Abstract
Among the different behavioral criteria used to discriminate substance dependence (or drug addiction) from other non-disordered forms of drug use, drug intake escalation presents a number of unique features that makes it particularly suitable for modeling in nonhuman animals. This criterion has stood the passage of time despite major revisions of diagnostic systems, it is common to all known drugs of abuse and it can be readily and unambiguously operationalized in laboratory animals. Here I exhaustively review evidence showing that escalation to heavy consumption of different drugs (except perhaps nicotine) can be rapidly induced in the majority of individual animals (i.e., rats) by increased drug availability. Such an escalation of drug use is probably paralleled by an authentic escalation to drug addiction, as it is associated with the co-occurrence of other addiction-like changes (i.e., increased motivation for drug use; increased difficulty to abstain from drug use; decreased sensitivity to negative consequences). In addition, during escalation of drug intake, most individual animals become increasingly responsive to drug- and stress-primed, but apparently not cue-primed, reinstatement of drug seeking after extinction. Finally, following increased drug use, most individuals present selective cognitive dysfunctions (e.g., deficits in executive functions) that may contribute to the establishment and/or persistence of addiction. Thus, the study of individuals with escalating patterns of drug use should provide a unique and valid approach to investigate, experimentally, the behavioral and neurobiological mechanisms that underlie the progression to addiction.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Edwards G, Gross MM (1976) Alcohol dependence: provisional description of a clinical syndrome. Br Med J 1:1058–1061
Jaffe JH (1992) Current concepts of addiction. In: O’Brien CP, Jaffe JH (eds) Addictive states, Association for Research in Nervous and Mental Disease research publications, vol 70. Raven Press, New York, pp 1–21
Saunders JB (2006) Substance dependence and non-dependence in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD): can an identical conceptualization be achieved? Addiction 101(Suppl 1): 48–58
Martin CS, Chung T, Langenbucher JW (2008) How should we revise diagnostic criteria for substance use disorders in the DSM-V? J Abnorm Psychol 117:561–575
Wolffgramm J (1991) An ethopharmacological approach to the development of drug addiction. Neurosci Biobehav Rev 15:515–519
Wolffgramm J, Heyne A (1995) From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat. Behav Brain Res 70:77–94
Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300
Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017
Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ (2008) High impulsivity predicts the switch to compulsive cocaine-taking. Science 320:1352–1355
Vanderschuren LJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305:1017–1019
Negus SS (2006) Choice between heroin and food in nondependent and heroin-dependent rhesusmonkeys: effects of naloxone, buprenorphine, and methadone. J Pharmacol Exp Ther 317:711–723
Panlilio LV, Goldberg SR (2007) Self-administration of drugs in animals and humans as a model and an investigative tool. Addiction 102:1863–1870
Becker G, Murphy KM (1988) A theory of rational addiction. J Polit Econ 96:675–700
Shiffman S (1989) Tobacco “chippers” – individual differences in tobacco dependence. Psychopharmacology 97:539–547
Hughes JR (2006) Should criteria for drug dependence differ across drugs? Addiction 101(Suppl 1):134–141
Ahmed SH, Koob GF (2005) Transition to drug addiction: a negative reinforcement model based on anallostatic decrease in reward function. Psychopharmacology 180:473–490
Khantzian EJ (2003) Understanding addictive vulnerability: an evolving psychodynamic perspective. Neuropsychoanalysis 5:5–21
Redish AD, Jensen S, Johnson A (2008) A unified framework for addiction: vulnerabilities in the decision process. Behav Brain Sci 31:415–437
Hursh SR (1991) Behavioral economics of drug self-administration and drug abuse policy. J Exp Anal Behav 56:377–393
Westermeyer J (1999) The role of cultural and social factors in the cause of addictive disorders. Psychiatr Clin North Am 22:253–273
Ahmed SH, Koob GF (1999) Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 146:303–312
Dalley JW, Lääne K, Pena Y, Theobald DE, Everitt BJ, Robbins TW (2005) Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin. Psychopharmacology 182:579–587
