psychopharmacology 180, 473–490 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Bozarth, M. A. & Wise, R. A. Toxicity associated with long-term intravenous heroin and cocaine self- administration in the rat. J. Am. Med. Assoc. 254, 81–83 (1985).

    Article  CAS  Google Scholar 

  118. Pickens, R. & Harris, W. C. Self-administration of damphetamine by rats. Psychopharmacologia 12, 158–163 (1968).

    Article  CAS  PubMed  Google Scholar 

  119. Covington, H. E., 3rd & Miczek, K. A. Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology 158, 388–398 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Belin, D., Economidou, D., Pelloux, Y. & Everitt, B. J. Habit formation and compulsion. Neuromethods 53, 337–378 (2011).

    Article  CAS  Google Scholar 

  121. Wolffgramm, J. & Heyne, A. From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat. Behav. Brain Res. 70, 77–94 (1995).

    Article  CAS  PubMed  Google Scholar 

  122. Deroche-Gamonet, V., Belin, D. & Piazza, P. V. Evidence for addiction-like behavior in the rat. Science 305, 1014–1017 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Pelloux, Y., Everitt, B. J. & Dickinson, A. Compulsive drug seeking by rats under punishment: effects of drug taking history. Psychopharmacology 194, 127–137 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Cooper, A., Barnea-Ygael, N., Levy, D., Shaham, Y. & Zangen, A. A conflict rat model of cue-induced relapse to cocaine seeking. Psychopharmacology 194, 117–125 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Vanderschuren, L. J. & Everitt, B. J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Heyne, A. & Wolffgramm, J. The development of addiction to damphetamine in an animal model: same principles as for alcohol and opiate. Psychopharmacology 140, 510–518 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Lenoir, M., Guillem, K., Koob, G. F. & Ahmed, S. H. Drug specificity in extended access cocaine and heroin self-administration. Addiction Biol. (in the press).

  128. Weeks, J. R. & Collins, J. Patterns of intravenous self-injection by morphine-addicted rats. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 46, 288–298 (1968).

    CAS  PubMed  Google Scholar 

  129. Miczek, K. A., Yap, J. J. & Covington, H. E. Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol. Ther. 120, 102–128 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Covington, H. E., 3rd, Tropea, T. F., Rajadhyaksha, A. M., Kosofsky, B. E. & Miczek, K. A. NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking. Psychopharmacology 197, 203–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Westerink, B. H., Kwint, H. F. & deVries, J. B. The pharmacology of mesolimbic dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and nucleus accumbens of the rat brain. J. Neurosci. 16, 2605–2611 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cruz, F. C., Quadros, I. M., Hogenelst, K., Planeta, C. S. & Miczek, K. A. Social defeat stress in rats: escalation of cocaine and “speedball” binge self-administration, but not heroin. Psychopharmacology 215, 165–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Dalley, J. W. et al. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315, 1267–1270 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. de Wit, H. Priming effects with drugs and other reinforcers. Exp. Clin. Psychopharmacol. 4, 5–10 (1996).

    Article  CAS  Google Scholar 

  135. Childress, A. R. et al. Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res. Monogr. 137, 73–95 (1993).

    CAS  PubMed  Google Scholar 

  136. Sinha, R. How does stress increase risk of drug abuse and relapse. Psychopharmacology 158, 343–359 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Heilig, M. et al. Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues. Neurosci. Biobehav. Rev. 35, 334–344 (2010).

    Article  PubMed  Google Scholar 

  138. de Wit, H. & Stewart, J. Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75, 134–143 (1981).

    Article  CAS  PubMed  Google Scholar 

  139. Meil, W. M. & See, R. E. Conditioned cued recovery of responding following prolonged withdrawal from self-administered cocaine in rats: an animal model of relapse. Behav. Pharmacol. 7, 754–763 (1996).

    CAS  PubMed  Google Scholar 

  140. Shaham, Y. & Stewart, J. Stress reinstates heroin self-administration behavior in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology 119, 334–341 (1995).

    Article  CAS  PubMed  Google Scholar 

  141. Everitt, B. J. & Robbins, T. W. Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology 153, 17–30 (2000).

    Article  CAS  PubMed  Google Scholar 

  142. Shalev, U., Grimm, J. W. & Shaham, Y. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol. Rev. 54, 1–42 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Pickens, C. L. et al. Neurobiology of incubation of drug craving. Trends Neurosci. 34, 411–420 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Bedi, G. et al. Incubation of cue-induced cigarette craving during abstinence in human smokers. Biol. Psychiatry 69, 708–711 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Shaham, Y., Erb, S. & Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res. Brain Res. Rev. 33, 13–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Crombag, H., Bossert, J. M., Koya, E. & Shaham, Y. Context-induced relapse to drug seeking: a review. Trans. R. Soc. Lond. B 363, 3233–3243 (2008).

