Delay discounting of cocaine by rhesus monkeys

The present, subjective value of a reinforcer typically decreases as a function of the delay to its receipt, a phenomenon termed delay discounting. Delay discounting, which is assumed to reflect impulsivity, is hypothesized to play an important role in drug abuse. The present study examined delay discounting of cocaine injections by rhesus monkeys. Subjects were studied on a discrete-trials task in which they chose between 2 doses of cocaine: a smaller, immediate dose and a larger, delayed dose. The immediate dose varied between 0.012 and 0.4 mg/kg/injection, whereas the delayed dose was always 0.2 mg/kg/injection and was delivered after a delay that varied between 0 and 300 s in different conditions. At each delay, the point at which a monkey chose the immediate and delayed doses equally often (i.e., the ED50) provided a measure of the present, subjective value of the delayed dose. Dose-response functions for the immediate dose shifted to the left as delay increased. The amount of the immediate dose predicted to be equal in subjective value to the delayed dose decreased as a function of the delay, and hyperbolic discounting functions provided good fits to the data (median R(2)=.86). The current approach may provide the basis for an animal model of the effect of delay on the subjective value of drugs of abuse.     

Economic choice between remifentanil and food in squirrel monkeys

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.Subject terms: Addiction, Decision     

A behavioral economic analysis of cocaine and remifentanil self-administration in rhesus monkeys

Rationale Behavioral economics can be used to evaluate the relative reinforcing effectiveness of drugs and the economic interaction between drugs, information which may help to explain patterns of polydrug abuse in humans. Objectives In phase 1, the reinforcing effectiveness of the opiate remifentanil and the stimulant cocaine was compared using a demand-curve analysis. In phase 2, the economic relation between these drugs was determined. Materials and methods Rhesus monkeys pressed levers according to fixed-ratio schedules for intravenous drug infusions. A demand-curve analysis was conducted (phase 1) in which drug consumption was measured as the response requirement, or price, was increased, and the rate at which consumption decreased with increases in price (demand elasticity) provided an index of the reinforcing effectiveness of each drug. Cocaine and remifentanil were then available concurrently (phase 2), and the price of one drug was increased (the manipulated-price alternative) while the price of the other drug was held constant (the fixed-price alternative). Consumption of the fixed-price alternative was measured as a function of increases in the price of the manipulated-price alternative, and demand for the manipulated-price alternative was assessed. Results The reinforcing effectiveness of cocaine and remifentanil did not significantly differ, and these drugs functioned as economic substitutes. As the price of the manipulated-price alternative increased, consumption of the fixed-price alternative increased. In addition, demand for the manipulated-price alternative became more elastic with the concurrent availability of the fixed-price alternative. Conclusion Polydrug use involving stimulants and opiates may occur because these drugs are highly substitutable. This work was supported by United States Public Health Service Grant DA 015449 and Training Grant DA 007268.     

Effects of punishment on choice between cocaine and food in rhesus monkeys

Rationale Punishment is widely used in an effort to control drug-taking behavior; however, only a few preclinical studies have investigated the effects of punishment on drug self-administration. Such studies may contribute to more rational use of punishment to control drug use. Objectives To evaluate the effects of punishment on choice between cocaine and food in rhesus monkeys. Methods Rhesus monkeys were trained under a concurrent-choice schedule of food delivery (1 g pellets, fixed-ratio 100 schedule) or cocaine injections (0–0.1 mg/kg per injection, fixed-ratio 10 schedule). Full cocaine choice dose–effect curves were determined under baseline conditions and under test conditions in which a putative punisher (intravenous histamine injection; 0.0032–0.032 mg/kg per injection) was paired with either food or cocaine delivery. Results Under baseline conditions, cocaine produced a dose-dependent increase in cocaine choice. Histamine functioned as a punisher of both food- and cocaine-maintained responding. Pairing histamine with food delivery reduced food choice, increased cocaine choice, and produced left shifts in the cocaine choice dose–effect curve. Conversely, pairing histamine with cocaine decreased cocaine choice, increased food choice, and produced right shifts in the cocaine choice dose–effect curve. The magnitude of histamine’s punishing effects was directly related to histamine dose and probability of histamine delivery, and inversely related to the magnitude of the reinforcer. Conclusions These results demonstrate that a primary effect of punishment in the context of food vs cocaine choice is not only a decrease in the behavior being punished, but also an increase in the unpunished alternative behavior.     