Dalley JW, Theobald DE, Berry D, Milstein JA, Lääne K, Everitt BJ, Robbins TW (2005) Cognitive sequelae of intravenous amphetamine self-administration in rats: evidence for selective effects on attentional performance. Neuropsychopharmacology 30:525–537
Dalley JW, Lääne K, Theobald DE et al (2007) Enduring deficits in sustained visual attention during withdrawal of intravenous methylenedioxymethamphetamine self-administration in rats: results from a comparative study with d-amphetamine and methamphetamine. Neuropsychopharmacology 32:1195–1206
Dworkin SI, Goeders NE, Grabowski J, Smith JE (1987) The effects of 12-hour limited access to cocaine: reduction in drug intake and mortality. NIDA Res Monogr 76:221–225
Piazza PV, Deminière JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513
Ahmed SH, Koob GF (2004) Changes in response to a dopamine receptor antagonist in rats with escalating cocaine intake. Psychopharmacology 172:450–454
Ahmed SH, Lin D, Koob GF, Parsons LH (2003) Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels. J Neurochem 86:102–113
Ahmed SH, Kenny PJ, Koob GF, Markou A (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5:625–626
Ahmed SH, Lutjens R, van der Stap LD et al (2005) Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc Natl Acad Sci USA 102:11533–11538
Ahmed SH, Cador M (2006) Dissociation of psychomotor sensitization from compulsive cocaine consumption. Neuropsycho-pharmacology 31:563–571
Allen RM, Dykstra LA, Carelli RM (2007) Continuous exposure to the competitive N-methyl-D: -aspartate receptor antagonist, LY235959, facilitates escalation of cocaine consumption in Sprague-Dawley rats. Psychopharmacology 191:341–351
Allen RM, Uban KA, Atwood EM, Albeck DS, Yamamoto DJ (2007) Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration andincreases break point for cocaine in Sprague-Dawley rats. Pharmacol Biochem Behav 88:82–88
Aujla H, Martin-Fardon R, Weiss F (2008) Rats with extended access to cocaine exhibit increased stress reactivity and sensitivity to the anxiolytic-like effects of the mGluR 2/3 agonist LY379268 during abstinence. Neuropsychopharmacology 33:1818–1826
Ben-Shahar O, Ahmed SH, Koob GF, Ettenberg A (2004) The transition from controlled to compulsive drug use is associated with a loss of sensitization. Brain Res 995:46–54
Ben-Shahar O, Moscarello JM, Jacob B, Roarty MP, Ettenberg A (2005) Prolonged daily exposure to i.v. cocaine results in tolerance to its stimulant effects. Pharmacol Biochem Behav 82:411–416
Ben-Shahar O, Moscarello JM, Ettenberg A (2006) One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter. Brain Res 1095:148–153
Ben-Shahar O, Keeley P, Cook M et al (2007) Changes in levels of D1, D2, or NMDA receptors during withdrawal from brief or extended daily access to IV cocaine. Brain Res 1131:220–228
Ben-Shahar O, Posthumus EJ, Waldroup SA, Ettenberg A (2008) Heightened drug-seeking motivation following extended daily access to self-administered cocaine. Prog Neuropsychopharmacol Biol Psychiatry 32:863–869
Briand LA, Gross JP, Robinson TE (2008) Impaired object recognition following prolonged withdrawal from extended-access cocaine self-administration. Neuroscience 155:1–6
Briand LA, Flagel SB, Garcia-Fuster MJ et al (2008) Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine. Neuropsychopharmacology 33:2969–2980
Ferrario CR, Gorny G, Crombag HS, Li Y, Kolb B, Robinson TE (2005) Neural and behavioral plasticity associated with the transition from controlled to escalated cocaine use. Biol Psychiatry 58:751–759
Ferrario CR, Robinson TE (2007) Amphetamine pretreatment accelerates the subsequent escalation of cocaine self-administration behavior. Eur Neuropsycho-pharmacol 17:352–357
Hansen ST, Mark GP (2007) The nicotinic acetylcholine receptor antagonist mecamylamine prevents escalation of cocaine self-administration in rats with extended daily access. Psychopharmacology 194:53–61
Kenny PJ, Boutrel B, Gasparini F, Koob GF, Markou A (2005) Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology 179:247–254
Kippin TE, Fuchs RA, See RE (2006) Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats. Psychopharmacology 187:60–67
Knackstedt LA, Kalivas PW (2007) Extended access to cocaine self-administration enhances drug-primed reinstatement but not behavioral sensitization. J Pharmacol Exp Ther 322:1103–1109
Madayag A, Lobner D, Kau KS et al (2007) Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci 27:13968–13976
Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, Serge JP (2008) Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats. Psychopharmacology 195:591–603