    Article  Google Scholar 

  147. Feltenstein, M. W. & See, R. E. The neurocircuitry of addiction: an overview. Br. J. Pharmacol. 154, 261–274 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Weiss, F. Neurobiology of craving, conditioned reward and relapse. Curr. Opin. Pharmacol. 5, 9–19 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Schindler, C. W., Panlilio, L. V. & Goldberg, S. R. Second-order schedules of drug self-administration in animals. Psychopharmacology 163, 327–344 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Grimm, J. W., Hope, B. T., Wise, R. A. & Shaham, Y. Incubation of cocaine craving after withdrawal. Nature 412, 141–142 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Shalev, U., Morales, M., Hope, B., Yap, J. & Shaham, Y. Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology 156, 98–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Shepard, J. D., Bossert, J. M., Liu, S. Y. & Shaham, Y. The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol. Psychiatry 55, 1082–1089 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Schmidt, H. D., Anderson, S. M., Famous, K. R., Kumaresan, V. & Pierce, R. C. Anatomy and pharmacology of cocaine priming-induced reinstatement of drug seeking. Eur. J. Pharmacol. 526, 65–76 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Bossert, J. M., Wihbey, K. A., Pickens, C. L., Nair, S. G. & Shaham, Y. Role of dopamine D1-family receptors in dorsolateral striatum in context-induced reinstatement of heroin seeking in rats. Psychopharmacology 206, 51–60 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Fuchs, R. A., Branham, R. K. & See, R. E. Different neural substrates mediate cocaine seeking after abstinence versus extinction training: a critical role for the dorsolateral caudate-putamen. J. Neurosci. 26, 3584–3588 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Vanderschuren, L. J., Di Ciano, P. & Everitt, B. J. Involvement of the dorsal striatum in cue-controlled cocaine seeking. J. Neurosci. 25, 8665–8870 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. LaLumiere, R. T. & Kalivas, P. W. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J. Neurosci. 28, 3170–3177 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. McFarland, K. & Kalivas, P. W. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 21, 8655–8663 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Shaham, Y., Highfield, D., Delfs, J. M., Leung, S. & Stewart, J. Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of the locus coeruleus noradrenergic neurons. Eur. J. Neurosci. 12, 292–302 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Shalev, U., Erb, S. & Shaham, Y. Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking. Brain Res. 1314, 15–28 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Rogers, J. L., Ghee, S. & See, R. E. The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151, 579–588 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Alderson, H. L., Robbins, T. W. & Everitt, B. J. The effects of excitotoxic lesions of the basolateral amygdala on the acquisition of heroin-seeking behaviour in rats. Psychopharmacology 153, 111–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  164. Whitelaw, R. B., Markou, A., Robbins, T. W. & Everitt, B. J. Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology 127, 213–224 (1996).

    Article  CAS  PubMed  Google Scholar 

  165. Fuchs, R. A. & See, R. E. Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology 160, 425–433 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. McLaughlin, J. & See, R. E. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology 168, 57–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  167. Fuchs, R. A. et al. The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats. Neuropsychopharmacology 30, 296–309 (2005).

    Article  CAS  PubMed  Google Scholar 

  168. Bossert, J. M. et al. Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Nature Neurosci. 14, 420–422 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Fuchs, R. A., Ramirez, D. R. & Bell, G. H. Nucleus accumbens shell and core involvement in drug context-induced reinstatement of cocaine seeking in rats. Psychopharmacology 200, 545–556 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Bossert, J. M., Poles, G. C., Sheffler-Collins, S. I. & Ghitza, U. E. The mGluR2/3 agonist LY379268 attenuates context- and discrete cue-induced reinstatement of sucrose seeking but not sucrose self-administration in rats. Behav. Brain Res. 173, 148–152 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Bossert, J. M., Poles, G. C., Wihbey, K. A., Koya, E. & Shaham, Y. Differential effects of blockade of dopamine D1-family receptors in nucleus accumbens core or shell on reinstatement of heroin seeking induced by contextual and discrete cues. J. Neurosci. 27, 12655–12663 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Bossert, J. M., Ghitza, U. E., Lu, L., Epstein, D. H. & Shaham, Y. Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur. J. Pharmacol. 526, 36–50 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Peters, J., LaLumiere, R. T. & Kalivas, P. W. Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J. Neurosci. 28, 6046–6053 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Peters, J., Kalivas, P. W. & Quirk, G. J. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn. Mem. 16, 279–288 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Lu, L. et al. Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving. Biol. Psychiatry 66, 137–145 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Airavaara, M. et al. Endogenous GDNF in ventral tegmental area and nucleus accumbens does not play a role in the incubation of heroin craving. Addiction Biol. 16, 261–272 (2011).

