Discriminative-stimulus effects of cannabidiol oil in Sprague-Dawley rats.

Cannabidiol (CBD) is one of the major centrally active phytocannabinoid components of cannabis, and has been approved by the FDA only for the treatment of seizures associated with three rare disorders. It has also been touted as a potential treatment for anxiety in place of more traditional treatments like benzodiazepines. Although there is some evidence of anxiolytic effects of CBD, its suitability as a substitute for benzodiazepines is unknown. This experiment was designed to assess the extent to which CBD shares interoceptive discriminative-stimulus properties with the anxiolytic drug chlordiazepoxide (CDP), a benzodiazepine. In the present experiment, a range of doses (0-1569 mg/kg) of over-the-counter CBD oil was administered (i.g.) in male Sprague-Dawley rats trained to discriminate 5.6 mg/kg CDP from saline. Due to the long time-course effects of CBD, generalization tests were conducted at 90 and 120 min post-CBD administration. The two highest doses of CBD tested (1064 and 1569 mg/kg) were found to partially substitute for 5.6 mg/kg CDP, with mean percent responding on the CDP-associated lever reaching above 20% at time 2 (120 min post-CBD administration), suggesting that high doses of the over-the-counter CBD oils used in this experiment share interoceptive discriminative-stimulus properties to some degree with CDP. These results are novel in comparison to existing research into stimulus effects of CBD, in which substitution for benzodiazepines has not previously been observed.

Effects of acute and chronic nicotine administration on probability discounting.

Nicotine use is a continuing public health concern. Smokers are more likely to make risky or maladaptive decisions compared to nonsmokers, so the relation between nicotine and risky choice warrants further investigation. Risky choice can be operationally defined as the choice for a larger, uncertain reinforcer over a smaller, certain reinforcer and can be assessed through a probability-discounting procedure. Acute nicotine administration has been shown to alter risky choice, but because the everyday smoker uses nicotine repeatedly, more research on chronic administration is needed and would allow for assessment of tolerance or sensitization of any effects. The present study examined effects of acute and repeated nicotine administration on probability discounting. Sprague-Dawley rats were used as subjects and the probability-discounting task involved discrete-trial choices between a small, certain reinforcer and a larger, uncertain reinforcer. The probability of larger-reinforcer delivery decreased across blocks within each session. Acute nicotine (0.1-1.0 mg/kg) administration dose-dependently increased risky choice, increased lose-stay ratios (a measure of response perseveration), and decreased reinforcement frequency. Tolerance to nicotine's effects on larger-reinforcer choice was observed after repeated 1.0 mg/kg nicotine administration. The results of the present study add to the existing literature that acute nicotine administration increases risky choice and demonstrates that tolerance to this effect develops after chronic exposure to the drug. Possible behavioral mechanisms behind this effect are discussed, as are suggestions for future research on nicotine and risky choice.

Differential effects of d-amphetamine and atomoxetine on risk-based decision making of Lewis and Fischer 344 rats.

Individuals with attention-deficit/hyperactivity disorder tend to make risker choices during probabilistic-discounting procedures. Thus, how common attention-deficit/hyperactivity disorder medications affect probabilistic discounting is of interest. In general, d-amphetamine increases risk-taking while atomoxetine has produced mixed effects in rats. Results from previous studies may result from genetic factors. Lewis and F344 rats have neurochemical differences that may be relevant to probabilistic discounting and how drugs affect such behavior. In this study, we evaluated dose-dependent effects of d-amphetamine and atomoxetine on probabilistic discounting of Lewis and F344. Male Lewis and F344 chose between one food pellet delivered 100% of the time and three food pellets delivered following decreasing probabilities of delivery (i.e. 100%, 66.7%, 33.3%, 16.5%, and 8.25%). Saline, d-amphetamine (0.1-1.8 mg/kg), and atomoxetine (0.1-7.8 mg/kg) were tested acutely. Lewis and F344 did not differ in choice at baseline. d-Amphetamine increased risky choice for both rat strains at low-to-moderate doses, although it did so at a lower dose (0.1 and 0.3 mg/kg) for F344 as compared to Lewis (0.3 mg/kg only). At high doses (1.0 and 1.8 mg/kg), d-amphetamine disrupted choice, increased frequencies of omitted trials, and reduced reinforcer sensitivity. Although atomoxetine increased frequencies of omitted trials at high doses (5.6 and 7.8 mg/kg), it had no effect on probabilistic discounting for either rat strain. Although Lewis and F344 differ in various types of impulsivity (i.e. motor, choice), with Lewis being the more impulsive of the two, the present results suggest that Lewis and F344 do not differ in risk-based decision-making. Effects of d-amphetamine on probabilistic discounting may be biology-dependent and differ from effects of atomoxetine.

