Antinociceptive and adverse effects of morphine:ketamine mixtures in rats.

Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague-Dawley rats (n = 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.

Interactions between opioids and stimulants: Behavioral pharmacology of abuse-related effects.

Opioid abuse continues to be a significant public health challenge, with rates of opioid-related overdose deaths increasing continuously over the last two decades. There also has been a sharp increase in overdose deaths involving stimulant drugs, primarily cocaine and methamphetamine. Recent estimates indicate a high prevalence of co-use of opioids and stimulants, which is a particularly complex problem. Behavioral pharmacology research over the last few decades has characterized interactions between opioids and stimulants as well as evaluated potential treatments. This chapter describes interactions between opioids and stimulants, with a focus on pre-clinical studies of abuse-related behavioral effects using self-administration, reinstatement, drug discrimination, place conditioning, and intracranial self-stimulation paradigms in laboratory animals. In general, the literature provides substantial evidence of mutual enhancement between opioids and stimulants for abuse-related effects, although such results are not ubiquitous. Enhanced abuse-related effects could manifest in many ways including engaging in drug seeking and taking behaviors with greater persistence, effort, and motivation and/or increased likelihood of relapse. Moreover, studies on opioid/stimulant combinations set the stage for evaluating potential treatments for polysubstance use. Behavioral pharmacology research has proven invaluable for elucidating these relationships using rigorous experimental designs and quantitative analyses of pharmacological and behavioral data.

Effects of remifentanil/histamine mixtures in rats responding under a choice procedure.

Intravenous drug self-administration remains the 'gold standard' for assessing abuse liability. Failure of a drug to maintain self-administration might indicate the absence of positive reinforcing effects but might also indicate the presence of aversive effects. Sensitivity to aversive and punishing effects of drugs (as well as nondrug stimuli) might collectively determine the likelihood of use, abuse and relapse. Using a choice procedure, this study compared the effects of remifentanil (mu opioid receptor agonist; 0.001-0.01 mg/kg/infusion) and histamine (H1-4 receptor agonist; 0.32-3.2 mg/kg/infusion), alone and in mixtures, to test the hypothesis that remifentanil/histamine mixtures are less reinforcing compared with remifentanil alone and less punishing compared with histamine alone. Male Sprague-Dawley rats (n = 10) chose between an intravenous infusion + a pellet and a pellet alone. Rats were indifferent to saline, chose remifentanil + a pellet over a pellet alone, and chose a pellet alone over histamine + a pellet. The effects of remifentanil/histamine mixtures generally were different from the constituent doses of histamine alone but not from remifentanil alone. A mixture containing 3.2 mg/kg/infusion histamine and either 0.001 or 0.0032 mg/kg/infusion remifentanil was not different from saline but was different from the effects of the constituent dose, insofar as choice increased compared with 3.2 mg/kg/infusion histamine alone and decreased compared with 0.001 or 0.0032 mg/kg/infusion remifentanil alone. Reinforcing doses of remifentanil combined with punishing doses of histamine can yield mixtures that are neither preferred nor avoided, offering 'proof-of-principle' for using drug mixtures to avoid adverse effects of opioid receptor agonists.

Behavioral effects of benzylideneoxymorphone (BOM), a low efficacy µ opioid receptor agonist and a δ opioid receptor antagonist.

RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects often limit use. Drugs acting concomitantly as agonists at µ opioid receptors and antagonists at δ opioid receptors produce antinociceptive effects with a reduced profile of adverse effects; one such drug, benzylideneoxymorphone (BOM), might further limit adverse effects because it appears to have lower pharmacological efficacy than other µ opioid receptor agonists. OBJECTIVES: The current study compared the acute behavioral effects of BOM with the effects of other µ opioid receptor agonists. METHODS: Discriminative stimulus and rate-decreasing effects were studied in 1 group of 7 rats discriminating 3.2 mg/kg morphine while responding under a fixed-ratio 10 schedule of food presentation. Antinociceptive effects were determined in a second group of 8 rats using a warm water tail withdrawal procedure. Reinforcing effects were evaluated in a third group of 12 rats with a history of remifentanil self-administration. RESULTS: BOM produced morphine-lever responding and both discriminative stimulus and rate-decreasing effects were antagonized by naltrexone. BOM did not markedly increase tail-withdrawal latencies from water maintained at 50 °C and did not substantially attenuate the antinociceptive effects of morphine. BOM was not self-administered and did not change remifentanil self-administration. CONCLUSIONS: Some effects of BOM (e.g., discriminative stimulus effects) appear to be mediated by µ opioid receptors; however, BOM is not self-administered by rats, suggesting that it might have limited abuse liability and a reduced profile of adverse effects compared with currently prescribed opioids.