    Article  CAS  Google Scholar 

  177. Ettenberg, A. The runway model of drug self-administration. Pharmacol. Biochem. Behav. 91, 271–277 (2009).

    Article  CAS  PubMed  Google Scholar 

  178. Wikler, A. Dynamics of drug dependence, implication of a conditioning theory for research and treatment. Arch. Gen. Psychiatry 28, 611–616 (1973).

    Article  CAS  PubMed  Google Scholar 

  179. Cain, M. E., Smith, C. M. & Bardo, M. T. The effect of novelty on amphetamine self-administration in rats classified as high and low responders. Psychopharmacology 176, 129–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  180. Klebaur, J. E., Phillips, S. B., Kelly, T. H. & Bardo, M. T. Exposure to novel environmental stimuli decreases amphetamine self-administration in rats. Exp. Clin. Psychopharmacol. 9, 372–379 (2001).

    Article  CAS  PubMed  Google Scholar 

  181. Cornish, J. L. et al. Heat increases 3,4-methylenedioxymethamphetamine self-administration and social effects in rats. Eur. J. Pharmacol. 482, 339–341 (2003).

    Article  CAS  PubMed  Google Scholar 

  182. Caprioli, D. et al. Opposite environmental regulation of heroin and amphetamine self-administration in the rat. Psychopharmacology 198, 395–404 (2008).

    Article  CAS  PubMed  Google Scholar 

  183. Caprioli, D. et al. Environmental modulation of cocaine self-administration in the rat. Psychopharmacology 192, 397–406 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. Caprioli, D. et al. Ambience and drug choice: cocaine- and heroin-taking as a function of environmental context in humans and rats. Biol. Psychiatry 65, 893–899 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Montanari, C. L., De Luca, M. T., Meringolo, M., Contu, L. & Badiani, A. Environmental modulation of drug-induced reinstatement of cocaine versus heroin drug seeking in rats trained to self-administer both drugs. Behav. Pharmacol. 22 (e-suppl. A), e21 (2011).

    Google Scholar 

  186. Stolerman, I. Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol. Sci. 13, 170–176 (1992).

    Article  CAS  PubMed  Google Scholar 

  187. Paolone, G., Palopoli, M., Marrone, M. C., Nencini, P. & Badiani, A. Environmental modulation of the interoceptive effects of amphetamine in the rat. Behav. Brain Res. 152, 149–155 (2004).

    CAS  PubMed  Google Scholar 

  188. Celentano, M. et al. Drug context differently regulates cocaine versus heroin self-administration and cocaine- versus heroin-induced Fos mRNA expression in the rat. Psychopharmacology 204, 349–360 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. De Luca, M. T. & Badiani, A. Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology 214, 549–556 (2011).

    Article  CAS  PubMed  Google Scholar 

  190. Testa, A., Nencini, P. & Badiani, A. The role of setting in the oral self-administration of alcohol in the rat. Psychopharmacology 215, 749–760 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Badiani, A. & Robinson, T. E. Drug-induced neurobehavioral plasticity: the role of environmental context. Behav. Pharmacol. 15, 327–339 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. Paolone, G. et al. Modulatory effect of environmental context and drug history on heroin-induced psychomotor activity and fos protein expression in the rat brain. Neuropsychopharmacology 32, 2611–2623 (2007).

    Article  CAS  PubMed  Google Scholar 

  193. Lenoir, M. & Ahmed, S. H. Heroin-induced reinstatement is specific to compulsive heroin use and dissociable from heroin reward and sensitization. Neuropsychopharmacology 32, 616–624 (2007).

    Article  CAS  PubMed  Google Scholar 

  194. Ahmed, S. H. & Cador, M. Dissociation of psychomotor sensitization from compulsive cocaine consumption. Neuropsychopharmacology 31, 563–571 (2006).