Pair Housing Alters Delay Discounting in Lewis and Fischer 344 Rats.

Impulsive choice underlies several psychological disorders and can be assessed in laboratory rats using delay-discounting tasks, in which choice is for either one food pellet immediately or three food pellets after a delay. Choice for the smaller, immediate reinforcer is considered the impulsive choice. Lewis (LEW) and Fischer 344 (F344) rats differ in the number of impulsive choices made during this task when singly housed, with LEW choosing the impulsive option more often. Due to increasing recommendations to provide environmental enrichment as a component of animal-husbandry practices, a systematic replication of two previous studies was conducted using pair-housed LEW and F344. Delay discounting was assessed with pair-housed LEW and F344 and compared to previous data from singly housed LEW and F344 collected from the same laboratory. Results showed that differences in impulsive choice between the two strains were attenuated with pair housing. The main result driving this change appears to be an increase in impulsive choice in pair-housed F344 relative to singly housed F344.

Preference reversals and effects of D-amphetamine on delay discounting in rats.

Impulsive choice is correlated with behavioral problems such as attention-deficit/hyperactivity disorder and substance abuse. Effects of stimulant drug administration on impulsive choice are not consistent and may depend on baseline differences in impulsive choice. A within-session delay-discounting procedure in which choice was between one food pellet delivered immediately (impulsive choice) and three food pellets delivered after increasing delays (self-controlled choice) was used to determine effects of adding and subtracting delays common to both reinforcers on impulsive choice in male Sprague-Dawley rats (n=8). Delay discounting was observed and impulsive choice was quantified using area under the curve (AUC). Adding delays common to both reinforcers decreased impulsive choice and subtracting delays common to both reinforcers increased impulsive choice. Before administration of D-amphetamine (0.03-1.80 mg/kg, intraperitoneally), subjects were rank ordered into a low-AUC or a high-AUC group. Select doses of D-amphetamine decreased impulsive choice for subjects in the low-AUC group but not for subjects in the high-AUC group. These results indicate that impulsive choice can be altered by changing the delay common to both reinforcers and suggest that effects of D-amphetamine may depend, in part, on baseline differences in impulsive choice.

Effects of acute and chronic administration of diazepam on delay discounting in Lewis and Fischer 344 rats.

Impulsive choice is often examined using a delay-discounting procedure, where there is a choice between two reinforcers of different magnitudes presented at varying delays. Individual discounting rates can be influenced by many factors including strain differences and drug effects. Lewis (LEW) and Fischer 344 (F344) rats have behavioral and neurochemical differences relevant to delay discounting and were used to examine effects of acute and chronic administration of diazepam on impulsive choice. Consistent with the previous literature, larger-reinforcer choice decreased as a function of increasing delays for all rats, and steeper discounting functions were obtained for LEW relative to F344 rats. Acute and chronic administration of diazepam resulted in differential effects between rat strains and sometimes between subjects within the same rat strain. Overall, larger-reinforcer choice remained unchanged across multiple phases of the experiment for LEW rats. For F344 rats, larger-reinforcer choice increased following the acute administration of smaller doses of diazepam and decreased following the acute administration of the largest dose tested. Decreases in larger-reinforcer choice occurred for F344 rats during chronic and postchronic administration and persisted throughout a nondrug return-to-baseline phase. These results suggest potential directions for future investigation of environmental, genetic, and neurochemical variables involved in delay discounting.

Effects of acute and repeated nicotine administration on delay discounting in Lewis and Fischer 344 rats.

