Research ReportThe compulsion zone: A pharmacological theory of acquired cocaine self-administration
Introduction
Cocaine reliably reinstates (primes) extinguished self-administration in rats trained to self-administer cocaine (De Witt and Stewart, 1981) and this response occurs when the cocaine concentration (level) exceeds the cocaine priming threshold (Norman et al., 1999, Norman et al., 2002). The priming threshold is defined as the minimum concentration of cocaine in the body that will reinstate self-administration (Norman et al., 1999). During the maintained self-administration of cocaine, the regularity and unit dose dependency of self-administration are long established (Pickens and Thompson, 1968). Several studies have demonstrated that pharmacological parameters can explain the regularity of maintained drug self-administration. The time between injections of amphetamine could be explained by first order drug elimination and a minimum maintained drug level (Yokel and Pickens, 1974) above which animals are in a state of satiety (Wise, 1987). Therefore, this minimum maintained drug level was termed the satiety threshold and was defined as the maximal level of cocaine at which the probability of self-administration is high and above which the probability of self-administration is low (Tsibulsky and Norman, 1999). Furthermore, in that same study, the relationship of the satiety threshold to the drug elimination half-life, the inter-injection interval and the unit dose was defined mathematically. This latter model of maintained self-administration is consistent with the report that plasma concentration of cocaine remained relatively constant during self-administration (Lau and Sun, 2002) and the hypothesis that falling dopamine levels when they reach a certain trigger point induce successive responses in the intravenous cocaine self-administration paradigm (Wise et al., 1995).
Based on the above stated definitions of the priming threshold and the satiety threshold, it can be hypothesized that self-administration occurs only when cocaine levels are between these thresholds. This is consistent with a previous proposal that once brain dopamine levels are slightly elevated by a priming injection or other manipulation, the probability of responding increases to almost one and remains high until levels of drug and nucleus accumbens levels of dopamine are sufficiently elevated (Wise, 1999). Furthermore, when the levels of cocaine at the time of each lever press during self-administration sessions were calculated the result was consistent with this hypothesis (Tsibulsky and Norman, 2005). Therefore, the priming and satiety threshold models may be unified into a comprehensive model of the self-administration paradigm.
It is commonly believed that in the self-administration paradigm the investigator controls the unit dose of drug and the animal controls the time of injection making the inter-injection interval the fundamental dependent measure. According to our unified priming and satiety thresholds model, the level of drug, rather than the unit dose, represents a critical parameter in the self-administration paradigm, therefore, the investigator should control this parameter. This is best achieved by administering the drug non-contingently. The contingency of responding on drug delivery is a central tenet of the operant theory of behavior, of which self-administration is assumed to be an example. However, if the level of drug controls responding, then it is not necessary to assume that the contingency of drug delivery is vital for the maintenance of responding. Therefore, in this study we determined whether rats would maintain lever-pressing behavior if cocaine was administered non-contingently at rates maintaining different minimal levels of cocaine in the body.
For clarification, it should be emphasized that the acquisition of self-administration behavior and environmental cue-induced priming are not included in the scope of this study. However, it is concluded herein that in rats that have acquired stable cocaine self-administration behavior cocaine induces two distinct pharmacodynamic responses relevant to the self-administration paradigm: selective facilitation of lever-presses and selective inhibition of lever-presses. Evidence is presented that the concentration of cocaine determines which of these cocaine-induced responses are observed at any time.
