Computational Approaches to the Neurobiology of Drug Addiction

 

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Abstract

To increase our understanding of drug addiction – notably its pharmacological and neurobiological determinants – researchers have begun to formulate computational models of drug self-administration. Currently, one can roughly distinguish between three classes of models which all have in common to attribute to brain dopamine signaling a key role in addiction. The first class of models contains quantitative pharmacological models that describe the influence of pharmacokinetic and pharmacodynamic factors on drug self-administration. These models fail, however, to explain how the drug self-administration behavior is acquired and how it eventually becomes rigid and compulsive with extended drug use. Models belonging to the second class circumvent some of these limitations by modeling how drug use usurps the function of dopamine in reinforcement learning and action selection. However, despite their behavioral plausibility, these latter models lack neurobiological plausibility and ignore the potential role of opponent processes in addiction. The third class of models attempts to surmount these pitfalls by providing a more realistic picture of the midbrain dopamine circuitry and of the complex action of drugs of abuse in the output of this circuitry. Here we provide a brief overview of these different models to illustrate the potential contribution of mathematical modeling to our understanding of the neurobiology of drug addiction.

References

• 1 Ahmed SH. Neuroscience. Addiction as compulsive reward prediction.  Science. 2004;  306 1901-1902
  CrossrefPubMedGoogle Scholar
• 2 Ahmed SH. Imbalance between drug and non-drug reward availability: a major risk factor for addiction.  Eur. J. Pharmacol. 2005;  526 9-20
  CrossrefPubMedGoogle Scholar
• 3 Ahmed SH, Kenny PJ, Koob GF. et al . Neurobiological evidence for hedonic allostasis associated with escalating cocaine use.  Nat. Neurosci. 2002;  5 625-626
  PubMedGoogle Scholar
• 4 Ahmed SH, Koob GF. Transition from moderate to excessive drug intake: change in hedonic set point.  Science. 1998;  282 298-300
  CrossrefPubMedGoogle Scholar
• 5 Ahmed SH, Koob GF. Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function.  Psychopharmacology. 2005;  180 473-490
  CrossrefPubMedGoogle Scholar
• 6 Ahmed SH, Lin D, Koob GF. et al . Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels.  J. Neurochem. 2003;  86 102-113
  CrossrefPubMedGoogle Scholar
• 7 Bauco P, Wise RA. Synergistic effects of cocaine with lateral hypothalamic brain stimulation reward: lack of tolerance or sensitization.  J. Pharmacol. Exp. Ther. 1997;  283 1160-1167
  PubMedGoogle Scholar
• 8 Beiser DG, Hua SE, Houk JC. Network models of the basal ganglia.  Curr Opin Neurobiol. 1997;  7 185-190
  CrossrefPubMedGoogle Scholar
• 9 Bobashev GV, Costenbader EM, Gutkin BS. Comprehensive Mathematical Modeling in Addiction Sciences.  Drug Alcohol Depend. 2007;  289 102-106
  PubMedGoogle Scholar
• 10 Buisson B, Bertrand D. Nicotine addiction: the possible role of functional upregulation.  Trends Pharmacol Sci. 2002;  23 130-136
  CrossrefPubMedGoogle Scholar
• 11 Champtiaux N, Gotti C, Cordero-Erausquin M. et al . Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice.  J Neurosci. 2003;  23 7820-7829
  PubMedGoogle Scholar
• 12 Changeux JP, Bertrand D, Corringer PJ. et al . Brain nicotinic receptors: structure and regulation, role in learning and reinforcement.  Brain Res Brain Res Rev. 1998;  26 198-216
  CrossrefPubMedGoogle Scholar
• 13 Cho RY, Nystrom LE, Brown ET. et al . Mechanisms underlying dependencies of performance on stimulus history in a two-alternative forced-choice task.  Cogn. Affect Behav. Neurosci. 2002;  2 283-299
