The progressive ratio and fixed ratio 1 schedules of cocaine self-administration in rats convey the same information.

Progressive ratio (PR) schedules of drug delivery are used to determine the 'motivational' state of an animal and drug 'reinforcing efficacy'. This widely held interpretation is supported mainly by the observation that the PR breakpoint (BP) is proportional to the unit dose of self-administered drug. The compulsion zone theory of cocaine self-administration was applied to determine whether it can explain the pattern of lever-pressing behavior and cocaine injections under the PR schedule in rats. This theory states that cocaine induces lever pressing when levels are below the satiety threshold and above the priming/remission threshold. Rats were trained to self-administer cocaine on a fixed ratio FR1 schedule over a range of cocaine unit doses. Then they were switched to a PR schedule. Typical for the self-administration under a PR schedule, long post-injection pauses occurred when calculated cocaine levels were in the satiety zone. The compulsion zone theory interprets BP simply as the maximal number of responses which rats can perform after an injection while cocaine levels remain within the compulsion zone. The thresholds delineating the compulsion zone were very stable and independent of the self-administration schedule. PR and fixed ratio schedules convey the same pharmacokinetic/pharmacodynamic information, i.e., these two schedules are invariant.

Differential effects of acute and chronic antagonist and an irreversible antagonist treatment on cocaine self-administration behavior in rats.

According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when the number of receptors is altered the fractional occupancy required to maintain this set number of receptors will change. Therefore, any change in dopamine receptor number will result in a change in the concentration of cocaine required to induce the satiety response. Rats that self-administered cocaine were treated with the irreversible monoamine receptor antagonist, EEDQ, or were infused continuously for 14 days with the D1-like antagonist, SCH23390, treatments known to decrease or increase, respectively, the number of dopamine receptors with a concomitant decrease or increase in response to dopaminergic agonists. The rate of cocaine maintained self-administration increased or decreased in rats treated with EEDQ or withdrawn from chronic SCH23390 infusion, respectively. After EEDQ treatment, the effect ratio of a single dose of SCH23390 or eticlopride were unchanged, indicating that the same SCH23390- and eticlopride-sensitive receptor populations (presumably dopamine) mediated the accelerated cocaine self-administration. Changing the receptor reserve is a key determinant of the rate of cocaine self-administration because the resulting increased or decreased concentration of cocaine results in an accelerated or decelerated rate of cocaine elimination as dictated by first-order kinetics.

Dramatic increase in lever-pressing activity in rats after training on the progressive ratio schedule of cocaine self-administration.

Transition from the highest rate of lever-pressing activity during the unloading (extinction) phase of a cocaine self-administration session to an extremely low activity rate during the remission phase is in many cases gradual. This makes it difficult to assess the duration of the unloading phase after a fixed ratio 1 (FR1) or breakpoint after a progressive-ratio (PR) self-administration session. In addition, 3-5 days of training under the PR schedule results in a dramatic and persistent increase in the rate of presses during PR sessions and in the unloading phase following FR1 self-administration sessions. The goals of this study were to find the definition of the last press demarcating the border between the unloading and remission phases of the session and to determine if this border was also affected by PR training. Rats were trained to self-administer cocaine under the FR1 schedule and then under the PR schedule of drug delivery. Distributions of inter-press intervals (IPIs) during the unloading phase in sessions before and after PR training were compared. It was found that the distribution of cocaine-induced IPIs during the unloading phase was lognormal, bimodal, and independent of previously injected cocaine unit doses. The first mode represented intervals within the short bouts of stereotypic presses and the second mode represented intervals between bouts. The two modes were approximately 0.7 s and 21 s during unloading prior to and 0.6 s and 1.5 s after PR self-administration training. The total number of presses per unloading phase increased eightfold. When the FR1 schedule was restored, the intervals between bouts remained very short for at least 7-10 days and only then started a gradual increase towards baseline levels. The last unloading press was defined as the press followed by the IPI longer than the defined criterion. PR training resulted in a substantial and long-lasting increase in lever-pressing activity during unloading. The duration of the unloading phase did not depend on the rate of lever-pressing activity.

Methodological and analytical issues of progressive ratio schedules: Definition and scaling of breakpoint.