Observing responses maintained by stimuli associated with cocaine or remifentanil reinforcement in rhesus monkeys

Abstract Rationale. The stimuli associated with drug reinforcement may be particularly relevant to drug abuse and relapse. Objectives. The study measured behavior maintained by conditioned reinforcing stimuli in an observing response procedure. Methods. The experiment was conducted with rhesus monkeys in three stages: 1) discriminative control was established by reinforcing responding on one lever with either intravenous cocaine or remifentanil in the presence of one stimulus and extinguishing the response in the presence of another stimulus, 2) discriminative control was suspended by not presenting the stimuli, and 3) a final stage was implemented wherein the stimuli from the first stage were presented only when one or more responses were made on a second (observing) lever. Results. Under FR1 conditions, observing responses were maintained at low rates, but increased markedly when the response requirement was increased. Conclusions. The procedure maintained observing responses quite well and may be useful to an analysis of conditioned reinforcement based on drug reinforcement. Electronic Publication     

Effects of food deprivation on cocaine base smoking in rhesus monkeys

Studies have shown that both food deprivation and response cost have important influences on the magnitude of self-administration of a wide variety of psychoactive drugs. In an attempt to extend these findings to the smoked route of drug self-administration, the effects of food allotment and fixed-ratio (FR) value were evaluated in four male rhesus monkeys trained to smoke cocaine base. In the first phase of the experiment, monkeys were trained to self-administer smoked cocaine base under a chained progressive-ratio (PR), fixed-ratio (FR) schedule during daily experimental sessions. Monkeys were required to make 20 lever-press responses and then five inhalations on a smoking spout to obtain the first smoke delivery. The lever ratio then increased to 60, 140, 300, 620, 1260, 2540, and 4940 for each successive smoke delivery. The initial lever ratio value was reset to 20 at the beginning of each daily session. The body weights of three monkeys were determined under free-feeding conditions. Monkeys were then restricted to 100 g food and, when body weights had stabilized, the daily food allotment was increased to 150 g, approximately 210 g, or greater than 400 g (satiation). As the daily food allotment and body weight increased, the mean number of smoke deliveries decreased in two of three monkeys. In the second phase of the experiment, three monkeys were maintained under either food-satiated or food-restricted conditions. Body weights were maintained at approximately 90% of their free-feeding weights under food-restricted conditions. The cost of the drug (lever FR value) was constant within each experimental session, but was increased after 3 consecutive days of stable responding. Fixed-ratio values were increased from 128 to 256, 512, 1024, and 2048. Monkeys were required to complete the lever FR value and then to make five inhalations on the smoking spout to gain access to 1.0 mg/kg per delivery cocaine base. The mean number of smoke deliveries increased at FR 256, 512, and 1024 when monkeys were food-restricted as opposed to food-satiated. Correspondingly, the mean number of responses increased under food-restricted conditions. Responding continued to increase over a wider range of FR values, and the peak number of responses was higher under food-restricted, as opposed to food-satiated conditions. These results, using the smoking route of administration, are consistent with the hypothesis that food deprivation increases the self-administration of reinforcing drugs.     

Delay discounting in college cigarette chippers

Individuals who smoke cigarettes regularly but do not become dependent on them provide a unique opportunity for studying the factors that inhibit drug dependence. Previous research on this population, sometimes referred to as 'cigarette chippers', showed that they did not differ from regular smokers in terms of smoking topography (e.g. puff number and duration) and circulating nicotine levels, but that they did show more self-control according to answers on a questionnaire. We evaluated the generality of this finding using a behavioral choice procedure. The participants were undergraduate students (n=71), who were regular smokers, chippers, or nonsmokers. In the choice procedure, one option was a smaller but sooner amount of money, and the other option was a larger but delayed amount of money. Under these conditions, preference for the sooner smaller amount implies that the later larger monetary amounts were discounted. It is widely assumed that the rate of discounting provides an operational definition of impulsivity. In one version of the procedure, the money was hypothetical. In a second version, each choice had a chance of producing an actual monetary outcome. When there was an actual monetary outcome, regular smokers were more likely to choose the sooner but smaller monetary option than chippers and nonsmokers. For all participants, the rate of discounting decreased as the magnitude of the monetary outcomes increased, and for smokers and chippers the differences in discount rates in the two versions of the delayed outcome procedure were the same. These findings are consistent with the view that chippers are less impulsive than smokers. Quantitative aspects of these findings led to the hypothesis that discount rates decrease as a negative power function of the monetary value of the options. This result establishes an analogy between delay discounting experiments and psychophysical experiments. Results from two earlier studies support the analogy.     

Choice between cocaine and food by rhesus monkeys: effects of conditions of food availability

The present experiment was designed to examine the effects of the conditions of food availability on choice between cocaine and food in rhesus monkeys. Monkeys (n = 3), maintained at approximately 90% of their free-feeding weights, were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.03-1.0mg/kg/injection) and food delivery (4 pellets; 1g/pellet) during daily 7-h sessions. When food was available both within the session and by supplemental post-session feeding, the frequency of cocaine choice increased in a dose-related manner for all monkeys. When supplemental post-session feeding was eliminated (i.e. food was only available within the session) the cocaine dose-response function was shifted to the right and down relative to that found initially. However, changes in the frequency of cocaine choice did not vary consistently with changes in body weight. Thus, these results suggest that the reinforcing efficacy of cocaine can be modified by changing the conditions of availability of an alternative non-drug reinforcer.     

Delay discounting of real and hypothetical rewards

The degree to which real and hypothetical rewards were discounted across delays ranging from 6 hr to 1 year was explored in a within-subjects design. An adjusting-amounts procedure was used to estimate the subjective value of real and hypothetical rewards at each delay. A hyperbolic discounting function provided a significantly better fit to individual participants' preferences than did an exponential function. No significant effect of reward type on degree of hyperbolic discounting or area under the discounting curves was detected. These findings offer some support for the validity of using hypothetical rewards to estimate discounting rates in substance-abusing and other populations, but caution is suggested because this support is gleaned from a failure to detect an effect of reward type.     

A novel protocol for studying food or drug seeking in rhesus monkeys

The purpose of this study was to determine if multiple aspects of drug and food-reinforced behavior could be measured in a single study. Drug or food seeking can be observed under four conditions: 1) internal drug or food cues and external stimulus cues present; self-administration, 2) only internal cues present; priming, 3) no internal or external stimulus cues present; abstinence, and 4) no internal cues, but external stimulus cues present; extinction. Six adult rhesus monkeys lived in three-chambered enclosures: fluid (0.26, 0.52 mg/kg per delivery cocaine hydrochloride, sweetened-vehicle, or water)- related cues and oral fluid self-administration were specific to one end chamber, food pellet-related cues and food self-administration were specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day, monkeys experienced multiple food, fluid, and stimulus-cue test sessions. Adding cocaine to the vehicle initially increased fluid intake during training (condition 1), but vehicle intake did not return to baseline levels after cocaine was later removed (condition 4). Monkeys developed a location preference for the fluid chamber, even when fluid was not available, when responding was reinforced by cocaine, but not when responding was reinforced by vehicle (condition 3). Non-contingent food or fluid delivery did not increase responding in non-deprived animals (condition 2). The current protocol provides both self-administration and place-preference measures of the motivational effects of drugs. Given that human drug abusers spend much time thinking about and seeking drugs prior to actual self-administration, an animal model that uses multiple measures of drug seeking may be useful in the preclinical testing of pharmacological adjuncts for the treatment of drug abuse. Received: 9 September 1996 / Final version: 14 March 1997     

Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys

Rhesus monkeys were trained in a discretetrials choice procedure and allowed to choose between intravenous injections of cocaine (0.01–1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When each reinforcer was available under a fixed-ratio (FR) 30 schedule, the frequency of cocaine choice and the total drug intake increased in a dose-related manner for all monkeys. When the FR for cocaine was differentially increased, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right and/or downward. When the FR for cocaine was at least 480, cocaine preference could not be recovered up to doses of 1.0 mg/kg/injection. In a second experiment, when the response requirement for food was differentially increased, the frequency of cocaine choice increased. These results demonstrate that altering the response requirement for cocaine or for alternative reinforcers that are available can substantially affect cocaine self-administration.     

Effects of antipsychotic compounds in rhesus monkeys given a choice between cocaine and food

Chlorpromazine (CPZ) and haloperidol (H) have been suggested as possible antagonists of the reinforcing effects of psychomotor stimulant drugs. To test this hypothesis in animals, four rhesus monkeys were trained in a preference procedure to choose between intravenous injections of cocaine or food presentation. Frequency of cocaine choice increased as unit dose of cocaine was increased. Continuous infusions of low or intermediate doses of CPZ or H either did not affect or increased the frequency of cocaine choice. Higher doses of CPZ or H completely suppressed responding for both reinforcers. Although there appears to be a mutual antagonism of some of the effects of cocaine and these antipsychotic compounds, the results of the present experiment fail to support the hypothesis that the reinforcing effects of cocaine can be antagonized with CPZ or H.     

The effects of food deprivation and satiation on oral pentobarbital self-administration in rhesus monkeys

The effects of food deprivation and satiation on oral pentobarbital self-administration were studied in four rhesus monkeys. Pentobarbital (1.0 mg/ml) or water was available during alternate daily 3-hr session; between sessions, water was freely available. Lip contacts on a drinking spout activated a solenoid operated liquid delivery system. Liquid deliveries (0.56 ml) occurred after a fixed number of lip contact responses were emitted; that is, liquids were delivered according to fixed-ratio (FR) schedules. Under food deprivation conditions, pentobarbital-maintained behavior exceeded water-maintained behavior. Thus, pentobarbital functioned as a reinforcer. Abrupt unlimited access to food resulted in decreased pentobarbital intake. Pentobarbital-maintained behavior increased to previous levels when food intake was again restricted. In a second experiment, the effects of pentobarbital availability on water-maintained behavior were studied. Access to pentobarbital during alternate sessions produced elevated levels of water drinking during intervening sessions. Water drinking decreased to low levels when pentobarbital access was terminated and water was present for consecutive sessions. When pentobarbital was again available during alternate sessions, high levels of water drinking recurred. In the third experiment, water and pentobarbital (1.0 mg/ml) were concurrently available via separate drinking spouts. All three monkeys drank much more pentobarbital solution than water.     

Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys

Rationale Although a delay between behavior and reinforcer has been shown to weaken behavior, little is known about the effects of delay on drug choice.Objectives The present study examined effects of delay between lever press and reinforcer presentation on the choice between a drug and non-drug reinforcer and between different drug doses.Materials and methods Monkeys (n=4) were allowed to choose 32 times/day between cocaine and four food pellets. The delay between lever press and a preferred dose of cocaine (0.05 mg/kg/injection) was increased systematically from 0 to 240 s, while the delay to food remained at 0 s. A second group of monkeys (n=4) was allowed to choose between 0.05 mg/kg/injection and a lower dose of cocaine (0.025 mg/kg/injection). Next, a delay that resulted in less than 20% choice of 0.05 mg/kg/injection cocaine was selected and delay to the alternative was varied.Results Results were similar across groups. The choice of 0.05 mg/kg/injection approximated 100% at 0 delay and decreased to near 0 as delay increased. As the delay to alternative was subsequently increased from 0 to 240 s, choice of 0.05 mg/kg/injection increased, though full cocaine choice was not generally restored. The delay estimated to maintain 50% choice (indifference point) was lower for the cocaine-food choice (mean=64 s) than for the cocaine–cocaine choice (mean=207 s).Conclusions This experiment demonstrates that the choice between cocaine and a non-drug or drug alternative can be modified by increasing the interval between behavior and drug injection. Overall, the results are consistent with a temporal discounting model of drug choice.     

Delay discounting by the children of smokers and nonsmokers

This research compared delay discounting in mothers and their children (12 or 13 years of age). Half of the mothers (n=15) were current smokers, and the other half (n=15) reported never smoking. Considerable research has shown that adult smokers discount more by delay than nonsmokers, and that parent smoking is a risk factor for adolescent smoking. Thus, it was hypothesized that the mothers who smoked would discount more by delay than the mothers who had never smoked. Also, it was expected that children at increased risk for smoking (i.e., mother is smoker) would discount more by delay than children at lower risk for smoking (i.e., mother is nonsmoker). The results confirmed these hypotheses: mothers who smoked discounted significantly more than nonsmoking mothers; and, in a parallel fashion, children with mothers who smoked discounted significantly more than children of nonsmokers. These findings indicate that delay discounting may be a behavioral risk factor for adolescent cigarette smoking that predates any substantial use of nicotine.     

Cigarette smoking in rhesus monkeys

In the present pilot study, an attempt was made to shape and maintain cigarette smoking behavior in rhesus monkeys both with and without the simultaneous use of other reinforcers. Initially, 14 monkeys were trained to suck air and puff on cigarettes using sweetened liquid reinforcer. After smoking had been established, the sweetened liquid reinforcement was removed. Smoking without this reinforcement, referred to as voluntary smoking, was then observed during 20-h daily sessions. Of 14 monkeys studied, 2 have engaged in voluntary smoking for 2 years or longer. The maximum figures recorded for any single 20-h session were 3,271 puffs (20 cigarettes) in one monkey and 16,384 puffs (47 cigarettes) in the other. Although the baseline variability of smoking by these monkeys was quite high, low-nicotine and nicotine-free cigarettes seemed to lead to clear decreases in smoking. In 2 other monkeys that did not perform voluntary smoking, smoking was reestablished under a randomtime or a tandem schedule for sweetened liquid reinforcement. Within this situation (schedule-controlled smoking) schedule manipulations also led to changes in intake of cigarrette smoke. The voluntary smoking model described in the present paper should be useful for studying the factors involved in initiating and maintaining smoking behavior and for studying the psychopharmacological effects of smoking, while the schedule-controlled smoking model should be useful for studying the physiological effects of smoking and for studying the relationship of smoking with various disease entities.     

Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys

This experiment tested whether bromocriptine or desmethylimipramine (DMI), both agents used clinically to treat cocaine abuse, could specifically alter behavior maintained by cocaine injections. Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025 or 0.050 mg/kg/injection, IV) was available under a FR 30 schedule. Monkeys received continuous (24 h/day) IV infusions of several doses of bromocriptine or DMI. Bromocriptine (0.8–6.4 mg/kg/day) was infused for at least the same number of sessions as was required for responding to decline to low levels when the monkeys were allowed to self-administer saline. DMI (0.8–12.8 mg/kg/day) was infused for a minimum of 3 weeks. In some instances, low doses of bromocriptine decreased responding maintained by cocaine without reducing food-maintained responding, while higher doses of bromocriptine decreased responding maintained by either food or cocaine. However, bromocriptine doses that reduced cocaine intake also caused overt stimulation of locomotor activity. In contrast, DMI, at doses as much as 10 times higher than those used clinically to treat cocaine abuse did not affect responding maintained by cocaine or food. These results indicate that bromocriptine can selectively reduce behavior maintained by cocaine, although apparently by a mechanism other than blockade of reinforcing effects. On the other hand, DMI did not alter the reinforcing effects of either cocaine or food under these conditions.     