Methocinnamox (MCAM) antagonizes the behavioral suppressant effects of morphine without impairing delayed matching-to-sample accuracy in rhesus monkeys.

RATIONALE: Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory. OBJECTIVE: This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption. RESULTS: Neither MCAM (0.32 mg/kg) nor morphine (1-5.6 mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days. Scopolamine (0.01-0.056 mg/kg) and phencyclidine (0.1-0.56 mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed. CONCLUSIONS: MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.

Effects of opioid/cannabinoid mixtures on impulsivity and memory in rhesus monkeys.

The opioid epidemic underscores the need for safer and more effective treatments for pain. Combining opioid receptor agonists with drugs that relieve pain through nonopioid mechanisms could be a useful strategy for reducing the dose of opioid needed to treat pain, thereby reducing risks associated with opioids alone. Opioid/cannabinoid mixtures might be useful in this context; individually, opioids and cannabinoids have modest effects on cognition, and it is important to determine whether those effects occur with mixtures. Delay discounting and delayed matching-to-sample tasks were used to examine effects of the mu-opioid receptor agonist morphine (0.32-5.6 mg/kg), the cannabinoid CB1/CB2 receptor agonist CP55940 (0.0032-0.1 mg/kg), and morphine/CP55940 mixtures on impulsivity (n = 3) and memory (n = 4) in rhesus monkeys. Alone, each drug decreased rate of responding without modifying choice in the delay-discounting task, and morphine/CP55940 mixtures reduced choice of one pellet in a delay dependent manner, with monkeys instead choosing delayed delivery of the larger number of pellets. With the exception of one dose in one monkey, accuracy in the delayed matching-to-sample task was not altered by either drug alone. Morphine/CP55940 mixtures decreased accuracy in two monkeys, but the doses in the mixture were equal to or greater than doses that decreased accuracy or response rate with either drug alone. Rate-decreasing effects of morphine/CP55940 mixtures were additive. These data support the notion that opioid/cannabinoid mixtures that might be effective for treating pain do not have greater, and might have less, adverse effects compared with larger doses of each drug alone.

Impact of order of fixed-ratio presentation on demand for self-administered remifentanil in male rats.

The behavioral economics framework has been used extensively to study factors that control operant behavior, including quantification of reinforcing effectiveness of drugs of abuse. Generally, consumption of a commodity decreases with increasing price, and the rate of decrease reflects demand elasticity, which is inversely related to reinforcing effectiveness. Drugs with low elasticity have greater effectiveness than those with greater elasticity. Price is often manipulated by varying the number of responses required to obtain an infusion (e.g. fixed ratio schedule); however, many studies present the fixed ratio in only one order (usually ascending), which could introduce sequence effects that influence estimates of demand. This study examined the impact of the order of fixed ratio presentation on demand for the mu opioid receptor agonist remifentanil (0.0032 mg/kg/infusion) using an ascending and a mixed order of fixed ratio presentation. Seven male rats lever pressed for intravenous infusions. The fixed ratio varied across 3-session blocks, yielding a demand curve. During the first and third phases, the fixed ratio increased, and, during the second phase, fixed ratio values were presented in a mixed order. On average, rats obtained more than 60 infusions per session under baseline (fixed ratio 1) during the each of the three phases, with the number of infusions received decreasing progressively with increasing fixed ratio values. Estimates of elasticity across the three phases were not statistically different indicating that the order of fixed ratio presentation did not markedly alter estimates of demand and further demonstrating the robustness of price as a source of control over operant behavior, including behavior maintained by drug reinforcers.

Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of µ-Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats.