Mantsch JR, Baker DA, Serge JP, Hoks MA, Francis DM, Katz ES (2008) Surgical adrenalectomy with diurnal corticosterone replacement slows escalation and prevents the augmentation of cocaine-induced reinstatement in ratsself-administering cocaine under long-access conditions. Neuropsychopharmacology 33:814–826
Mantsch JR, Cullinan WE, Tang LC, Baker DA, Katz ES, Hoks MA, Ziegler DR (2007) Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats. Brain Res 1167:101–111
Oleson EB, Roberts DC (2009) Behavioral economic assessment of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake. Neuropsycho-pharmacology 34:796–804
Paterson NE, Markou A (2004) Prolonged nicotine dependence associated with extended access to nicotine self-administration in rats. Psychopharmacology 173:64–72
Perry JL, Morgan AD, Anker JJ, Dess NK, Carroll ME (2006) Escalation of i.v. cocaine self-administration and reinstatement of cocaine-seeking behavior in rats bred for high and low saccharin intake. Psychopharmacology 186:235–245
Roth ME, Carroll ME (2004) Sex differences in the escalation of intravenous cocaine intake following long-or short-access to cocaine self-administration. Pharmacol Biochem Behav 78:199–207
Specio SE, Wee S, O’Dell LE, Boutrel B, Zorrilla EP, Koob GF (2008) CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats. Psychopharmacology 196:473–482
Wee S, Mandyam CD, Lekic DM, Koob GF (2008) Alpha 1-noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access. Eur Neuropsychopharmacol 18:303–311
Wee S, Specio SE, Koob GF (2007) Effects of dose and session duration on cocaine self-administration in rats. J Pharmacol Exp Ther 320:1134–1143
Larson EB, Anker JJ, Gliddon LA, Fons KS, Carroll ME (2007) Effects of estrogen and progesterone on the escalation of cocaine self-administration in female rats during extended access. Exp Clin Psychopharmacol 15:461–471
Liu Y, Roberts DC, Morgan D (2005) Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats. Psychopharmacology 179:644–651
Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ (2004) Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats. Psychopharmacology 175:26–36
Mandyam CD, Wee S, Eisch AJ, Richardson HN, Koob GF (2007) Methamphetamine self-administration and voluntary exercise have opposing effects on medial prefrontal cortex gliogenesis. J Neurosci 27:11442–11450
Rogers JL, De Santis S, See RE (2008) Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats. Psychopharmacology 199:615–624
Kitamura O, Wee S, Specio SE, Koob GF, Pulvirenti L (2006) Escalation of methamphetamine self-administration in rats: a dose-effect function. Psychopharmacology 186:48–53
Kenny PJ, Markou A (2006) Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31:1203–1211
Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF (2006) Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J Neurosci 26:5894–5900
Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D (2008) GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc Natl Acad Sci USA 105:8114–8119
Wise RA (1973) Voluntary ethanol intake in rats following exposure to ethanol on various schedules. Psychopharmacologia 29:203–210
Simms JA, Steensland P, Medina B et al (2008) Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol Clin Exp Res 32:1816–1823
O’Dell LE, Koob GF (2007) ‘Nicotine deprivation effect’ in rats with intermittent 23-hour access to intravenous nicotine self-administration. Pharmacol Biochem Behav 86:346–353
George O, Ghozland S, Azar MR et al (2007) CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci U S A 104:17198–17203
Bozarth MA, Wise RA (1985) Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat. JAMA 254:81–83
Morgan AD, Campbell UC, Fons RD, Carroll ME (2002) Effects of agmatine on the escalation of intravenous cocaine and fentanyl self-administration in rats. Pharmacol Biochem Behav 72:873–880
Chen SA, O’Dell LE, Hoefer ME, Greenwell TN, Zorrilla EP, Koob GF (2006) Unlimited access to heroin self-administration: independent motivational markers of opiate dependence. Neuropsychopharmacology 31:2692–2707 [Erratum, Neuropsycho-pharmacology 2006;31:2802]
Ahmed SH, Walker JR, Koob GF (2000) Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22:413–421
Lenoir M, Cantin L, Serre F, Ahmed SH (2008) The value of heroin increases with extended use but not above the value of a non-essential alternative reward. In: 38th annual meeting of the society for neuroscience, Washington, DC, 14–19 November 2008
Lenoir M, Ahmed SH (2007) Heroin-induced reinstatement is specific to compulsive heroin use and dissociable from heroin reward and sensitization. Neuropsychopharmacology 32:616–624