    Article  CAS  PubMed  Google Scholar 

  195. Nutt, D. J., King, L. A. & Phillips, L. D. Drug harms in the UK: a multicriteria decision analysis. Lancet 376, 1558–1565 (2010).

    Article  PubMed  Google Scholar 

  196. Anthony, J. C., Warner, L. A. & Kessler, R. C. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Drug Alcohol Depend. 2, 244–268 (1994).

    Google Scholar 

  197. Hubbard, R. L. & Marsden, M. E. in NIDA Research Monograph 72: Relapse and Recovery in Drug Abuse (eds Tims, F. M. & Leukefeld, C. G.) 157–166 (Department of Health and Human Services, Rockville, Maryland, 1986).

    Google Scholar 

  198. Dutra, L. et al. A meta-analytic review of psychosocial interventions for substance use disorders. Am. J. Psychiatry 165, 179–187 (2008).

    Article  PubMed  Google Scholar 

  199. Higgins, S. T., Heil, S. H. & Lussier, J. P. Clinical implications of reinforcement as a determinant of substance use disorders. Annu. Rev. Psychol. 55, 431–461 (2004).

    Article  PubMed  Google Scholar 

  200. Khantzian, E. J. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am. J. Psychiatry 142, 1259–1264 (1985).

    Article  CAS  PubMed  Google Scholar 

  201. Craig, R. J. & Olson, R. E. MCMI comparisons of cocaine abusers and heroin addicts. J. Clin. Psychol. 46, 230–237 (1990).

    Article  CAS  PubMed  Google Scholar 

  202. O'Connor, L. & Berry, J. W. The drugofchoice phenomenon: why addicts start using their preferred drug. J. Psychoactive Drugs 22, 305–311 (1990).

    Article  CAS  PubMed  Google Scholar 

  203. Suh, J. J., Robins, C. E., Ruffins, S., Albanese, M. J. & Khantzian, E. J. Self-medication hypothesis: connecting affective experience and drug choice. Psychoanal. Psychol. 25, 518–532 (2008).

    Article  Google Scholar 

  204. Tarter, R. E. & Mezzich, A. C. in Vulnerability to Drug Abuse (eds Glantz, M. & Pickens, R.) 149–178 (American Psychological Association, Washington DC, 1992).

    Book  Google Scholar 

  205. Kendler, K. S., Jacobson, K. C., Prescott, C. A. & Neale, M. C. Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am. J. Psychiatry 160, 687–695 (2003).

    Article  PubMed  Google Scholar 

  206. Yuferov, V., Levran, O., Proudnikov, D., Nielsen, D. A. & Kreek, M. J. Search for genetic markers and functional variants involved in the development of opiate and cocaine addiction and treatment. Ann. NY Acad. Sci. 1187, 184–207 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Spagnolo, P. A., Celentano, M., Dubla, A. & Badiani, A. Setting preferences for heroin versus cocaine taking in human co-abusers: role of environmental variables in drug use and relapse. Behav. Pharmacol. 22 (e-suppl. A), e21 (2011).

    Google Scholar 

  208. Epstein, D. H. et al. Real-time electronic diary reports of cue exposure and mood in the hours before cocaine and heroin craving and use. Arch. Gen. Psychiatry 66, 88–94 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Heather, N., Stallard, A. & Tebbutt, J. Importance of substance cues in relapse among heroin users: comparison of two methods of investigation. Addictive Behav. 16, 41–49 (1991).

    Article  CAS  Google Scholar 

  210. Marlatt, G. A. & Gordon, J. R. E. Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors (Guilford, New York, 1985).

    Google Scholar 

  211. Dole, V. P., Nyswander, M. E. & Kreek, M. J. Narcotic blockade. Arch. Intern. Med. 118, 304–309 (1966).

    Article  CAS  PubMed  Google Scholar 

  212. Shearer, J. The principles of agonist pharmacotherapy for psychostimulant dependence. Drug Alcohol Rev. 27, 301–308 (2008).

    Article  PubMed  Google Scholar 

  213. Mello, N. K. & Negus, S. S. Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14, 375–424 (1996).

    Article  CAS  PubMed  Google Scholar 

  214. Nielsen, D. A. et al. Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction. Psychiatr. Genet. 20, 207–214 (2010).