  CrossrefPubMedGoogle Scholar
• 14 Christie MJ, Bridge S, James LB. et al . Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area.  Brain Res. 1985;  333 169-172
  CrossrefPubMedGoogle Scholar
• 15 Cornwall J, Cooper JD, Phillipson OT. Afferent and efferent connections of the laterodorsal tegmental nucleus in the rat.  Brain Res Bull. 1990;  25 271-284
  CrossrefPubMedGoogle Scholar
• 16 Corrigall WA, Coen KM, Adamson KL. Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area.  Brain Res. 1994;  653 278-284
  CrossrefPubMedGoogle Scholar
• 17 Dani J, Heinemann S. Molecular and cellular aspects of nicotine abuse.  Neuron. 1996;  16 905-908
  CrossrefPubMedGoogle Scholar
• 18 Dani JA, Ji D, Zhou FM. Synaptic plasticity and nicotine addiction.  Neuron. 2001;  31 349-352
  CrossrefPubMedGoogle Scholar
• 19 David V, Besson M, Changeux JP. et al . Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: dependence on cholinergic nicotinic and dopaminergic D1 receptors.  Neuropharmacology. 2006;  50 1030-1040
  CrossrefPubMedGoogle Scholar
• 20 Daw ND, O’Doherty JP, Seymour B. et al . Cortical substrates for exploratory decisions in humans.  Nature. 2006;  441 876-879
  CrossrefPubMedGoogle Scholar
• 21 Dehaene S, Changeux JP. Reward-dependent learning in neuronal networks for planning and decision making.  Prog. Brain Res. 2000;  126 217-229
  PubMedGoogle Scholar
• 22 Dehaene S, Kerszberg M, Changeux JP. A neuronal model of a global workspace in effortful cognitive tasks.  Proc. Natl. Acad. Sci. USA. 1998;  95 14529-14534
  CrossrefPubMedGoogle Scholar
• 23 Di Chiara G. Drug addiction as a dopamine-dependent associative learning disorder.  European J. Pharmacology. 1999;  375 13-30
  PubMedGoogle Scholar
• 24 Donny EC. et al . Nicotine self-administration in rats on a progressive ratio schedule of reinforcement.  Psychopharmacology (Berl). 1999;  147 135-142
  CrossrefPubMedGoogle Scholar
• 25 Donny EC, Caggiula AR, Rowell PP. et al . Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding.  Psychopharmacology (Berl). 2000;  151 392-405
  CrossrefPubMedGoogle Scholar
• 26 Garzón M, Vaughan RA, Uhl GR. 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;  410 197-210
  CrossrefPubMedGoogle Scholar
• 27 Gotti C, Moretti M, Gaimarri A. et al . Heterogeneity and complexity of native brain nicotinic receptors.  Biochem Pharmacol. 2007;  74 1102-1111
  CrossrefPubMedGoogle Scholar
• 28 Granon S, Faure P, Changeux JP. Executive and social behaviors under nicotinic receptor regulation.  Proc. Natl. Acad. Sci. USA. 2003;  100 9596-9601
  CrossrefPubMedGoogle Scholar
• 29 Gutkin BS, Dehaene S, Changeux JP. A neurocomputational hypothesis for nicotine addiction.  Proc Natl Acad Sci USA. 2006;  103 1106-1111
  CrossrefPubMedGoogle Scholar
• 30 Henningfield JE, Stapleton JM, Benowitz NL. et al . Higher levels of nicotine in arterial than in venous blood after cigarette smoking.  Drug Alcohol Depend. 1993;  33 23-29
  CrossrefPubMedGoogle Scholar
• 31 Hernandez G, Hamdani S, Rajabi H. et al . Prolonged rewarding stimulation of the rat medial forebrain bundle: neurochemical and behavioral consequences.  Behav. Neurosci. 2006;  120 888-904
  CrossrefPubMedGoogle Scholar
• 32 Johnson SW, North RA. Two types of neurone in the rat ventral tegmental area and their synaptic inputs.  J Physiol. 1992;  450 455-468
  PubMedGoogle Scholar
• 33 Kalivas PW, Churchill L, Klitenick MA. GABA and enkephalin projection from the nucleus accumbens and ventral pallidum to the ventral tegmental area.  Neuroscience. 1993;  57 1047-1060
  CrossrefPubMedGoogle Scholar
• 34 Kenny PJ, Chen SA, Kitamura O. et al . Conditioned withdrawal drives heroin consumption and decreases reward sensitivity.  J. Neurosci. 2006;  26 5894-5900