A novel µ-opioid receptor antagonist, methocinnamox (MCAM), attenuates some abuse-related and toxic effects of opioids. This study further characterized the pharmacology of MCAM in separate groups of rats using procedures to examine antinociception, gastrointestinal motility, and withdrawal in morphine-dependent rats. Antinociceptive effects of opioid receptor agonists were measured before and after MCAM (1-10 mg/kg) using warm water tail withdrawal and sensitivity to mechanical stimulation in inflamed paws (complete Freund's adjuvant). Before MCAM, morphine, fentanyl, and the κ-opioid receptor agonist spiradoline dose dependently increased tail-withdrawal latency from 50°C water; MCAM attenuated the antinociceptive effects of morphine and fentanyl, but not spiradoline. Morphine increased sensitivity to mechanical stimulation and decreased gastrointestinal motility, and MCAM blocked both effects. These antagonist effects of 10 mg/kg MCAM were persistent, lasting for 2 weeks or longer. Withdrawal emerged after discontinuation of morphine treatment or administration of 10 mg/kg MCAM or 17.8 mg/kg naloxone; other than the day of antagonist administration when withdrawal signs were greater in rats that received antagonist compared with rats that received vehicle, there was no difference among groups in directly observable withdrawal signs or decreased body weight. These results confirm that MCAM is a selective µ-opioid receptor antagonist with an exceptionally long duration of action, likely due to pseudoirreversible binding. Despite its sustained antagonist effects, the duration of withdrawal precipitated by MCAM is not different from that precipitated by naloxone, suggesting that the long duration of antagonism provided by MCAM could be particularly effective for treating opioid abuse and overdose. SIGNIFICANCE STATEMENT: The opioid receptor antagonist MCAM attenuates some abuse-related and toxic effects of opioids. This study demonstrates that MCAM selectively antagonizes multiple effects mediated by µ-opioid receptor agonists for 2 weeks or longer, and like naloxone, MCAM precipitates withdrawal in morphine-dependent rats. Despite this persistent antagonism, withdrawal signs precipitated by MCAM are not significantly different from signs precipitated by naloxone or occurring after discontinuation of morphine, suggesting that using MCAM for opioid abuse or overdose would not produce sustained withdrawal.

Effect of Food Predictability on Life Span in Male Mice.

The purpose of this study is to compare the effect of unpredictable (U) or predictable (P) food delivery on health and longevity in mice. From 2 months of age until end of life, singly-housed male C57BL/6 mice were fed a semisynthetic diet either ad libitum (AL), or as imposed meals delivered as small pellets at either P or U times, frequencies, or amounts. The total daily food consumed by all groups was the same. The AL group gained body weight faster than either P or U groups, and had ~12% shorter median life span compared with either P or U groups. Bimonthly noninvasive body composition determinations showed that the differences in body weights were due to differences in fat and lean mass. Postmortem examinations revealed that the organ pathologies were similar in all groups, but a larger fraction of P and U mice were euthanized due to end-of-life suffering. There were no systematic differences in outcome measures between P and U groups suggesting that, within the range studied, the temporal pattern of food delivery did not have a significant metabolic effect.

Punishment and reinforcement by opioid receptor agonists in a choice procedure in rats.

Intravenous (i.v.) drug self-administration remains the 'gold standard' for assessing abuse potential of drugs. Failure of a drug to maintain self-administration might indicate merely the absence of positive-reinforcing effects but might also indicate presence of aversive effects. Sensitivity to aversive effects is thought to affect the initiation and maintenance of drug use as well as relapse. Choice procedures are used to study positive-reinforcing effects of drugs and to a much lesser extent to study punishing effects of drugs. Experiment 1 compared the µ-opioid receptor agonist remifentanil (0.001-0.01 mg/kg/infusion), the κ-opioid receptor agonist spiradoline (0.0056-0.056 mg/kg/infusion), and histamine (1.0 mg/kg/infusion) in rats choosing between a food pellet only and an i.v. infusion+a food pellet. To test whether a history with one punishing drug affects the punishing effects of a second drug, experiment 2 compared sensitivity with spiradoline in rats with and without a history of histamine punishment. All rats predominantly chose a pellet alone when histamine+a pellet was the alternative, and they predominantly chose remifentanil+a pellet over a pellet alone. In experiment 2, spiradoline was punishing in rats with a history of histamine punishment but not drug-naive rats. This food choice procedure is sensitive to reinforcing and punishing effects of different drugs in the same subjects, suggesting that the procedure is well-suited for studying drug mixtures (e.g. µ and κ agonists) and the impact of different physiological conditions (e.g. pain) on reinforcement and punishment.

Interactions between kappa and mu opioid receptor agonists: effects of the ratio of drugs in mixtures.