Section snippets
The distinct phases of a cocaine self-administration session
Fig. 1A shows the cumulative event record from a representative session illustrating that several different phases can be distinguished on the basis of the effect of unit dose and contingency on the rate of responding within a cocaine self-administration session. Lever presses induced by environmental cues extinguished quickly after placing the animals into the experimental chambers. The highest rate of self-administration was observed immediately after reinstatement. During the loading phase,
The probability of a response is determined by the cocaine concentration, not by the cocaine unit dose
Consistent with the definitions of the priming threshold and satiety threshold, lever-pressing behavior occurred only when cocaine levels were at or between these thresholds. Therefore, this range of cocaine levels constitutes operationally a “response zone” and when cocaine levels are above this response zone they are in a satiety zone. This suggests that responding may be all-or-nothing depending upon the cocaine concentration in the body. The drug unit dose is considered an important
Cocaine self-administration training
Male Sprague–Dawley rats (Sasco, Portage, MI, initial weight 180–220 g and 400–500 g over the duration of the studies) were housed individually on a 12-h light–dark cycle (lights on at 6 a.m.) and food and water were available ad lib. All studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals. Rats were surgically implanted with an indwelling catheter into the right jugular vein under halothane anesthesia (Caine et al., 1993). Beginning six or 7 days
Acknowledgments
Supported by PHS grants DA12043, DA018538 and DA14189 from the National Institute on Drug Abuse. We thank Mantana K. Norman, William R. Buesing, Michael R. Tabet and Jeremy S. Gibson for expert technical assistance.
References (23)
- et al.
Dose-response pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats
Neurotoxicol. Teratol.
(1997) - et al.
Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures
Neuropsychopharmacology
(1996) - et al.
Priming threshold: a novel quantitative measure of the reinstatement of cocaine self-administration
Brain Res.
(1999) - et al.
Characterization of the distribution of the cocaine priming threshold and the effect of SCH23390
Brain Res.
(2002) - et al.
The self-administration of WIN 35,428 and cocaine: comparisons of satiety threshold and elimination half-life in rats
Eur. J. Pharmacol.
(2004) - et al.
Satiety threshold: a quantitative model of maintained cocaine self-administration
Brain Res.
(1999) - et al.
Real time computation of in vivo drug levels during drug self-administration experiments
Brain Res. Brain Res. Protoc.
(2005) - et al.
Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function
Psychopharmacology
(2005) - et al.
Intravenous drug self-administration techniques in animals
- et al.
Instrumental conditioning of jugular self-infusion in the rhesus monkey
Science
(1961)
Reinstatement of cocaine-reinforced responding in the rat
Psychopharmacology
Cited by (48)
Differential Effect of Fixed Ratio Magnitude on the Rate of Lever-Pressing and Interinjection Intervals of Cocaine Self-Administration in Rats
2023, Current Therapeutic Research - Clinical and ExperimentalNew directions in modelling dysregulated reward seeking for food and drugs
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Although regulated patterns of cocaine intake are commonly observed with limited daily access to cocaine self-administration, dysregulated patterns are observed during continuous or long access. With limited access, rats typically self-administer cocaine in a stable manner that appears guided by satiety, with rats displaying consistent pauses after each infusion, modulating inter-infusion intervals according to dose, and achieving a consistent concentration of cocaine in the brain (Tsibulsky and Norman, 1999; Norman and Tsibulsky, 2006; Lau and Sun, 2002; Zimmer et al., 2011). However, with continuous or long access to cocaine self-administration, a dysregulated pattern emerges that is not directly guided by satiety, with rats displaying escalation of intake, alternating periods of bingeing and abstinence, and increased variability in inter-infusion intervals (Bozarth and Wise, 1985; Ahmed and Koob, 1998; Tornatzky and Miczek, 2000).
Methodological and analytical issues of progressive ratio schedules: Definition and scaling of breakpoint
2021, Journal of Neuroscience MethodsPre-trial cocaine biases choice toward cocaine through suppression of the nondrug option
2018, Pharmacology Biochemistry and BehaviorCitation Excerpt :This option-specific interference effect may contribute to explain why rats would shift choice to cocaine after pre-trial cocaine. Second, previous research has shown that once the reward satiating effects of cocaine have dissipated, the motivation for cocaine can be transiently enhanced either because of a drug-induced increase in the drug incentive value (Robinson and Berridge, 1993), a compulsive-like mechanism (Norman and Tsibulsky, 2006) and/or an attempt to avoid a transient post-cocaine withdrawal affective state (Ettenberg, 2004). Importantly, in absence of the drug option (i.e., no-choice sessions of sweet water), such enhanced motivation for the drug may be reoriented toward a nondrug option, provided that it can function as a drug substitute (Green and Freed, 1993; Hursh, 1980).