BACKGROUND: The break point (BP) of the progressive ratio (PR) schedule of drug delivery is a well-recognized parameter in self-administration studies. Nonetheless, two problems remain unresolved: there is no rationally justified criterion for the last response at BP; the both commonly used definitions of BP as the number of deliveries or the last complete progressive ratio requirement are not the best assuming that BP is a measure of motivation. NEW METHOD: A criterion for the last lever press is proposed in this study using intravenous cocaine self-administration in rats. The rationale is based on the finding that long inter-press intervals have initially very low probability to occur during the self-administration phase of the session under the PR schedule. But this probability dramatically increases when inter-injection intervals increase due to high ratio requirements. RESULTS: For cocaine these critical inter-press intervals were 7.5 min and longer. This novel criterion was applied to measure BP according to all four theoretically plausible definitions of BP including the new one: the higher of the two numbers of presses before or after the last delivery of the reinforcer. COMPARISON WITH EXISTING METHOD: The conventionally defined BP is significantly lower (by 12 %) than BP defined according to the new proposed definition. The new definition of BP provides not only a more accurate value of BP but now the variance of BP at different cocaine doses is homogeneous as required by many statistical tests. CONCLUSION: These new definitions of the last press and BP provide more accurate and statistically homogenous measure of BP.

The effects of a repeated dose of a recombinant humanized anti-cocaine monoclonal antibody on cocaine self-administration in rats.

BACKGROUND: Immunotherapy has shown potential as a treatment for cocaine abuse. The humanized recombinant anti-cocaine monoclonal antibody (mAb) with the preclinical designation h2E2 has been shown to decrease cocaine concentrations in the brain in rats, but its effects on cocaine self-administration behavior have never been tested. METHODS: The amount of cocaine needed to reinstate self-administration behavior (priming threshold) was calculated and the inter-injection intervals at unit doses of 0.3µmol/kg and 3µmol/kg during maintained self-administration were measured over a five-week baseline period. Rats trained to self-administer cocaine were infused with two doses of h2E2 (120mg/kg i.v.) 35days apart. Priming threshold and inter-injection intervals were measured for 35days after both injections. RESULTS: After both injections of h2E2, priming thresholds were significantly increased (3-fold) compared to expected baseline and then gradually declined over 35days. A significant decrease (15-33%) in inter-injection intervals during maintained self-administration was also observed following both h2E2 infusions at the lower dose, and after the first injection at the higher dose. No significant decreases in body weight were observed after either injection, indicating a lack of toxicity following a second injection. CONCLUSIONS: These data predict that the safety and effectiveness of h2E2 will be maintained after multiple treatments of this potential immunotherapy for cocaine abuse.

Maintained cocaine self-administration is determined by quantal responses: implications for the measurement of antagonist potency.

The change in frequency of cocaine self-administration as a function of the unit dose is widely assumed to represent a graded pharmacodynamic response. Alternatively, a pharmacological theory states that during maintained self-administration, a quantal response occurs at a minimum maintained cocaine concentration (satiety threshold). Rats self-administered cocaine at unit doses spanning an 8-fold range from 0.75 to 6 µmol/kg. Despite an approximately 7-fold difference in the interinjection intervals, there were no differences in the plasma cocaine concentration at the time of lever press across this range of unit doses, consistent with the satiety threshold representing an equiactive cocaine concentration. Because self-administration always occurs when cocaine concentrations decline back to the satiety threshold, this behavior represents a process of automatic back titration of equiactive agonist concentrations. Therefore, the lower frequency of self-administration at higher unit doses is caused by an increase in the duration of the cocaine-induced satiety response, and the graded dose-frequency relationship is due to cocaine pharmacokinetics. After the interinjection intervals at a particular unit dose were stable, rats were injected with the competitive D1-like dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390; 15 nmol/kg intravenously) and the session continued. At all cocaine unit doses, SCH23390 accelerated self-administration with a concomitant increase in the calculated satiety threshold, and these equiactive cocaine concentration ratios were independent of the cocaine unit dose. Therefore, the measurement of antagonist potency requires only a single unit dose of cocaine, selected on the basis of convenience, and using multiple cocaine unit doses is redundant.

The affinity of D2-like dopamine receptor antagonists determines the time to maximal effect on cocaine self-administration.