Lenoir M, Ahmed SH (2008) Supply of a nondrug substitute reduces escalated heroin consumption. Neuropsychopharmacology 33:2272–2282
Doherty J, Ogbomnwan Y, Williams B, Frantz K (2009) Age-dependent morphine intake and cue-induced reinstatement, but not escalation in intake, by adolescent and adult male rats. Pharmacol Biochem Behav 92:164–172
Mormede P, Colas A, Jones BC (2004) High ethanol preferring rats fail to show dependence following short- or long-term ethanol exposure. Alcohol Alcohol 39:183–189
Ward SJ, Läck C, Morgan D, Roberts DC (2006) Discrete-trials heroin self-administration produces sensitization to the reinforcing effects of cocaine in rats. Psychopharmacology 185:150–159
Winger G, Woods JH (2001) The effects of chronic morphine on behavior reinforced by several opioids or by cocaine in rhesus monkeys. Drug Alcohol Depend 62:181–189
Ahmed SH, Bobashev G, Gutkin BS (2007) The simulation of addiction: pharmacological and neurocomputational models of drug self-administration. Drug Alcohol Depend 90:304–311
Epstein DH, Preston KL, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189:1–16
Jaffe JH, Cascella NG, Kumor KM, Sherer MA (1989) Cocaine-induced cocaine craving. Psychopharmacology 97:59–64
Volkow ND, Wang GJ, Ma Y et al (2005) Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction. J Neurosci 25:3932–3939
Bickel WK, DeGrandpre RJ, Higgins ST, Hughes JR (1990) Behavioral economics of drug self-administration. I. Functional equivalence of response requirement and drug dose. Life Sci 47:1501–1510
Zittel-Lazarini A, Cador M, Ahmed SH (2007) A critical transition in cocaine self-administration: behavioral and neurobiological implications. Psychopharmacology 192:337–346
Christensen CJ, Silberberg A, Hursh SR, Roma PG, Riley AL (2008) Demand for cocaine and food over time. Pharmacol Biochem Behav 91:209–216
Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944
Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447
Paterson NE, Markou A (2003) Increased motivation for self-administered cocaine after escalated cocaine intake. Neuroreport 14(14):2229–2232
Wee S, Wang Z, Woolverton WL, Pulvirenti L, Koob GF (2007) Effect of aripiprazole, a partial dopamine D2 receptor agonist, on increased rate of methamphetamine self-administration in rats with prolonged session duration. Neuropsychopharmacology 32:2238–2247
Li DH, Depoortere RY, Emmett-Oglesby MW (1994) Tolerance to the reinforcing effects of cocaine in a progressive ratio paradigm. Psychopharmacology 116:326–332
Zhou W, Zhang F, Liu H, Tang S, Lai M, Zhu H, Kalivas PW (2009) Effects of training and withdrawal periods on heroin seeking induced by conditioned cue in an animal of model of relapse. Psychopharmacology 203:677–684
Sorge RE, Stewart J (2005) The contribution of drug history and time since termination of drug taking to footshock stress-induced cocaine seeking in rats. Psychopharmacology 183:210–217
Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation: incubation of cocaine craving after withdrawal. Nature 412:141–142
Campbell ND (2007) Discovering addiction: the science and politics of substance abuse research. The University of Michigan Press, Ann Arbor
Deneau G, Yanagita T, Seevers MH (1969) Self-administration of psychoactive substances by the monkey. Psychopharmacologia 16:30–48
Sutton MA, Karanian DA, Self DW (2000) Factors that determine a propensity for cocaine-seeking behavior during abstinence in rats. Neuropsychopharmacology 22:626–641
Baker DA, Tran-Nguyen TL, Fuchs RA, Neisewander JL (2001) Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats. Psychopharmacology 155:18–26
Mantsch JR, Ho A, Schlussman SD, Kreek MJ (2001) Predictable individual differences in the initiation of cocaine self-administration by rats under extended-access conditions are dose-dependent. Psychopharmacology 157:31–39
Edwards S, Whisler KN, Fuller DC, Orsulak PJ, Self DW (2007) Addiction-related alterations in D1 and D2 dopamine receptor behavioral responses following chronic cocaine self-administration. Neuropsychopharmacology 32:354–366
Dalley JW, Fryer TD, Brichard L et al (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315:1267–1270
Heyne A, Wolffgramm J (1998) The development of addiction to d-amphetamine in an animal model: same principles as for alcohol and opiate. Psychopharmacology 140:510–518
Anker JJ, Perry JL, Gliddon LA, Carroll ME. (2009) Impulsivity predicts the escalation of cocaine self-administration in rats. Pharmacol Biochem Behav 93:343–8.