    Article  PubMed  Google Scholar 

  215. Compton, P. A., Ling, W., Charuvastra, V. C. & Wesson, D. R. Buprenorphine as a pharmacotherapy for cocaine abuse: a review of the evidence. J. Addictive Dis. 14, 97–114 (1995).

    Article  CAS  Google Scholar 

  216. Schottenfeld, R. S., Pakes, J. R., Oliveto, A., Ziedonis, D. & Kosten, T. R. Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch. Gen. Psychiatry 54, 713–720 (1997).

    Article  CAS  PubMed  Google Scholar 

  217. Epstein, D. H. et al. Promoting abstinence from cocaine and heroin with a methadone dose increase and a novel contingency. Drug Alcohol Depend. 101, 92–100 (2009).

    Article  PubMed  Google Scholar 

  218. Kosten, T. R., Rounsaville, B. J. & Kleber, H. D. A 2.5-year follow-up of cocaine use among treated opioid addicts. Have our treatments helped? Arch. Gen. Psychiatry 44, 281–284 (1987).

    Article  CAS  PubMed  Google Scholar 

  219. Montoya, I. D. et al. Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence. Clin. Pharmacol. Ther. 75, 34–48 (2004).

    Article  CAS  PubMed  Google Scholar 

  220. Wolf, M. E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog. Neurobiol. 54, 679–720 (1998).

    Article  CAS  PubMed  Google Scholar 

  221. Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neuronal mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006).

    Article  CAS  PubMed  Google Scholar 

  222. Kalivas, P. W. The glutamate homeostasis hypothesis of addiction. Nature Rev. Neurosci. 10, 561–572 (2009).

    Article  CAS  Google Scholar 

  223. Laviolette, S. R. & van der Kooy, D. Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol. Psychiatry 8, 50–59 (2003).

    Article  CAS  PubMed  Google Scholar 

  224. Laviolette, S. R. & van der Kooy, D. The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nature Rev. Neurosci. 5, 55–65 (2004).

    Article  CAS  Google Scholar 

  225. Rassnick, S., Stinus, L. & Koob, G. F. The effects of 6hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat. Brain Res. 623, 16–24 (1993).

    Article  CAS  PubMed  Google Scholar 

  226. Amit, Z. & Brown, Z. W. Actions of drugs of abuse on brain reward systems: a reconsideration with specific attention to alcohol. Pharmacol. Biochem. Behav. 17, 233–238 (1982).

    Article  CAS  PubMed  Google Scholar 

  227. Belin, D., Jonkman, S., Dickinson, A., Robbins, T. W. & Everitt, B. J. Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav. Brain Res. 199, 89–102 (2009).

    Article  PubMed  Google Scholar 

  228. Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neurosci. 8, 1481–1489 (2005).

    Article  CAS  PubMed  Google Scholar 

  229. Glickman, S. E. & Schiff, B. B. A biological theory of reinforcement. Psychol. Rev. 74, 81–109 (1967).

    Article  CAS  PubMed  Google Scholar 

  230. Beach, H. D. Morphine addiction in rats. Can. J. Psychol. 11, 104–112 (1957).

    Article  CAS  PubMed  Google Scholar 

  231. Weeks, J. R. Experimental morphine addiction: method for automatic intravenous injections in unrestrained rats. Science 143, 143–144 (1962).

    Article  Google Scholar 

  232. Stretch, R. & Gerber, G. J. Drug-induced reinstatement of amphetamine self-administration behaviour in monkeys. Can. J. Psychol. 27, 168–177 (1973).

    Article  CAS  PubMed  Google Scholar 

  233. Colpaert, F. C., Lal, H., Niemegeers, C. J. & Janssen, P. A. Investigations on drug produced and subjectively experienced discriminative stimuli. I. The fentanyl cue, a tool to investigate subjectively experience narcotic drug actions. Life Sci. 16, 705–715 (1975).

    Article  CAS  PubMed  Google Scholar 

  234. Wise, R. A. & Rompre, P. P. Brain dopamine and reward. Annu. Rev. Psychol. 40, 191–225 (1989).

    Article  CAS  PubMed  Google Scholar 

  235. Pierce, R. C. & Kumaresan, V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci. Biobehav. Rev. 30, 215–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  236. Tzschentke, T. M. Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog. Neurobiol. 56, 613–672 (1998).