Differences in the time to maximal effect (T(max)) of a series of dopamine receptor antagonists on the self-administration of cocaine are not consistent with their lipophilicity (octanol-water partition coefficients at pH 7.4) and expected rapid entry into the brain after intravenous injection. It was hypothesized that the T(max) reflects the time required for maximal occupancy of receptors, which would occur as equilibrium was approached. If so, the T(max) should be related to the affinity for the relevant receptor population. This hypothesis was tested using a series of nine antagonists having a 2500-fold range of K(i) or K(d) values for D(2)-like dopamine receptors. Rats self-administered cocaine at regular intervals and then were injected intravenously with a dose of antagonist, and the self-administration of cocaine was continued for 6 to 10 h. The level of cocaine at the time of every self-administration (satiety threshold) was calculated throughout the session. The satiety threshold was stable before the injection of antagonist and then increased approximately 3-fold over the baseline value at doses of antagonists selected to produce this approximately equivalent maximal magnitude of effect (maximum increase in the equiactive cocaine concentration, satiety threshold; C(max)). Despite the similar C(max), the mean T(max) varied between 5 and 157 min across this series of antagonists. Furthermore, there was a strong and significant correlation between the in vivo T(max) values for each antagonist and the affinity for D(2)-like dopamine receptors measured in vitro. It is concluded that the cocaine self-administration paradigm offers a reliable and predictive bioassay for measuring the affinity of a competitive antagonist for D(2)-like dopamine receptors.

Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self-administration.

Competitive dopamine receptor antagonists increase the rate of cocaine self-administration. As the rate of self-administration at a particular unit dose is determined by the satiety threshold and the elimination half-life (t(½)) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters in rats. The plasma cocaine concentration at the time of each self-administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self-administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self-administer cocaine, SCH23390 had no effect on the plasma steady-state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t(½) at a dose that accelerated cocaine self-administration. A constant cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self-administration. SCH23390, or the D2 dopamine receptor antagonist (-)eticlopride, reinstated self-administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist-induced acceleration of cocaine self-administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first-order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased interinjection intervals.

Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists.

Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or C(min). The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration, i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D1-like or D2-like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA2 (or K(dose)) to be measured. Antagonist K(dose) values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self-administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects.

The effect of a chimeric human/murine anti-cocaine monoclonal antibody on cocaine self-administration in rats.

The predominantly human sequence anti-cocaine monoclonal antibody (mAb), 2E2, has high affinity and specificity for cocaine and antagonizes cocaine distribution to the brain in mice. To determine whether 2E2 can alter the self-administration of cocaine in rats, both cocaine-induced reinstatement (priming) of self-administration, and the rates of cocaine consumption were assessed during daily sessions. After self-administration training, the rats' cocaine priming threshold values were stable over a 2-week baseline period. Furthermore, the rates of cocaine consumption at unit doses of 0.3 and 3.0 micromol/kg were steady within sessions and stable between sessions. Then, 2E2 (120 mg/kg i.v.) or an equivalent dose of nonspecific human polyclonal IgG (control) was infused and daily sessions continued. 2E2 produced an initial, approximately 3-fold, increase in the cocaine priming threshold that declined toward baseline values over the subsequent 3 weeks, with an effect t((1/2)) of approximately 4 days. In contrast to the substantial increase in the cocaine priming threshold, 2E2 produced only modest dose-dependent increases (42 and 18%) in the cocaine consumption rates, and these also gradually declined toward baseline values. There was no significant effect of the control IgG on the priming threshold or rates of consumption of cocaine. After infusion, antibody blood concentrations declined over time, and a two-compartment pharmacokinetic model generated values for the distribution and elimination half-lives of 0.5 and 11.6 days for 2E2 and 0.4 and 6.0 days for control IgG. 2E2 had a long-lasting effect on cocaine-induced priming, which may predict its efficacy as an immunotherapy for cocaine abuse.

Mathematical models of behavior of individual animals.

This review is focused on mathematical modeling of behaviors of a whole organism with special emphasis on models with a clearly scientific approach to the problem that helps to understand the mechanisms underlying behavior. The aim is to provide an overview of old and contemporary mathematical models without complex mathematical details. Only deterministic and stochastic, but not statistical models are reviewed. All mathematical models of behavior can be divided into two main classes. First, models that are based on the principle of teleological determinism assume that subjects choose the behavior that will lead them to a better payoff in the future. Examples are game theories and operant behavior models both of which are based on the matching law. The second class of models are based on the principle of causal determinism, which assume that subjects do not choose from a set of possibilities but rather are compelled to perform a predetermined behavior in response to specific stimuli. Examples are perception and discrimination models, drug effects models and individual-based population models. A brief overview of the utility of each mathematical model is provided for each section.

The compulsion zone: a pharmacological theory of acquired cocaine self-administration.