  CrossrefPubMedGoogle Scholar
• 35 Klink R, de Kerchove d’Exaerde A, Zoli M. et al . Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei.  J Neurosci. 2001;  21 1452-1463
  PubMedGoogle Scholar
• 36 Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation.  Science. 1997;  278 52-58
  Google Scholar
• 37 Lenoir M, Ahmed SH. Supply of a nondrug substitute reduces escalated heroin consumption.  Neuropsychopharmacology. 2008;  33 2272-2282
  CrossrefPubMedGoogle Scholar
• 38 Lenoir M, Serre F, Cantin L. et al . Intense sweetness surpasses cocaine reward.  PLoS ONE. 2007;  2 e698
  CrossrefPubMedGoogle Scholar
• 39 Mameli-Engvall M, Evrard A, Pons S. et al . Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors.  Neuron. 2006;  50 911-921
  CrossrefPubMedGoogle Scholar
• 40 Mansvelder HD, McGehee DS. Long-term potentiation of excitatory inputs to brain reward areas by nicotine.  Neuron. 2000;  27 349-357
  CrossrefPubMedGoogle Scholar
• 41 Mansvelder HD, Keath JR, MacGehee DS. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.  Neuron. 2002;  33 905-919
  CrossrefPubMedGoogle Scholar
• 42 Mansvelder HD, Rover MD, MacGehee DS. et al . Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction.  Eur J Pharmacol. 2003;  480 117-123
  CrossrefPubMedGoogle Scholar
• 43 Martellotta MC, Kuzmin A, Zvartau E. et al . Isradipine inhibits nicotine intravenous self-administration in drug-naive mice.  Pharmacol Biochem Behav. 1995;  52 271-274
  CrossrefPubMedGoogle Scholar
• 44 Maskos U, Molles BE, Pons S. et al . Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.  Nature. 2005;  436 103-107
  CrossrefPubMedGoogle Scholar
• 45 Mateo Y, Lack CM, Morgan D. et al . Reduced dopamine terminal function and insensitivity to cocaine following cocaine binge self-administration and deprivation.  Neuropsychopharmacology. 2005;  30 2455-2463
  PubMedGoogle Scholar
• 46 McClure SM, Daw ND, Montague PR. A computational substrate for incentive salience.  Trends in Neurosciences. 2003;  26 423-428
  CrossrefPubMedGoogle Scholar
• 47 Montague PR, Dayan P, Sejnowski TJ. A framework for mesencephalic dopamine systems based on predictive Hebbian learning.  J. Neurosci. 1996;  16 1936-1947
  PubMedGoogle Scholar
• 48 Montague PR, Hyman SE, Cohen JD. Computational roles for dopamine in behavioural control.  Nature. 2004;  431 760-767
  CrossrefPubMedGoogle Scholar
• 49 Nashmi R, Xiao C, Deshpande P. et al . Chronic nicotine cell specifically upregulates functional alpha 4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path.  J Neurosci. 2007;  27 8202-8218
  CrossrefPubMedGoogle Scholar
• 50 Niv Y, Schoenbaum G. Dialogues on prediction errors.  Trends Cogn Sci. 2008;  12 265-272
  CrossrefPubMedGoogle Scholar
• 51 Norman AB, Tsibulsky VL. The compulsion zone: a pharmacological theory of acquired cocaine self-administration.  Brain Res. 2006;  1116 143-152
  CrossrefPubMedGoogle Scholar
• 52 Oleson EB, Roberts DC. Behavioral economic assessment of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake.  Neuropsychopharmacology. 2009;  34 796-804
  CrossrefPubMedGoogle Scholar
• 53 Otani S, Daniel H, Roisin M-P. et al . Dopaminergic modulation of long-term synaptic plasticity in rat prefrontal neurons.  Cereb Cortex. 2003;  13 1251-1256
  CrossrefPubMedGoogle Scholar
• 54 Panlilio LV, Thorndike EB, Schindler CW. A stimulus-control account of regulated drug intake in rats.  Psychopharmacology. 2008;  196 441-450
  CrossrefPubMedGoogle Scholar
• 55 Picciotto MR, Zoli M, Rimondini R. et al . Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.  Nature. 1998;  391 173-177
  CrossrefPubMedGoogle Scholar