    Article  CAS  PubMed  Google Scholar 

  237. Roberts, D. C., Koob, G. F., Klonoff, P. & Fibiger, H. C. Extinction and recovery of cocaine self-administration following 6hydroxydopamine lesions of the nucleus accumbens. Pharmacol. Biochem. Behav. 12, 781–787 (1980).

    Article  CAS  PubMed  Google Scholar 

  238. Wise, R. A., Leone, P., Rivest, R. & Leeb, K. Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration. Synapse 21, 140–148 (1995).

    Article  CAS  PubMed  Google Scholar 

  239. Bozarth, M. A. & Wise, R. A. Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sci. 28, 551–555 (1981).

    Article  CAS  PubMed  Google Scholar 

  240. Phillips, A. G. & LePiane, F. G. Reinforcing effects of morphine microinjection into the ventral tegmental area. Pharmacol. Biochem. Behav. 12, 965–968 (1980).

    Article  CAS  PubMed  Google Scholar 

  241. Olds, M. E. Reinforcing effects of morhpine in the nucleus accumbens. Brain Res. 237, 429–440 (1982).

    Article  CAS  PubMed  Google Scholar 

  242. van der Kooy, D., Mucha, R. F., O'Shaughnessy, M. & Bucenieks, P. Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference. Brain Res. 243, 107–117 (1982).

    Article  CAS  PubMed  Google Scholar 

  243. McBride, W. J., Murphy, J. M. & Ikemoto, S. Localization of brain reinforcement mechanisms: intracranial self- administration and intracranial place-conditioning studies. Behav. Brain Res. 101, 129–152 (1999).

    Article  CAS  PubMed  Google Scholar 

  244. Shippenberg, T. S., Bals-Kubik, R. & Herz, A. Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D1 vs. D2 dopamine receptors. J. Pharmacol. Exp. Ther. 265, 53–59 (1993).

    CAS  PubMed  Google Scholar 

  245. Bechara, A., Nader, K. & van der Kooy, D. A twoseparatemotivational-systems hypothesis of opioid addiction. Pharmacol. Biochem. Behav. 59, 1–17 (1998).

    Article  CAS  PubMed  Google Scholar 

  246. Sellings, L. H. & Clarke, P. B. Segregation of amphetamine reward and locomotor stimulation between nucleus accumbens medial shell and core. J. Neurosci. 23, 6295–6303 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Olmstead, M. C. & Franklin, K. B. The development of a conditioned place preference to morphine: effects of lesions of various CNS sites. Behav. Neurosci. 111, 1313–1323 (1997).

    Article  CAS  PubMed  Google Scholar 

  248. Mackey, W. B. & van der Kooy, D. Neuroleptics block the positive reinforcing effects of amphetamine but not of morphine as measured by place conditioning. Pharmacol. Biochem. Behav. 22, 101–105 (1985).

    Article  CAS  PubMed  Google Scholar 

  249. Nader, K., Bechara, A., Roberts, D. C. & van der Kooy, D. Neuroleptics block high- but not low-dose heroin place preferences: further evidence for a two-system model of motivation. Behav. Neurosci. 108, 1128–1138 (1994).

    Article  CAS  PubMed  Google Scholar 

  250. Van Ree, J. M. & Ramsey, N. The dopamine hypothesis of opiate reward challenged. Eur. J. Pharmacol. 134, 239–243 (1987).

    Article  CAS  PubMed  Google Scholar 

  251. Winger, G. Dopamine antagonist effects on behavior maintained by cocaine and alfentanil in rhesus monkeys. Behav. Pharmacol. 5, 141–152 (1994).

    Article  CAS  PubMed  Google Scholar 

  252. Gerrits, M. A. F. M., Ramsey, N. F., Wolterink, G. & Van Ree, J. M. Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration. Psychopharmacology 114, 486–494 (1994).

    Article  CAS  PubMed  Google Scholar 

  253. Gerrits, M. A. & Van Ree, J. M. Effect of nucleus accumbens dopamine depletion on motivational aspects involved in initiation of cocaine and heroin self-administration in rats. Brain Res. 713, 114–124 (1996).

    Article  CAS  PubMed  Google Scholar 

  254. Dworkin, S. I., Guerin, G. F., Co, C., Goeders, N. E. & Smith, J. E. Lack of an effect of 6hydroxydopamine lesions of the nucleus accumbens on intravenous morphine self-administration. Pharmacol. Biochem. Behav. 30, 1051–1057 (1988).