Biological differences may underlie individual differences in impulsive behavior, such as choice for a smaller, more immediate reinforcer over a larger, more delayed reinforcer. Repeated exposure to drugs of abuse may have different effects on such behavior. To evaluate the acute and repeated effects of nicotine on impulsive choice, two strains of rats that have been shown to differ in impulsive choice were tested in a delay-discounting paradigm. Eight Lewis and eight Fischer 344 rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after a delay. The delay systematically increased in blocks of trials within each session, and the delay value at which the choice for the two alternatives was equal (i.e. the indifference point) was interpolated. Effects of nicotine (0.1-1.0 mg/kg, subcutaneous) on percent choice and indifference points were determined during the acute-testing phase and during the redetermination of effects of each dose after at least 30 sessions of repeated 1.0 mg/kg nicotine exposure. The Lewis rats had shorter indifference points (i.e. made fewer larger-reinforcer choices) compared with the Fischer 344 rats. Acute nicotine administration increased the mean larger-reinforcer choices at the 0.3 mg/kg dose in the Lewis rats and at the 1.0 mg/kg dose in the Fischer 344 rats. After repeated exposure to nicotine, indifference points returned to near-baseline (predrug) levels for both the strains. Strain differences were observed in the rates of delay discounting, and nicotine may decrease the impulsive choice acutely, but this effect does not seem to be long lasting.

Effects of variable training, signaled and unsignaled delays, and d-amphetamine on delay-discounting functions.

One common procedure for obtaining delay-discounting functions consists of a choice between a larger reinforcer that is presented after an increasing delay and a smaller reinforcer that is always presented immediately within session. Repeating the same context of delay presentation (e.g. ascending delay order) in a discrete-choice paradigm, however, may lead to a perseverative response pattern when rats are used as subjects. The purpose of this study was to increase the variability in delay presentation (i.e. ascending and descending delays) in an attempt to reduce a perseverative response pattern and gain tighter control over choice by reinforcer amount and delay. For one group of rats (n = 8), delays to reinforcer presentation were differentially signaled by a flashing houselight and for one group of rats (n = 8) the delays were unsignaled. Effects of delay signal and d-amphetamine on choice were evaluated in both groups. Similar rates of delay discounting and area under the curve (AUC) were observed with both ascending and descending delay presentations and with signaled and unsignaled delays to reinforcement. Increasing the variability in delay order resulted in differences in the choice pattern during 0-s probe sessions. d-Amphetamine had little or no effect on AUC at low doses, but decreased AUC at the highest doses tested, that is, 1.0 and 1.7 mg/kg. Some of the changes in AUC after d-amphetamine administration may have been because of disruption in discrimination of the different food amounts.

Discriminative-stimulus and time-course effects of kava-kava (Piper methysticum) in rats.

Kava is a widely available and used herbal medicine that is not regulated in many countries. There are many questions concerning kava's stimulus properties, potential for therapeutic use, and potential for abuse. Although there is evidence that kava may possess some anxiolytic properties, kava's mechanism of action and the extent to which it may serve as an alternative to pharmaceutical anxiolytics are not fully known. The current study was designed to evaluate whether kava shares discriminative-stimulus properties with the anxiolytic chlordiazepoxide (CDP). Effects of different doses of kava extract were evaluated in two groups of rats trained to discriminate either a high or low training dose of CDP (i.p.). In order to assess time-course effects, two tests were conducted/session at 60 (Test One) and 90 (Test Two) min following oral administration of kava, CDP, or d-amphetamine. Dose-dependent substitution of CDP was found in both training groups in both tests. Kava (560 mg/kg, p.o.) occasioned responding indicative of partial substitution in both groups during Test One and only the low-dose group during Test Two. Partial substitution of kava extract for CDP suggests that the herbal compound may share a mechanism of action similar to CDP, but is less potent.

Contingency tracking during unsignaled delayed reinforcement: Effects of delay duration and d-amphetamine.

In two experiments, the role of the response-reinforcer relation in maintaining low-rate responding under unsignaled delay conditions was investigated. In both experiments pecking by pigeons on one response key, denoted the relevant key, was reinforced under an unsignaled delay-of-reinforcement procedure (defined as tandem variable-interval (VI) differential-reinforcement-of-other behavior [DRO] schedule). Responding on a second key, denoted the irrelevant key, had no programmed consequences. Between sessions, the location of the relevant key varied (after one, two, or three sessions) pseudorandomly. In Experiment 1, the delay (DRO) duration was manipulated parametrically. Overall, proportional relevant-key response rates (relevant-key response rates / [relevant-key response rates + irrelevant key response rates]) increased across 3-session sequences in which the relevant key remained in the same location and decreased as the DRO duration was changed systematically (2, 5, and 10 s). In Experiment 2, acute administration of d-amphetamine increased proportional relevant-key response rates during 1-day sequences for only the DRO 5-s duration, and results over 3-day sequences, once a discrimination had already been established, were inconsistent. Results support that the response-reinforcer relation is the primary determinant of responding, and such discriminations are relatively resistant to disruption or potentiation by behaviorally active doses of d-amphetamine.