RATIONALE: Pain is the leading reason for seeking health care, and mu opioid receptor agonists continue to be prescribed despite well-documented adverse effects. Kappa opioid receptor agonists have antinociceptive effects with little to no abuse liability and might be useful for treating pain in mixtures. Kappa:mu opioid mixtures might be useful if therapeutic effects of each drug can be selectively increased while reducing or avoiding the adverse effects that occur with larger doses of each drug alone. OBJECTIVE: This study characterized the effects of the kappa opioid receptor agonist spiradoline alone (0.32-56 mg/kg) and in 1:10, 1:3, 1:1, and 3:1 mixtures with the mu opioid receptor agonists morphine (1.0-32 mg/kg) and etorphine (1-10 µg/kg) on warm water tail-withdrawal latency, body temperature, responding for food, and fecal output in male Sprague-Dawley rats (n = 24). RESULTS: Antinociceptive effects were greater than additive for 1:10 and 1:3 spiradoline:morphine mixtures and for 1:10, 1:3, and 1:1 spiradoline:etorphine mixtures. The potency of spiradoline to produce hypothermia was greater with 1:3 and 3:1 spiradoline:etorphine mixtures but not with 1:10 or 1:1 mixtures or with any spiradoline:morphine mixture. The effects of 1:3 spiradoline:morphine on responding for food were additive, whereas 1:1 and 3:1 were greater than additive. Spiradoline did not significantly alter morphine-induced decreases in fecal output. CONCLUSIONS: Overall, mixtures of kappa and mu opioids might have therapeutic potential for treating pain, particularly when the mixture has a greater ratio of mu to kappa agonist. If adverse effects of each constituent drug are reduced or avoided, then kappa:mu mixtures might be advantageous to mu opioids alone.

Effects of morphine/CP55940 mixtures on an impulsive choice task in rhesus monkeys.

µ-Opioid receptor agonists are commonly used to treat pain despite their adverse effects. In preclinical studies, cannabinoid receptor agonists increase the potency of opioids for producing antinociceptive but not reinforcing effects. It is unknown whether other adverse effects of these drugs, such as impairment of complex behavior, are enhanced by their co-administration. This study characterized the effects of morphine (µ-opioid receptor agonist; 0.32-5.6 mg/kg, subcutaneously) and CP55940 (CB1/CB2 cannabinoid receptor agonist; 0.0032-0.32 mg/kg, subcutaneously), alone and in mixtures, in monkeys (n=3) choosing between one pellet delivered immediately and two pellets delivered after a delay. Two consecutive choices of the immediate or delayed reward decreased or increased, respectively, the delay. The median adjusted delay, indicating indifference between the immediate and delayed reinforcers, was increased by morphine (3.2 mg/kg) and CP55940 (0.01-0.032 mg/kg). Performance after administration of morphine (0.32 and 1 mg/kg)/CP55940 (0.0032-0.032 mg/kg) mixtures was not different from performance after CP55940 alone. Neither morphine, CP55940, nor mixtures decreased the median adjusted delay (i.e. increased impulsivity). These findings failed to confirm previous studies showing that morphine increases impulsivity, perhaps because of procedural differences among studies. Treatment of pain often requires repeated drug administration; thus, it remains to be determined whether the present findings predict the effects of chronically administered morphine/CP5540 mixtures on impulsive choice.

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats.

Pain is a significant clinical problem, and there is a need for more effective treatments with reduced adverse effects that currently limit the use of µ opioid receptor agonists. Synthetic κ opioid receptor agonists have no abuse liability and well-documented antinociceptive effects; however, adverse effects (diuresis, dysphoria) preclude their use in the clinic. Combining κ opioids with nonopioid drugs (cannabinoid receptor agonists) allows for smaller doses of each drug to produce antinociception. This study tested whether a potentially useful effect of the κ opioid receptor agonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl] (spiradoline; antinociception) is selectively enhanced by the cannabinoid receptor agonist 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP55940). Cumulative dose-response functions were determined in eight male Sprague-Dawley rats for spiradoline (0.032-32.0 mg/kg, i.p.) and CP55940 (0.0032-1.0 mg/kg, i.p.) for antinociception, hypothermia, food-maintained responding, and diuresis. Alone, each drug dose dependently increased tail withdrawal latencies from 50°C water, decreased body temperature by ∼4°C, and eliminated food-maintained responding. Spiradoline, but not CP55940, significantly increased urine output at doses that eliminated responding. Smaller doses of spiradoline and CP55940 in mixtures (3:1, 1:1, and 1:3 spiradoline:CP55940) had effects comparable to those observed with larger doses of either drug administered alone: the interaction was additive for antinociception and additive or greater than additive for hypothermia and food-maintained responding. Collectively, these data fail to provide support for the use of these mixtures for treating acute pain; however, κ opioid/cannabinoid mixtures might be useful for treating pain under other conditions (e.g., chronic pain), but only if the adverse effects of both drugs are not enhanced in mixtures.

Differences in temporal aspects of food acquisition between rats and two strains of mice in a closed operant economy.

