Satiety threshold: a quantitative model of maintained cocaine self-administration

Tsibulsky, Vladimir L.; Norman, Andrew B.

doi:10.1016/s0006-8993(99)01717-5

Cited by 134 publications

(177 citation statements)

References 29 publications

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“…determined largely by the duration of the effect of each injection (Gerber and Wise, 1989;Panlilio et al, 2003;Tsibulsky and Norman, 1999), but drug-seeking under progressive-ratio schedules is essentially independent of duration of effect (Panlilio and Schindler, 2000; see also Ko et al, 2002). Thus, cross-tolerance to heroin's locomotorsuppressant effects would be expected to increase heroin intake under the FR1 schedule, but it should not alter the reinforcing efficacy of heroin under the progressive-ratio schedule.…”

Section: Discussionmentioning

confidence: 99%

Previous Exposure to THC Alters the Reinforcing Efficacy and Anxiety-Related Effects of Cocaine in Rats

Panlilio

Solinas

Matthews

et al. 2006

Neuropsychopharmacol

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The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to other drugs can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. In Experiment 1, THC preexposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Experiment 2 examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THCexposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC preexposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effectFwhich was verified in Experiment 3 using another model of anxiety, the light-dark testFmay explain the reduced reinforcing value of cocaine observed in THC-exposed rats in Experiment 1.

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Section: Discussionmentioning

confidence: 99%

Previous Exposure to THC Alters the Reinforcing Efficacy and Anxiety-Related Effects of Cocaine in Rats

Panlilio

Solinas

Matthews

et al. 2006

Neuropsychopharmacol

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“…3, demonstrate that very good correlation with lever-pressing activity can be found if we assume that the cocaine level, not the unit dose, represents the independent variable in the self-administration paradigm. The probability of lever-pressing activity was very high when the cocaine level was below (during loading and extinction phases of the session) or in the vicinity of (during maintenance phase) the critical level called the satiety threshold [16,19]. The cocaine levels calculated according to Eqs.…”

Section: Drug Concentration As a Determinant Of Behavior In The Self-mentioning

confidence: 99%

Real time computation of in vivo drug levels during drug self-administration experiments

Tsibulsky

Norman

2005

Brain Research Protocols

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A growing body of evidence suggests that the drug concentration in the effect compartment of the body is the major factor regulating self-administration behavior. A novel computer-based protocol was developed to facilitate studies on mechanisms of drug addiction by determining correlations between drug levels and behavior during multiple drug injections and infusions. The core of the system is a user's program written in Medstate Notation language® (Med-Associates, Inc.), which runs the self-administration session (with MED-PC® software and hardware, Med-Associates, Inc.) and calculates the levels of infused and/or injected drugs in real time during the session. From the comparison of classical exponential and simple linear models of first-order kinetics, it is concluded that exponential solutions for the appropriate differential equations may be replaced with linear equations if the cycle of computation is much shorter than the shortest half-life for the drug. The choice between particular computation equations depends on assumptions about the pharmacokinetics of the particular drug: (i) one-, two-or three-compartment model, (ii) zero-, first-or second-order process of elimination, (iii) the constants of distribution and elimination half-lives of the drug are known or can be reasonably assumed, (iv) dependence of the constants on the drug level, and (v) temporal stability of all parameters during the session. This method of drug level computation can be employed not only for self-administration but also for other behavioral paradigms to advance pharmacokinetic/pharmacodynamic modeling.

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“…When each response delivers a fixed dose of a reinforcing drug, there tends to be a consistent pause following each injection. This phenomenon of regulated drug intake has been observed numerous times with a variety of drugs of abuse in rodents, nonhuman primates, and humans (Sughondhabirom et al 2005), but the question of why it occurs continues to be the subject of debate (Lynch and Carroll, 2001;Panlilio et al 2003;Tsibulsky and Norman 1999).There is evidence that animals tend to self-administer an injection whenever the level of drug effect drops below a certain point (Yokel and Pickens 1974), termed the "satiety threshold" (Tsibulsky and Norman 1999), "trigger point" (Ranaldi et al 1999), or "set point" (Ahmed and Koob 1998, 1999. For example, Tsibusky and Norman (1999) showed that the durations of post-injection pauses are well described by a pharmacokinetic/ pharmacodynamic model in which the rat self-administers the next injection whenever its whole-body level of cocaine drops below a certain point.…”

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confidence: 99%

A stimulus-control account of regulated drug intake in rats

2007

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Rationale-Patterns of drug self-administration are often highly regular, with a consistent pause following 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-To emulate this hypothetical stimulus-control aspect of drug self-administration using a schedule of food reinforcement.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 (delivered during a 5-s timeout). 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-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. KeywordsSelf-administration; Incentive Learning; Titration; Cocaine; Remifentanil; Food A prominent characteristic of intravenous drug self-administration is that it tends to occur in highly regular patterns. When each response delivers a fixed dose of a reinforcing drug, there tends to be a consistent pause following each injection. This phenomenon of regulated drug intake has been observed numerous times with a variety of drugs of abuse in rodents, nonhuman primates, and humans (Sughondhabirom et al. 2005), but the question of why it occurs continues to be the subject of debate (Lynch and Carroll, 2001;Panlilio et al. 2003;Tsibulsky and Norman 1999).There is evidence that animals tend to self-administer an injection whenever the level of drug effect drops below a certain point (Yokel and Pickens 1974), termed the "satiety threshold" (Tsibulsky and Norman 1999), "trigger point" (Ranaldi et al. 1999), or "set point" (Ahmed and Koob 1998, 1999. For example, Tsibusky and Norman (1999) showed that the durations of post-injection pauses are well described by a pharmacokinetic/ pharmacodynamic model in which the rat self-administers the next injection whenever its whole-body level of cocaine drops below a certain point. The terms "satiety" and "satiation," which have been used to describe this process, imply that it might involve drive reduction, in which the motivation to receive the drug is satisfied as long as the drug level is above the threshold (Wise 1987). In this state of satiety, the need state ha...

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Satiety threshold: a quantitative model of maintained cocaine self-administration

Cited by 134 publications

References 29 publications

Previous Exposure to THC Alters the Reinforcing Efficacy and Anxiety-Related Effects of Cocaine in Rats

Previous Exposure to THC Alters the Reinforcing Efficacy and Anxiety-Related Effects of Cocaine in Rats

Real time computation of in vivo drug levels during drug self-administration experiments

A stimulus-control account of regulated drug intake in rats

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