Long-term deficits in risky decision-making after traumatic brain injury on a rat analog of the Iowa gambling task.

Traumatic brain injury (TBI) affects 2.8 million people annually in the United States, with significant populations suffering from ongoing cognitive dysfunction. Impairments in decision-making can have major implications for patients and their caregivers, often enduring for years to decades, yet are rarely explored in experimental TBI. In the current study, the Rodent Gambling Task (RGT), an Iowa Gambling Task analog, was used to assess risk-based decision-making and motor impulsivity after TBI. During testing, rats chose between options associated with different probabilities of reinforcement (sucrose) or punishment (timeout). To determine effects of TBI on learned behaviors versus the learning process, rats were trained either before, or after, a bilateral frontal controlled cortical impact TBI, and then assessed for 12 weeks. To evaluate the degree to which monoamine systems, such as dopamine, were affected by TBI, rats were given an amphetamine challenge, and behavior recorded. Injury immediately and chronically decreased optimal decision-making, and biased rats towards both riskier, and safer (but suboptimal) choices, regardless of prior learning history. TBI also increased motor impulsivity across time, reflecting ongoing neural changes. Despite these similarities in trained and acquisition rats, those that learned the task after injury demonstrated reduced effects of amphetamine on optimal decision-making, suggesting a lesser role of monoamines in post-injury learning. Amphetamine also dose-dependently reduced motor impulsivity in injured rats. This study opens up the investigation of psychiatric-like dysfunction in animal models of TBI and tasks such as the RGT will be useful in identifying therapeutics for the chronic post-injury period.

Effects of acute and repeated administration of caffeine on temporal discounting in rats.

Delay to presentation is one variable that can weaken the reinforcing efficacy of an outcome in a choice situation and drugs have been shown to modify such choices. A growing body of literature has examined effects of stimulant drugs on temporal (delay) discounting, but effects of caffeine, the most widely used stimulant in the world, have not previously been assessed. In the present experiment, effects of caffeine (administered acutely and repeatedly) on temporal discounting were analyzed. Male Sprague-Dawley rats (n=7) chose between a single food pellet delivered immediately after a lever press and three food pellets delivered after a delay. The delay to the three pellets increased within each session, from 0 to 16 s. High doses of caffeine increased large-reinforcer choice relative to control conditions. With repeated caffeine exposure, percent choice for the large reinforcer decreased relative to acute administration, but was still greater than pre-drug baseline. Following withdrawal of drug administration, choice returned to levels seen during pre-drug baseline. Reintroduction of caffeine increased the percent choice for a larger, delayed reinforcer to near acute levels. The results from the present study are consistent with previous research in which stimulant drugs have decreased temporal (delay) discounting.

Reduction in delay discounting due to nicotine and its attenuation by cholinergic antagonists in Lewis and Fischer 344 rats.

RATIONALE: Nicotine acts as an agonist for nicotinic acetylcholine receptors (nAChRs), and mecamylamine, a nonselective nAChR antagonist, attenuates effects of nicotine on delay discounting in some rat strains; whether nicotine's attenuation is specific to nAChR antagonism is unknown. OBJECTIVE: During experiment 1, we evaluated dose-dependent effects of nicotine on delay discounting of pair-housed Lewis (LEW) and Fischer 344 (F344) rats. During experiment 2, we examined the sensitivity of nicotine's effects on delay discounting to pharmacological antagonism of nAChRs or muscarinic AChRs (mAChRs). MATERIALS AND METHODS: Male LEW and F344 were trained to choose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. During experiment 1, saline and nicotine (0.1-1.0 mg/kg) were tested acutely. During experiment 2, mecamylamine (0.25-1.0 mg/kg) or a nonselective mAChR antagonist, scopolamine (0.01-0.056 mg/kg), was administered prior to nicotine administration. RESULTS: Nicotine dose dependently reduced delay discounting for both rat strains, and no strain differences were observed (ΔAUC = + 107% for 1.0 mg/kg and + 69.6% for 0.3 mg/kg relative to saline). At some doses, pretreatment with mecamylamine (range ΔAUC = - 27.6 to - 7.3%) or scopolamine (range ΔAUC = - 0.74 to - 51.6%) significantly attenuated the nicotine-induced reduction in some measures of delay discounting for both strains. CONCLUSIONS: Results from experiment 1 suggest that when LEW and F344 are pair housed, there are no strain differences in delay discounting in response to nicotine. Results from experiment 2 suggest that attenuation of nicotine's effects on delay discounting may not be specific to nAChR antagonism.