    Article  CAS  PubMed  Google Scholar 

  255. Stinus, L. et al. Chronic flupenthixol treatment potentiates the reinforcing properties of systemic heroin administration. Biol. Psychiatry 26, 363–371 (1989).

    Article  CAS  PubMed  Google Scholar 

  256. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Elsevier Academic Press, Amsterdam, 2005).

    Google Scholar 

Download references

Acknowledgements

This Perspective was written with financial support from the Ricerche di Università Program of the Sapienza University of Rome, Italy (A.B.), the Institut National de la Santé et de la Recherche Médicale (INSERM) (D.B.) and the Intramural Research Program of the US National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) (D.C., D.E. and Y.S.). We thank R. See for sharing with us unpublished data that are included in the summary diagram in Fig. 4, A. Ettenberg for sharing historical data with us, and M. Heilig and E. Koya for very helpful comments.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Aldo Badiani or Yavin Shaham.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Summary of the main differences between opiates and psychostimulants (PDF 384 kb)

Related links

Related links

FURTHER INFORMATION

Yavin Shaham's homepage

Glossary

AMPA:NMDA ratio

A measure of postsynaptic changes in synaptic strength. It is defined as the peak synaptic AMPA receptor current relative to the peak synaptic NMDA receptor current.

Craving

An affective state that can be induced in human drug users by exposure to the drug itself, drug-associated cues or stress. In laboratory animals, craving is often inferred from the subjects' behavioural response (for example, lever-pressing) to drugs, drug-associated cues or stress.

Direct and indirect striatal pathways

The two efferent pathways in the basal ganglia. The direct pathway connects the striatum with the substantia nigra pars reticulata and entopeduncular nucleus. The indirect pathway connects the striatum with the globus pallidus and ventral pallidum.

Extinction

The decrease in the frequency or intensity of learned responses after the removal of the unconditioned stimulus (for example, food or a drug) that has reinforced the learning.

Incentive motivational state

A motivational state that is induced by exposure to unconditioned aversive or appetitive stimuli or cues that become associated with these stimuli.

Incubation of drug craving

A hypothetical motivational process that is inferred from findings of time-dependent increases in cue-induced drug seeking after withdrawal from drug self-administration in rats.

In vivo extracellular recording

A set of methods in which bundles of microwires are targeted to specific areas of the brain to allow measurement of extracellular currents (action potentials) of single cells.

Long-term depression

(LTD). A form of synaptic plasticity that is defined by a persistent weakening of synaptic strength.

Long-term potentiation

(LTP). A form of synaptic plasticity that is defined by a persistent increase in synaptic strength.

LTDGABA

A form of long-term depression (LTD) that is observed in dopaminergic neurons in the ventral tegmental area and that reduces synaptic efficacy between presynaptic GABAergic neurons and postsynaptic dopaminergic neurons.

LTPGABA

A form of long-term potentiation (LTP) that is observed in dopaminergic neurons in the ventral tegmental area. It results in increased GABA release and in the strengthening of inhibitory synapses.

Mesotelencephalic dopamine system

Also known as the mesocorticolimbic dopamine system. A major ascending dopaminergic pathway that originates in the ventral tegmental area and projects to, among other regions, the nucleus accumbens, the bed nucleus of the stria terminalis, the amygdala, the olfactory tubercle and the medial prefrontal cortex.

Psychic (or psychological) dependence

A concept, established early in the addiction field, that refers to a compulsion that requires periodic or continuous intake of an abused drug to produce psychological pleasure or to avoid psychological distress, regardless of whether physical dependence is also present.

Psychomotor sensitization

A progressive increase in locomotor activity or stereotypy with repeated drug (for example, cocaine) administration.

Relapse

The resumption of drug-taking behaviour after self-imposed or forced abstinence in humans with a history of abuse or dependence.

Second-order schedule of reinforcement

A complex reinforcement schedule in which the completion of the response requirement of one schedule is treated as a unitary response that is reinforced according to another schedule.

Stress

In animal models, stress typically refers to forced exposure to events or conditions that the animal would normally avoid. In humans, stress often refers to a condition in which the environmental demands exceed the coping abilities of the individual.

Synaptic plasticity

Activity-dependent direct or indirect modifications of the strength of synaptic transmission at pre-existing synapses.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Badiani, A., Belin, D., Epstein, D. et al. Opiate versus psychostimulant addiction: the differences do matter. Nat Rev Neurosci 12, 685–700 (2011). https://doi.org/10.1038/nrn3104

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3104

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing