Abstract
Currently dominating psychological theories of drug self-administration explain some experimentally observed facts, however, at the same time they lead to logical contradictions to other accepted facts. A quantitative pharmacological theory of self-administration behavior states that cocaine-induced lever pressing behavior occurs only when cocaine concentrations are within a certain range, termed the compulsion zone. These concentrations can be calculated using standard pharmacokinetic mathematical models. The lower and upper limits of this range of concentrations are the priming and satiety thresholds, respectively. This pharmacological theory explains all phases of the self-administration session but is particularly useful at explaining the intervals between drug injections during maintained self-administration in terms of a mathematical model that contains only three parameters: the drug unit dose, the satiety threshold and the drug elimination rate constant. The satiety threshold represents the equiactive agonist concentration. Because competitive antagonists increase equiactive agonist concentrations and the agonist concentration ratio increases linearly with antagonist concentration, the satiety threshold model allows the measurement of the in vivo potency of dopamine receptor antagonists using the classical mathematical method of Schild. In addition, applying pharmacokinetic models to the time course of the magnitude of the antagonist-induced increase in the satiety threshold allows the pharmacokinetics of antagonists to be calculated. Pharmacokinetic/pharmacodynamic models explain self-administration behavior and make this paradigm a rapid and high-content bioassay system useful for screening agonists and antagonists that interact with important neurotransmitter systems in the brain.
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References
Ahmed SH, Koob GF (2005) Transition to drug addiction: A negative reinforcement model based on an allostatic decrease in reward function. Neuropsychopharmacology 180:473–490
Arunlakshana O, Schild HO (1959) Some quantitative use of drug antagonists. Br J Pharmacol Chemother 14:48–58
Baxter BL, Gluckman MI, Stein L, Scerni RA (1974) Self-injection of apomorphine in the rat: Positive reinforcement by a dopamine receptor stimulant. Pharmacol Biochem Behav 2:387–391
Bertalmio AJ, Woods JH (1989) Reinforcing effect of alfentanil is mediated by mu opioid receptors: Apparent pA2 analysis. J Pharmacol Exp Ther 251:455–460
Colquhoun D (2007) Why the Schild method is better than Schild realised. Trends Pharmacol Sci 28:608–614
Flory GS, Woods JH (2003) The ascending limb of the cocaine dose–response curve for reinforcing effect in rhesus monkeys. Neuropsychopharmacology 166:91–94
Kenakin TP (1997) Pharmacological analysis of drug-receptor interaction, 3rd edn. Lippincott-Raven, Philadelphia
Mello NK, Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14:375–424
Nicolaysen LC, Pan HT, Justice JB Jr (1988) Extracellular cocaine and dopamine concentrations are linearly related in rat striatum. Brain Res 456:317–323
Norman AB, Norman MK, Hall JF, Tsibulsky VL (1999) Priming threshold: a novel quantitative measure of the reinstatement of cocaine self-administration. Brain Res 831:165–174
Norman AB, Tsibulsky VL (2001) Satiety threshold regulates maintained self-administration: comment on Lynch and Carroll (2001). Exp Clin Psychopharmacol 9:151–154
Norman AB, Tsibulsky VL (2006) The compulsion zone: A pharmacological theory of acquired cocaine self-administration. Brain Res 1116:143–152
Norman AB, Tabet MR, Norman MK, Tsibulsky VL (2011a) Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists. J Neurosci Methods 194:152–258
Norman AB, Norman MK, Tabet MR, Tsibulsky VL, Pesce AJ (2011b) Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self-administration. Synapse 65:404–411
Pettit HO, Justice JB Jr (1989) Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis. Pharmacol Biochem Behav 34:899–904
Pickens R, Thompson T (1968) Cocaine-reinforced behavior in rats: Effects of reinforcement magnitude and fixed-ratio size. J Pharmacol Exp Ther 161:122–129
Rang HP (2006) The receptor concept: Pharmacology’s big idea. Br J Pharmacol 147(Suppl 1):S9–S16
Roberts DCS, Vickers G (1984) Atypical neuroleptics increase self-administration of cocaine: An evaluation of a behavioural screen for antipsychotic activity. Neuropsychopharmacology 82:135–139
Rowlett JK, Wilcox KM, Woolverton WL (1998) Self-administration of cocaine-heroin combinations by rhesus monkeys: Antagonism by naltrexone. J Pharmacol Exp Ther 286:61–69
Schild HO (1949) pAx and competitive drug antagonism. Br J Pharmacol Chemother 4:277–280
Schild HO (1957) Drug antagonism and pAx. Pharmacol Rev 9:242–246
Sizemore GM, Martin TJ (2000) Toward a mathematical description of dose-effect functions for self-administered drugs in laboratory animal models. Neuropsychopharmacology 153:57–66
Tsibulsky VL, Norman AB (1999) Satiety threshold: A quantitative model of maintained cocaine self-administration. Brain Res 839:85–93
Tsibulsky VL, Norman AB (2005) Real time computation of in vivo drug levels during drug self-administration experiments. Brain Res Brain Res Protoc 15:38–45
Weeks JR (1962) Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rats. Science 138:143–144
Wilson MC, Hitomi M, Schuster CR (1971) Psychomotor stimulant self administration as a function of dosage per injection in the rhesus monkey. Neuropsychopharmacology 22:271–281
Wise RA (1987) Intravenous drug 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, Newton P, Leeb K, Burnette B, Pocock D, Justice JB Jr (1995) Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Neuropsychopharmacology 120:10–20
Yokel RA, Pickens R (1974) Drug level of d- and l-amphetamine during intravenous self-administration. Neuropsychopharmacology 34:255–264
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”? Neuropsychopharmacology 171:349–351
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
Zittel-Lazarini A, Cador M, Ahmed SH (2007) A critical transition in cocaine self-administration: Behavioral and neurobiological implications. Neuropsychopharmacology 192:337–346
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Tsibulsky, V.L., Norman, A.B. (2012). Simple Deterministic Mathematical Model of Maintained Drug Self-administration Behavior and Its Pharmacological Applications. In: Gutkin, B., Ahmed, S. (eds) Computational Neuroscience of Drug Addiction. Springer Series in Computational Neuroscience, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0751-5_1
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