Abstract
Rationale
Patterns of drug self-administration are often highly regular, with a consistent pause after each self-injection. This pausing might occur because the animal has learned that additional injections are not reinforcing once the drug effect has reached a certain level, possibly due to the reinforcement system reaching full capacity. Thus, interoceptive effects of the drug might function as a discriminative stimulus, signaling when additional drug will be reinforcing and when it will not.
Objective
This hypothetical stimulus control aspect of drug self-administration was emulated using a schedule of food reinforcement.
Materials and methods
Rats’ nose-poke responses produced food only when a cue light was present. No drug was administered at any time. However, the state of the light stimulus was determined by calculating what the whole-body drug level would have been if each response in the session had produced a drug injection. The light was only presented while this virtual drug level was below a specific threshold. A range of doses of cocaine and remifentanil were emulated using parameters based on previous self-administration experiments.
Results
Response patterns were highly regular, dose-dependent, and remarkably similar to actual drug self-administration.
Conclusion
This similarity suggests that the emulation schedule may provide a reasonable model of the contingencies inherent in drug reinforcement. Thus, these results support a stimulus control account of regulated drug intake in which rats learn to discriminate when the level of drug effect has fallen to a point where another self-injection will be reinforcing.
Similar content being viewed by others
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 (1999) Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 146:303–312
Ahmed SH, Koob GF (2005) Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function. Psychopharmacology 180:473–490
Balleine B (1992) Instrumental performance following a shift in primary motivation depends on incentive learning. J Exp Psychol Anim Behav Process 18:236–250
Crespo JA, Panlilio LV, Schindler CW, Sturm K, Saria A, Zernig G (2006) Peri-response pharmacokinetics of remifentanil during a self-administration session indicates that neither blood nor brain levels are titrated. Ann N Y Acad Sci 1074:497–504
Colpaert FC (1991) The discriminative response: an elementary particle of behavior. Behav Pharmacol 2:283–286
Colpaert FC (1999) Drug discrimination in neurobiology. Pharmacol Biochem Behav 64:337–345
Dickinson A, Balleine B (1994) Motivational control of goal-directed action. Anim Learn Behav 22:1–18
Hutcheson DM, Everitt BJ, Robbins TW, Dickinson A (2001) The role of withdrawal in heroin addiction: enhances reward or promotes avoidance? Nat Neurosci 4:943–947
Ko MC, Terner J, Hursh S, Woods JH, Winger G (2002) Relative reinforcing effects of three opioids with different durations of action. J Pharmacol Exp Ther 301:698–704
Lynch WJ, Carroll ME (2001) Regulation of drug intake. Exp Clin Psychopharmacol 9:131–143
Marcucella H (1974) Signalled reinforcement in differential-reinforcement-of-low rate schedules. J Exp Anal Behav 22:381–390
National Research Council (1996) Guide for care and use of laboratory animals. National Academy Press, Washington
Norman AB, Tsibulsky VL (2006) The compulsion zone: a pharmacological theory of acquired cocaine self-administration. Brain Res 1116:143–152
Panlilio LV, Schindler CW (2000) Self-administration of remifentanil, an ultra-short acting opioid, under continuous and progressive-ratio schedules of reinforcement in rats. Psychopharmacology 150:61–66
Panlilio LV, Weiss SJ, Schindler CW (1996) Cocaine self-administration increased by compounding discriminative stimuli. Psychopharmacology 125:202–208
Panlilio LV, Goldberg SR, Gilman JP, Jufer R, Cone EJ, Schindler CW (1998a) Effects of delivery rate and non-contingent infusion of cocaine on cocaine self-administration in rhesus monkeys. Psychopharmacology 137:253–258
Panlilio LV, Weiss SJ, Schindler CW (1998b) Motivational effects of compounding discriminative stimuli associated with food and cocaine. Psychopharmacology 136:70–74
Panlilio LV, Weiss SJ, Schindler CW (2000) Effects of compounding drug-related stimuli: Escalation of heroin self-administration. J Exp Anal Behav 73:211–224
Panlilio LV, Katz JL, Pickens RW, Schindler CW (2003) Variability of drug self-administration in rats. Psychopharmacology 167:9–19
Panlilio LV, Thorndike EB, Schindler CW (2006) Cocaine self-administration under variable-dose schedules in squirrel monkeys. Pharmacol Biochem Behav 84:235–243
Pickens R, Thompson R (1968) Cocaine-reinforced behavior in rats: effects of reinforcement magnitude and fixed-ratio size. J Pharmacol Exp Ther 161:122–129
Ranaldi R, Pocock D, Zereik R, Wise RA (1999) Dopamine fluctuations in the nucleus accumbens during maintenance, extinction, and reinstatement of intravenous D-amphetamine self-administration. J Neurosci 19:4102–4109
Schindler CW, Thorndike EB, Ma JD, Goldberg SR (2000) Conditioned suppression with cocaine as the unconditioned stimulus. Pharmacol Biochem Behav 65:83–89
Sughondhabirom A, Jain D, Gueorguieva R, Coric V, Berman R, Lynch WJ, Self D, Jatlow P, Malison RT (2005) A paradigm to investigate the self-regulation of cocaine administration in humans. Psychopharmacology 180:436–446
Tella SR (1996) Possible novel pharmacodynamic action of cocaine: cardiovascular and behavioral evidence. Pharmacol Biochem Behav 54:343–354
Tsibulsky VL, Norman AB (1999) Satiety threshold: a quantitative model of maintained cocaine self-administration. Brain Res 839:85–93
Weiss SJ, Kearns DN, Cohn SI, Schindler CW, Panlilio LV (2003) Stimulus control of cocaine self-administration. J Exp Anal Behav 79:111–135
Wise RA (1987) Intravenous self-administration: a special case of positive reinforcement. In: Bozarth MA (ed) Methods of assessing the reinforcing properties of abused drugs. Springer, New York, pp 117–141
Wise RA, Yokel RA, Hansson PA, Gerber GJ (1977) Concurrent intracranial self-stimulation and amphetamine self-administration in rats. Pharmacol Biochem Behav 7:459–461
Yokel RA, Pickens RW (1974) Drug level of d- and l-amphetamine during intravenous self-administration. Psychopharmacologia 34:255–264
Zernig G, Ahmed SH, Cardinal RN, Morgan D, Acquas E, Foltin RW, Vezina P, Negus SS, Crespo JA, Stockl P, Grubinger P, Madlung E, Haring C, Kurz M, Saria A (2007) Explaining the escalation of drug use in substance dependence: models and appropriate animal laboratory tests. Pharmacology 80:65–119
Acknowledgments
This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse. Thanks to Jonathan Katz, who commented on the manuscript, and to Roy Wise, Serge Ahmed, and Vladimir Tsibulsky for sharing their views of regulated drug intake.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Panlilio, L.V., Thorndike, E.B. & Schindler, C.W. A stimulus-control account of regulated drug intake in rats. Psychopharmacology 196, 441–450 (2008). https://doi.org/10.1007/s00213-007-0978-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-007-0978-6