Response acquisition with delayed reinforcement in Lewis and Fischer 344 rats.

Previous work has shown neurochemical and behavioral differences between Lewis rats and Fischer 344 rats. Some of this work suggests that there might be differential sensitivity to delayed reinforcement between the two strains. To further explore this possibility, Lewis (n=8) and Fischer 344 (n=8) rats were exposed to a response-acquisition task with a non-resetting 20s delay to reinforcement. A tandem fixed-ratio 1, fixed-time 20s schedule of reinforcement was programmed for one of two levers; presses on the alternate lever had no programmed consequences. A greater number of Lewis rats (5/8) acquired lever pressing compared to the Fischer 344 rats (2/8). Future work with these strains may lead to a better understanding of the genetic and/or neurochemical factors involved in temporal control of behavior.

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.

Reinforcer magnitude affects delay discounting and influences effects of d-amphetamine in rats.

Impulsive choice in humans can be altered by changing reinforcer magnitude; however, this effect has not been found in rats. Current levels of impulsive choice can also influence effects of d-amphetamine. This study used a within-subject assessment to determine if impulsive choice is sensitive to changes in reinforcer magnitude, and whether effects of d-amphetamine are related to current levels of impulsive choice. A discounting procedure in which choice was for a smaller reinforcer available immediately or a larger reinforcer available after a delay that increased within session was used. Reinforcer magnitude was manipulated between conditions and impulsive choice was quantified using area under the curve (AUC). In the Smaller-Magnitude (SM) Condition, choice was between one food pellet and three food pellets. In the Larger-Magnitude (LM) Condition, choice was between two food pellets and six food pellets. Impulsive choice was greater in the SM Condition compared to the LM Condition. Further, effects of d-amphetamine (0.1-1.8mg/kg) were related to differences in impulsive choice. d-Amphetamine increased impulsive choice in the LM Condition, but had no effect on impulsive choice in the SM Condition. Overall, these results show that impulsive choice in rats is sensitive to changes in reinforcer magnitude, and that effects of d-amphetamine are influenced by current levels of impulsive choice.

Effects of clomipramine on self-control choice in Lewis and Fischer 344 rats.

Rates of delay discounting (impulsive choice) have been shown to vary among individuals, particularly people who abuse drugs relative to those who do not, but factors that may contribute to these differences have not been identified. To explore a role for possible genetic and neurochemical determinants, Lewis (n = 8) and Fischer 344 (n = 8) rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after increasing delays. The delays to the large reinforcer (0, 10, 20, 40, 60 s) were increased across five blocks of trials in daily experimental sessions. For both groups of rats, choice for the larger reinforcer decreased as the delay to presentation increased. However, the Lewis rats were more likely to choose the smaller, immediate reinforcer earlier in the session, i.e., at shorter large-reinforcer delays, than the Fisher 344 rats. This difference in choice was statistically significant. Repeated administration of 3.0 mg/kg, i.p. clomipramine (mean of last five sessions) did not significantly alter choice, relative to baseline, for either strain. The present findings suggest that differences in delay discounting/impulsive choice may involve genetic, e.g., neurochemical, differences.

Extra (non-contingent) food does not affect behavioral tolerance to d-amphetamine's rate-decreasing effects.