Rats and mice were studied for changes in meal-taking structure in a closed operant food economy, in which the consummatory or unit prices for food were increased. In experiment 1, as food price increased, male rats modestly decreased the number of meals per day and increased mean meal size. Female rats were similar to males but had smaller meal size and, at low costs, took more meals per day. In experiment 2, male and female B6 mice reduced food intake as price increased, accompanied by decreased meal number without change in meal size. They showed grazing-like behavior in the first part of the night. In contrast, we report in experiment 3, a large increase in intake and meal size during the final trimester of pregnancy. In experiment 4, we report that CD1 male mice subjected to a unit price series performed comparably to rats, and not like B6 mice. Other CD1 mice were tested using an interval schedule, and we found that mice were able to adapt eating patterns to greatly increased time demands without compromising total intake. Data are discussed in terms of the intercalation of food acquisition with global patterns of activity. Such interactions of organism and food environment are in particular need of mechanistic investigation.

Role of estrogen receptor-α on food demand elasticity.

Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype ß, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions.

Economics of food intake in mice: energy yield of the reinforcer.

One of the Zeitgeists of the field for the study of ingestive behavior is that organisms are endowed with internal self-regulatory mechanisms that ensure optimal nutrition. However, the alarming increase in the prevalence of obesity challenges us to reconsider the extent to which internal regulatory mechanisms affect food intake, especially in a free market economy. Cued by the pioneering work of George Collier and his students, we have been examining food intake (demand) in mice when the effort or price of food is manipulated. We present two new experiments in mice that investigate the effect of energy yield per unit of food earned on working for food. The first experiment shows that when the nominal energy yield of each food pellet is halved by cellulose dilution, mice show relatively inelastic calorie-related demand despite the fact the cellulose diluted diet is unpalatable. The second experiment shows that the size of the pellet reinforcer does not have a major effect on food demand except in the extreme condition of small reward and high unit price. New analyses of distributions of responding are presented which suggest that mice work for "target" numbers of food rewards with only a small influence of price or energy gain.

Effects of price and pellet type on food waste in mice.

When laboratory mice are provided with free access to food, they often fragment their food such that it collects on the cage floor - wasted. An operant analysis of food waste, however, has not yet been conducted. The purpose of the present study was to evaluate the effect of response requirement and pellet type on food waste using a behavioral economic paradigm. Sixteen mice responded under a series of escalating fixed ratio schedules. Nose pokes were reinforced with either a grain-based pellet or a fiber-based pellet (diluted with non-digestible cellulose) across conditions. We found that mice spilled a greater percent of the total earned pellets at low response requirements. Additionally, mice spilled more fiber-based pellets relative to grain-based pellets. This difference was most pronounced when the fixed ratio requirement was low and was attenuated as the fixed ratio was increased, and this decrease in food waste across prices was well accounted for by an exponential model. Mice may have been extracting the calorically dense components of the fiber-based pellets only when the schedule of reinforcement was rich. When the schedule of reinforcement was lean, responding for a new pellet likely was a more functional behavior than fragmenting a pellet and discarding portions.

Tolerance to cocaine's effects following chronic administration of a dose without detected effects on response rate or pause.

To observe tolerance to drug effects on operant behavior, the dose that researchers have often selected for chronic administration is one that disrupts, but does not abolish, responding. Some evidence suggests that tolerance may develop after chronic administration of relatively smaller doses. The purpose of the present experiment was to assess systematically effects of chronic administration of a dose without detected effect on responding. Specifically, response rates and post-reinforcement pauses of five pigeons key pecking under a three-component multiple fixed-ratio schedule of food reinforcement were observed under chronic cocaine administration. We evaluated the effects of a range of doses (1.0 mg/kg to 17.0 mg/kg) during acute administration. The largest dose that failed to alter responding acutely then was administered chronically (1.0 mg/kg for 1 pigeon, 3.0 mg/kg for 3 pigeons, and 5.6 mg/kg for 1 pigeon). After 30 consecutive sessions of chronic administration, smaller and larger doses occasionally were substituted for the chronic dose. Pigeons then received pre-session saline administration for 30 consecutive sessions, and the post-chronic effects of the series of doses on responding were determined. All subjects developed tolerance to doses of cocaine that initially had caused large decreases in rate, with the magnitude of the effects varying across components of the multiple schedule and subjects. Specifically, tolerance generally was greatest in the components with smaller ratios. Following post-chronic saline administration, tolerance was usually diminished. Overall, the results demonstrate that under these conditions, repeated experience with disruptive effects of cocaine on food-maintained responding is not a necessary factor in the development of tolerance.