• 56 Pidoplichko VI, DeBiasi M, Williams JT. et al . Nicotine activates and desensitizes midbrain dopamine neurons.  Nature. 1997;  390 401-404
  CrossrefPubMedGoogle Scholar
• 57 Rahman S, Zhang J, Engleman EA. et al . Neuroadaptive changes in the mesoaccumbens dopamine system after chronic nicotine self-administration: a microdialysis study.  Neuroscience. 2004;  129 415-424
  CrossrefPubMedGoogle Scholar
• 58 Rasmussen T, Swedberg MD. Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice.  Pharmacol Biochem Behav. 1998;  60 567-573
  CrossrefPubMedGoogle Scholar
• 59 Redish AD. Addiction as a computational process gone awry.  Science. 2004;  306 1944-1947
  CrossrefPubMedGoogle Scholar
• 60 Redish AD, Jensen S, Johnson A. A unified framework for addiction: vulnerabilities in the decision process.  Behav Brain Sci. 2008;  31 415-437 , ; discussion 437–487
  PubMedGoogle Scholar
• 61 Reynolds JN, Wickens JR. Dopamine-dependent plasticity of corticostriatal synapses.  Neural Netw. 2002;  15 507-521
  CrossrefPubMedGoogle Scholar
• 62 Risner ME, Goldberg SR. A comparison of nicotine and cocaine self-administration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion.  J Pharmacol Exp Ther. 1983;  224 319-326
  PubMedGoogle Scholar
• 63 Robinson TE, Berridge KC. Addiction.  Annu Rev Psychol. 2003;  54 25-53
  CrossrefPubMedGoogle Scholar
• 64 Schultz W. Multiple reward signals in the brain.  Nat Rev Neurosci. 2000;  1 199-207
  PubMedGoogle Scholar
• 65 Schultz W. Reward signaling by dopamine neurons.  Neuroscientist. 2001;  7 293-302
  CrossrefPubMedGoogle Scholar
• 66 Semba K, Fibiger HC. 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;  323 387-410
  CrossrefPubMedGoogle Scholar
• 67 Shoaib M, Schindler CW, Goldberg SR. Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition.  Psychopharmacology (Berl). 1997;  129 35-43
  CrossrefPubMedGoogle Scholar
• 68 Sizemore GM, Martin TJ. Toward a mathematical description of dose-effect functions for self-administered drugs in laboratory animal models.  Psychopharmacology. 2000;  153 57-66
  CrossrefPubMedGoogle Scholar
• 69 Sughondhabirom A, Jain D, Gueorguieva R. et al . A paradigm to investigate the self-regulation of cocaine administration in humans.  Psychopharmacology. 2005;  180 436-446
  CrossrefPubMedGoogle Scholar
• 70 Thomsen M, Hall FS, Uhl GR. et al . Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice.  J Neurosci. 2009;  29 1087-1092
  CrossrefPubMedGoogle Scholar
• 71 Tsibulsky VL, Norman AB. Satiety threshold: a quantitative model of maintained cocaine self-administration.  Brain Res. 1999;  839 85-93
  CrossrefPubMedGoogle Scholar
• 72 Usher M, MacClelland JL. The time course of perceptual choice: the leaky, competing accumulator model.  Psychol. Rev. 2001;  108 550-592
  CrossrefPubMedGoogle Scholar
• 73 Volkow ND, Wang GJ, Fowler JS. et al . Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects.  Nature. 1997;  386 830-833
  CrossrefPubMedGoogle Scholar
• 74 Wise RA, Newton P, Leeb K. et al . Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats.  Psychopharmacology. 1995;  120 10-20
  CrossrefPubMedGoogle Scholar
• 75 Yokel RA, Pickens R. Drug level of d- and l-amphetamine during intravenous self-administration.  Psychopharmacologia. 1974;  34 255-264
  CrossrefPubMedGoogle Scholar
• 76 Zittel-Lazarini A, Cador M, Ahmed SH. A critical transition in cocaine self-administration: behavioral and neurobiological implications.  Psychopharmacology. 2007;  192 337-346
  CrossrefPubMedGoogle Scholar

Correspondence

B. Gutkin

Group for Neural Theory

DEC

ENS-Paris and College de France

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75005 Paris

France

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Fax: +33/01/44 27 13 65

Email: boris.gutkin@gmail.com