Tolerance refers to the diminished effect of a drug following its repeated administration such that a larger dose is needed to obtain the initial effect. Tolerance to a drug's effects on operant behavior is more likely to develop when initial drug administration results in a loss of reinforcement. It remains unknown how offsetting loss of reinforcement influences the development of tolerance. Providing extra (non-contingent) food pellets was hypothesized to impede the development of tolerance to effects of a repeatedly administered dose of d-amphetamine that reduced the number of food pellets earned by rats. A multiple schedule with two variable-interval (VI) 60-s components resulting in food delivery was used to maintain lever pressing. Extra food pellets were provided in one of those components according to a variable-time (VT) 120-s or a VT 30-s schedule for separate groups of rats (n=6 for each group). Effects of d-amphetamine (0.1-3.0mg/kg) were tested before (acute) and during (chronic) injections (45days) of an individually selected, repeatedly administered dose that reduced the number of food pellets earned by at least 50% compared to when saline was tested acutely. There was a dose-dependent decrease in lever-press rates and food pellets earned. The development of tolerance was quantified by dividing the area-under-the-curve (AUC) of the chronic dose-effect function by the AUC of the acute dose-effect function. Tolerance developed to a similar extent in components with and without extra food pellets for rats in both groups. These results indicate that offsetting reinforcement loss, at least as studied here, did not differentially affect tolerance development.

Effects of dose and infusion delay on cocaine self-administration choice in rhesus monkeys.

RATIONALE: Drug abuse is often considered a problem related to impulse-control disorders, but little is known about the factors that determine the choice to self-administer a drug in a self-control/impulsivity paradigm. OBJECTIVE: The objective of the present study was to evaluate choice between a low dose of cocaine administered after a relatively short delay (impulsive option) and a high dose of cocaine following a relatively longer delay (self-control option). METHODS: Rhesus monkeys self-administered intravenous cocaine in a discrete-trials choice procedure. First, choice was between different 3:1 doses (0.3/0.1 and 0.1/0.03 mg/kg per injection) following equal 30-s delays to infusion. Second, choice was between equal doses (0.1 mg/kg per injection) following 3:1 delays (30 s/10 s, 90 s/30 s, 270 s/90 s, 810 s/270 s). Third, choice was between 0.1 or 0.03 mg/kg per injection after the same 3:1 delays with the larger dose following the longer delay and the smaller dose following the shorter delay. Fourth, the same 3:1 delays were used to study choice between 0.3 and 0.1 mg/kg per injection. RESULTS: With equal delays, the larger dose of cocaine was chosen almost exclusively, and with equal doses, the shorter delay was chosen almost exclusively. When both dose and delay were manipulated, mean large-dose (0.1 mg/kg per injection) choices for three of four subjects was 98% when the delays were the shortest (30 s/10 s), but this preference reversed as the delays increased, so that 74% of choices were for the smaller dose (0.03 mg/kg per injection) at the longest delays (810 s/270 s). This systematic decrease in large-dose choices as the absolute, but not relative, values of the delays were increased, was also observed with the higher dose combination. CONCLUSION: Delay discounting was supported by the present findings in that the value of a large reinforcer (higher cocaine dose) was decreased as its delay to presentation was increased. The importance of not only relative, but absolute, values of delays to drug reinforcement in determining drug choice was also demonstrated. Thus, a self-control/impulsivity paradigm can be extended to conditions with non-human subjects and drug reinforcers.

Dose and schedule determinants of cocaine choice under concurrent variable-interval schedules in rhesus monkeys.

RATIONALE: Drug abuse can be characterized as a condition in which the choice to self-administer a drug is excessive, even exclusive of the choice of other reinforcers. Under concurrent interval schedules of reinforcement, subjects typically distribute behavior to match reinforcement allocation. However, research has shown that when behavior is maintained by different doses of cocaine under concurrent variable-interval (conc VI) schedules, exclusive choice of the higher dose is the rule. OBJECTIVE: The present study was designed to examine the generality of this finding to other behavioral conditions. METHODS: Rhesus monkeys ( n=5) lever pressed under a conc VI 60-s VI 60-s or a conc VI 600-s VI 600-s schedule of cocaine (i.v.) presentation. Doses differing by 4-fold (0.025 versus 0.1, 0.05 versus 0.2 mg/kg per injection) were available for lever pressing. RESULTS: Monkeys responded more on the lever associated with the higher dose when saline or a lower dose was the alternative. The distribution of responses was well predicted by relative drug intake, but with consistent undermatching. Exclusive high-dose responding was seen in about half of the individual session intervals under the shorter schedule, rarely under the longer schedule, and was not seen over the session. CONCLUSION: Under conc VI schedules, behavior was apportioned between two different doses in a manner that favored the higher dose but undermatched relative intake. Exclusive high-dose choice may occur when cocaine is frequently available but is not an invariable outcome of the choice between a low and a high dose of cocaine.