Abstract
Rationale
Behavioral procedures that incorporate dynamic changes in drug-maintained behavior are needed to model the development of cocaine addiction in humans.
Objectives
Because sensitization may occur to some aspects of drug administration during the addiction process, the objective of the present study was to define the critical features of self-administration histories that result in subsequent increases in the reinforcing efficacy of cocaine (measured using the progressive ratio (PR) schedule).
Methods
Animals were trained to self-administer cocaine on a fixed ratio (FR) schedule, baseline performance on a PR schedule was determined, and animals were given various histories of cocaine self-administration and drug deprivation. PR performance was reassessed following this experience.
Results
Cocaine self-administration under a discrete-trials procedure (24 h/day) for 10 days, followed by a 7-day deprivation period resulted in sensitization to the reinforcing effects of cocaine as assessed by the PR schedule (increases in maximal breakpoints maintained by cocaine with no change in sensitivity at lower doses). Similar levels of daily cocaine intake on a FR schedule (typically completed within 6 h) coupled with a deprivation period failed to produce changes in breakpoint. Providing access to cocaine during the “deprivation period” by repeated testing on a PR schedule prevented the sensitization.
Conclusions
These data suggest that these self-administration-induced changes in breakpoint reflect sensitization, and show that a drug-free deprivation period is necessary, but not sufficient, to produce this increase.
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References
Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300
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, Kenny PJ, Koob GF, Markou A (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5:625–626
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
Arnold JM, Roberts DCS (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447
Balster RL (1991) Drug abuse potential evaluation in animals. Br J Addict 86:1549–1558
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
Caine SB, Negus SS, Mello NK, Bergman J (1999) Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine. J Pharmacol Exp Ther 291:353–360
Cami J, Farre M (2003) Drug addiction. N Engl J Med 349:975–986
Covington HE III, Miczek KA (2001) Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology 158:388–398
Dackis CA, O’Brien CP (2001) Cocaine dependence: a disease of the brain’s reward centers. J Subst Abuse Treat 21:111–117
Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251:1580–1586
Griffiths RR, Bigelow GE, Ator NA (2003) Priniciples of initial experimental drug abuse liability assessment in humans. Drug Alcohol Depend 70:S41–S54
Henry DJ, White FJ (1995) The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons. J Neurosci 15:6287–6299
Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944
Hooks MS, Duffy P, Striplin C, Kalivas PW (1994) Behavioral and neurochemical sensitization following cocaine self-administration. Psychopharmacology 115:265–272
Kalivas PW, Duffy P (1993) Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. J Neurosci 13:266–275
Katz JL (1990) Models of relative reinforcing efficacy of drugs and their predictive utility. Behav Pharmacol 1:283–301
Kopnisky KL, Cowan WM, Hyman SE (2002) Levels of analysis in psychiatric research. Dev Psychopathol 14:437–461
LeSage MG, Stafford D, Glowa JR (1999) Preclinical research on cocaine self-administration: environmental determinants and their interaction with pharmacological treatment. Neurosci Biobehav Rev 23:717–741
Lorrain DS, Arnold GM, Vezina P (2000) Previous exposure to amphetamine increases incentive to obtain the drug: long-lasting effects revealed by the progressive ratio schedule. Behav Brain Res 107:9–19
Mantsch JR, Saphier D, Goeders NE (1998) Corticosterone facilitates the acquisition of cocaine self-administration in rats: opposite effects of the type II glucocorticoid receptor agonist dexamethasone. J Pharmacol Exp Ther 287:72–80
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
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. DOI 10.1007/s00213-004-1778-x
Mendrek A, Blaha CD, Phillips AG (1998) Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule. Psychopharmacology 135:416–422
Morgan D, Roberts DCS (2004) Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration. Neurosci Biobehav Rev 27:803–812
Morgan D, Brebner K, Lynch WJ, Roberts DCS (2002) Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement. Behav Pharmacol 13:389–396
Mutschler NH, Miczek KA (1998) Withdrawal from a self-administered or non-contingent cocaine binge: differences in ultrasonic distress vocalizations in rats. Psychopharmacology 136:402–408
Mutschler NH, Covington HE III, Miczek KA (2001) Repeated self-administered cocaine “binges” in rats: effects on cocaine intake and withdrawal. Psychopharmacology 154:292–300
O’Brien CP (1996) Recent developments in the pharmacotherapy of substance abuse. J Consult Clin Psychol 64:677–686
Paterson NE, Markou A (2003) Increased motivation for self-administered cocaine after escalated cocaine intake. Neuroreport 14:2229–2232
Paulson PE, Camp DM, Robinson TE (1991) Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Psychopharmacology 103:480–492
Pierce RC, Kalivas PW (1995) Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine. J Pharmacol Exp Ther 275:1019–1029
Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11
Roberts DCS, Goeders NE (1989) Drug self-administration: experimental methods and determinants. In: Boulton AA, Baker GB, Greenshaw AJ (eds) Neuromethods: psychopharmacology, vol 13. Humana, Clifton, pp 349–398
Roberts DCS, Phelan R, Hodges LM, Hodges MM, Bennett B, Childers S, Davies H (1999) Self-administration of cocaine analogs by rats. Psychopharmacology 144:389–397
Roberts DCS, Corcoran ME, Fibiger HC (1977) On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav 6:615–620
Roberts DCS, Brebner K, Vincler M, Lynch WJ (2002) Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure. Drug Alcohol Depend 67:291–299
Rocha BA (2003) Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur J Pharmacol 479:107–115
Schuster CR, Johanson CE (1981) An analysis of drug-seeking behavior in animals. Neurosci Biobehav Rev 5:315–323
Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology 139:169–184
Suto N, Austin JD, Tanabe LM, Kramer MK, Wright DA, Vezina P (2002) Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner. Neuropsychopharmacology 27:970–979
Suto N, Tanabe LM, Austin JD, Creekmore E, Vezina P (2003) Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner. Neuropsychopharmacology 28:629–639
Tornatzky W, Miczek KA (2000) Cocaine self-administration “binges”: transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology 148:289–298
Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120
Vezina P (2004) Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27:827–839
Zapata A, Chefer VI, Ator R, Shippenberg TS, Rocha BA (2003) Behavioural sensitization and enhanced dopamine response in the nucleus accumbens after intravenous cocaine self-administration in mice. Eur J Neurosci 17:590–596
Zernig G, Wakonigg G, Madlung E, Haring C, Saria A (2004) Do vertical shifts in dose-response rate-relationships in operant conditioning procedures indicate “sensitization” to “drug wanting”? Psychopharmacology 171:349–351
Acknowledgements
The authors wish to thank David Yancey and Leanne Thomas for technical assistance, and Sara Jane Ward for reading an earlier version of this manuscript. This research was supported by National Institute of Health grants P50DA06643, R01DA14030 to DCSR, and K01DA13957 to D.M. Portions of these data were recently described and summarized in a review article (Morgan and Roberts 2004).
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Morgan, D., Smith, M.A. & Roberts, D.C.S. Binge self-administration and deprivation produces sensitization to the reinforcing effects of cocaine in rats. Psychopharmacology 178, 309–316 (2005). https://doi.org/10.1007/s00213-004-1992-6
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DOI: https://doi.org/10.1007/s00213-004-1992-6