In rats trained to reliably self-administer cocaine, the cumulative drug level was calculated during sessions in which cocaine was administered either contingently or non-contingently. During both types of sessions a high rate of responding was observed only when cocaine levels were above the priming threshold but below the satiety threshold. When the levels of non-contingently administered cocaine were maintained between the priming and satiety thresholds for at least 5 h rats continuously maintained high rates of responding. Although it is generally assumed that rats are responding for cocaine during self-administration sessions, the persistence of responding during non-contingent administration is consistent with responding being induced by cocaine. Therefore, in contrast to the basic assumptions underlying the operant theory of self-administration behavior, choice, contingency and reinforcement are not necessary to explain acquired cocaine self-administration. The presented data demonstrate that there is no ascending limb of the dose-response curve and that the cocaine priming and satiety thresholds delineate the lower and upper limits, respectively, of a cocaine "compulsion zone". It is concluded that the self-administration paradigm is the sum of cocaine induced responding and cocaine induced satiety and which of these cocaine-induced effects occur at any time is dependent on the cocaine level. This novel pharmacokinetic/pharmacodynamic theory provides a basis for a comprehensive understanding of the cocaine self-administration paradigm.

How to achieve chronic intravenous drug self-administration in mice.

INTRODUCTION: Self-administration, the best animal model of drug addiction, requires implantation of indwelling jugular catheters. Surgical procedures in mice, the most common species for transgenic modeling, are difficult owing to size and scale. The goal of this paper was to describe how to achieve successful intravenous drug self-administration in mice. METHOD: The surgical and self-administration training procedures developed for rats and other species have been adopted for mice and described in a step-by-step manner with reference to sources for equipment, materials, and parts. RESULTS: The method can be used for studying self-administration behavior in freely moving mice up to 4 weeks. The relatively quick loss of catheter patency was due to growth of neointima tissue. DISCUSSION: Drug self-administration is achievable in mice, and the model is limited only by eventual loss of catheter patency, a process probably triggered by mechanical damage of the endothelium, by the effect of drug injections, or a combination of these factors.

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

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.

The self-administration of WIN 35,428 and cocaine: comparisons of satiety threshold and elimination half-life in rats.

Rats that self-administered cocaine at unit doses between 0.75 and 12 micromol/kg with mean inter-injection intervals between approximately 2 and 18 min also reliably self-administered the cocaine analogue WIN 35,428 (beta-CFT; (-)-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester) at unit doses between 0.1 and 1.6 micromol/kg with mean intervals between 10 and 116 min. The long inter-injection intervals of WIN 35,428 necessitated sessions of more than 12 h. The inter-injection intervals were regular and proportional to the unit dose, consistent with the satiety threshold model. Analysis of the mean intervals as a function of unit doses generated values for the mean satiety threshold of cocaine and WIN 35,428 of 6.10 and 0.87 micromol/kg, respectively. The mean t(1/2) for cocaine and WIN 35,428 were 11.1 and 69.4 min, respectively. The approximately 43-fold lower rate of consumption of WIN 35,428 relative to cocaine was a product of the seven-fold greater pharmacodynamic potency and the six-fold greater pharmacokinetic potency.

Characterization of the distribution of the cocaine priming threshold and the effect of SCH23390.

The cocaine-induced reinstatement (priming) of cocaine self-administration occurs when the cumulative concentration of cocaine reaches a threshold level that we have previously termed the cocaine priming threshold. The present studies used a modified procedure to measure the cocaine priming threshold over 4-8-month periods in individual rats. The values for the priming threshold varied between days but there was no evidence of a systematic change in the priming threshold over time, indicating that neither tolerance nor sensitization occurred. The frequency distribution of the priming threshold was significantly different from a normal distribution but was not significantly different from a log-normal distribution. Therefore, the geometric mean with its associated variance estimates, but not the arithmetic mean, appropriately describe the distribution of the cocaine priming threshold. The estimate of the geometric mean value of the priming threshold for this group of Sprague-Dawley rats was 284 (CI(95): 234-344) microg/kg of cocaine. The log-normal distribution of equieffective doses of cocaine is typical of agonist-induced pharmacological responses. In the presence of the D(1) dopamine receptor-selective antagonist SCH23390, the geometric means of the cocaine priming threshold were significantly increased in a dose-dependent manner, implying a role for D(1) dopamine receptors in the priming response. This technique provides a quantitative method for the measurement of antagonist-induced increases in the cocaine priming threshold.