The generalized matching law as a predictor of choice between cocaine and food in rhesus monkeys

Rationale: The generalized matching law predicts that the relative rate of behavior maintained by different reinforcers will match the relative rate of reinforcement. It has previously been shown that responding maintained by either food deliveries or cocaine injections under concurrent variable-interval (conc VI) schedules is well described by the generalized matching law. However, the generality of this conclusion to the choice between a drug and a non-drug reinforcer has not been well established. Objective: The objective of the present study was to determine the extent to which the generalized matching law could account for choice between cocaine and food. Methods: Four male rhesus monkeys (Macaca mulatta) lever pressed under various pairs of conc VI schedules with food and/or cocaine injection as the maintaining events. Two doses of cocaine (0.025 and 0.05 mg/kg per injection) were selected to provide information about reinforcer magnitude. Results: As has been found in a context of choice between identical reinforcers, the generalized matching law accounted for most behavior. As in earlier studies with identical reinforcers, there was less responding apportioned to the alternative with the greater reinforcement frequency than predicted by the generalized matching law, i.e., undermatching was observed frequently. There was a tendency for more responding to be emitted toward the food alternative when the lower dose of cocaine was available and toward the drug alternative when the higher dose of cocaine was available. Conclusion: These results suggest that, as proposed by the generalized matching law, relative reinforcement rate is an important determinant of choice between a drug and a non-drug reinforcer. Electronic Publication     

Self-administration of minaprine in rhesus monkeys

Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and minaprine [3-(2-morpholinoethylamino)-4-methyl-6-phenyl pyridazine dihydrochloride, 3-300 micrograms/kg per infusion] during daily 1-h sessions. From 4 to over 25 times more cocaine infusions were obtained than saline infusions during baseline sessions. When minaprine was substituted for cocaine, none of the tested doses maintained responding above saline levels in two of the monkeys. Some doses of minaprine did maintain responding slightly above those of saline in the other two monkeys; however, the average number of infusions and the within-session time course of minaprine infusions at these doses were markedly more similar to saline than to that of cocaine. It was concluded that minaprine did not serve as a positive reinforcer under the present experimental conditions for any of the monkeys and it was predicted that minaprine would have low liability for recreational use in humans.     

Delay discounting predicts adolescent substance abuse treatment outcome

The purpose of the current study was to identify predictors of delay discounting among adolescents receiving treatment for marijuana abuse or dependence, and to test delay discounting as a predictor of treatment outcome. Participants for this study were 165 adolescents (88% male) between the ages of 12 and 18 (mean age = 15.8 years; standard deviation = 1.3 years) who enrolled in a clinical trial comparing three behavioral treatments for adolescent marijuana abuse or dependence. Participants completed a delay discounting task at treatment onset for $100 and $1,000 of hypothetical money and marijuana. Overall, smaller magnitude rewards were discounted more than larger magnitude rewards. Delay discounting rates were concurrently related to demographic variables (socioeconomic status, race). Delay discounting of $1,000 of money predicted during treatment abstinence outcomes among adolescent marijuana abusers, over and above the effects of type of treatment received. Teens who show higher levels of discounting of the future may be an important subgroup to identify at treatment onset. Youth with a greater tendency to discount the future may require different intervention strategies that address their impulsivity (e.g., targeting executive function or inhibitory control) and/or different schedules of reinforcement to address their degree of preference for immediate rewards.