Quadros IM, Miczek KA (2009) Two modes of intense cocaine bingeing: increased persistence after social defeat stress and increased rate of intake due to extended access conditions in rats. Psychopharmacology 206:109–20.)
Ahmed SH (2005) Imbalance between drug and non-drug reward availability: a major risk factor for addiction. Eur J Pharmacol 526:9–20
Winstanley CA, Bachtell RK, Theobald DE et al (2009) Increased impulsivity during withdrawal from cocaine self-administration: role for DeltaFosB in the orbitofrontal cortex. Cereb Cortex 19:435–444
Perry JL, Nelson SE, Carroll ME (2008) Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats. Exp Clin Psychopharmacol 16:165–177
Calu DJ, Stalnaker TA, Franz TM, Singh T, Shaham Y, Schoenbaum G (2007) Withdrawal from cocaine self-administration produces long-lasting deficits in orbitofrontal-dependent reversal learning in rats. Learn Mem 14:325–328
Liu S, Heitz RP, Sampson AR, Zhang W, Bradberry CW (2008) Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration. Cereb Cortex 18:2109–2116
Diergaarde L, Pattij T, Poortvliet I, Hogenboom F, de Vries W, Schoffelmeer AN, De Vries TJ (2008) Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats. Biol Psychiatry 63:301–308
Shaffer HJ, Eber GB (2002) Temporal progression of cocaine dependence symptoms in the US National Comorbidity Survey. Addiction 97:543–554
Lenoir M, Serre F, Cantin L, Ahmed SH (2007) Intense sweetness surpasses cocaine reward. PLoS ONE 2:e698
Koob GF (2008) A role for brain stress systems in addiction. Neuron 59:11–34
Mantsch JR, Katz ES (2007) Elevation of glucocorticoids is necessary but not sufficient for the escalation of cocaine self-administration by chronic electric footshock stress in rats. Neuropsychopharmacology 32:367–376
Czoty PW, Reboussin BA, Calhoun TL, Nader SH, Nader MA (2007) Long-term cocaine self-administration under fixed-ratio and second-order schedules in monkeys. Psychopharmacology 191:287–295
Henry PK, Howell LL (2009) Cocaine-induced reinstatement during limited and extended drug access conditions in rhesus monkeys. Psychopharmacology 204:523–529
Lattanzio SB, Eikelboom R (2003) Wheel access duration in rats: I. Effects on feeding and running. Behav Neurosci 117:496–504
Goeders JE, Murnane KS, Banks ML, Fantegrossi WE (2009) Escalation of food maintained responding and sensitivity to the locomotor stimulant effects of cocaine in mice. Pharmacol Biochem Behav 93:67–74
George O, Mandyam CD, Wee S, Koob GF (2008) Extended access to cocaine self-administration produces long-lasting prefrontal cortex-dependent working memory impairments. Neuropsychopharmacology 33:2474–2482
Acknowledgments
This work was supported by grants from the French Research Council (CNRS), Université Victor-Segalen Bordeaux 2 and Mission Interministérielle de Lutte contre la Drogue et la Toxicomaine (MILDT). I thank Drs. Magalie Lenoir, Karyn Guillem, and Kelly Clemens for their comments on a previous draft of this book chapter. I also thank the reviewer and the editor for their constructive comments. I dedicate this book chapter to my wife, Dr. Saloua Aidoudi.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Ahmed, S.H. (2011). Escalation of Drug Use. In: Olmstead, M. (eds) Animal Models of Drug Addiction. Neuromethods, vol 53. Humana Press. https://doi.org/10.1007/978-1-60761-934-5_10
Download citation
DOI: https://doi.org/10.1007/978-1-60761-934-5_10
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-60761-933-8
Online ISBN: 978-1-60761-934-5
eBook Packages: Springer Protocols