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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.

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.

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.

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.

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.

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.

The Graduate Education Diversity Internship (GEDI) program empowers students of color to become adaptive leaders, change agents, partners, and facilitators through exposure to theory, experiential training, leadership development, and mentorship in order to advance culturally responsive evaluation (CRE) practices that respond to context and community values in a respectful and positive manner (Nelson-Barber, LaFrance, Trumbull, & Aburto, 2005). A case study of the first six GEDI cohorts was conducted to evaluate the program's impact on CRE leadership development. This chapter validates how GEDI transformative leadership strategies can be applied by any profession to champion CRE practitioners and promote a society that values social justice, equity, and democratic change.

Studies concerning the relation between stimulant drug exposure and subsequent delay discounting (impulsive choice) have resulted in mixed findings that could be related to the type of stimulant drug exposure or the use of between-subject comparisons. The purpose of the present study was to examine effects of prior d -amphetamine exposure on subsequent delay discounting using a within-subject assessment. Two groups of rats were trained under a discrete-trials choice procedure until delay discounting was stable. One group of rats then received repeated administration of 3.0 mg/kg d -amphetamine in their home cage for 14 consecutive days, while the other group received saline. After a three-week drug-free period, delay discounting was reassessed. No significant differences in area under the curve within (before or after drug exposure) or between (saline or d -amphetamine) groups were found. Thus, delay discounting was not systematically affected following termination of repeated 3.0 mg/kg d -amphetamine exposure in the present experimental arrangement. The current results, coupled with past research, indicate that there may be a distinction between cocaine exposure and d -amphetamine exposure on subsequent delay discounting; however, within-subject comparisons of cocaine exposure on delay discounting are warranted.

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.

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 20 s delay to reinforcement. A tandem fixed-ratio 1, fixed-time 20 s 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.

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.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).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.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.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.

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.

Rationale: The neuronal actions of methamphetamine (MA) include an increase in extracellular levels of monoamines, presumably via reverse transport involving the monoamine transporters. This action is thought to play an important role in the effects of MA. Therefore, in the present experiment, it was hypothesized that a monoamine uptake blocker would block behavioral effects of MA related to its abuse. Objective: RTI 111, a newly synthesized 3-phenyltropane analog with high affinity for the dopamine, norepinephrine, and serotonin transporters, was evaluated alone and in combination with MA for its ability to block the reinforcing and discriminative stimulus effects of MA in rhesus monkeys. Methods: RTI 111 (0.0003–0.03 mg/kg, i.v.) was made available to four rhesus monkeys for self-administration under a fixed-ratio 25 (FR 25) schedule of reinforcement. RTI 111 (0.01–0.1 mg/kg, i.m.) was also administered as a pretreatment (15 min prior) to four monkeys self-administering MA (0.0–0.3 mg/kg per injection, i.v.) on a progressive-ratio schedule of reinforcement. MA (0.01–1.0 mg/kg, i.m.), RTI 111 (0.001–0.1 mg/kg, i.m.), or the combination of MA and RTI 111 were administered to four monkeys trained to discriminate (+)-amphetamine (AMPH; 1.0 or 1.7 mg/kg, intragastric) from saline. Results: When RTI 111 was made available for self-administration under an FR 25 schedule it functioned as a positive reinforcer in all four monkeys tested. When RTI 111 was given as a pretreatment to monkeys self-administering MA under a progressive-ratio schedule, the MA dose-response function shifted to the left and down. When RTI 111 or MA were given to monkeys trained to discriminate AMPH from saline, full AMPH-like responding was observed for both drugs. Given in combination, RTI 111 shifted the MA dose-response function to the left. Conclusions: These data suggest that RTI 111 is behaviorally similar to traditional psychomotor stimulants that act at the DA transporter and that it increases, rather than blocks, the behavioral potency of MA.

Male and female rats were trained to discriminate 10.0 mg/kg cocaine from saline in a two-lever discrimination task. Injection-appropriate responding was reinforced by food pellet presentation on a tandem random-interval 30-s fixed-ratio 10 schedule. Generalization testing was conducted in extinction 10 min following an injection of saline, 1.0, 3.0, 5.6, or 10.0 mg/kg cocaine. No differences in the generalization gradients and ED(50)s were observed between male and female rats. Following the determination of the cocaine generalization gradient, the dopamine D(1) antagonist SCH-23390 (0.01-0.10 mg/kg) and the dopamine D(2) antagonist raclopride (0.1-1.6 mg/kg) were administered (independently) prior to the injection of the training dose of cocaine (10.0 mg/kg). Cocaine-antagonism tests were conducted in extinction. It was found, for each dopamine antagonist, that as the dose increased, the percentage of cocaine-appropriate responding decreased. No sex differences were observed between these generalization gradients.

VAN HAAREN, F., K. G. ANDERSON, S. C. HAWORTH AND W. R. KEM. GTS-21, a mixed nicotinic receptor agonist/antagonist, does not affect the nicotine cue. PHARMACOL BIOCHEM BEHAV 64(2) 439–444, 1999.—Identification of nicotinic receptor subtypes involved in nicotine dependence is required for guiding the design of more selective antagonists capable of blocking the nicotine cue and nicotine self-administration. Due to the multiplicity of nicotinic receptors in the mammalian brain, selective agonists and antagonists are needed to assess the functional involvement of a particular subtype in vivo. Only recently have a few nicotinic receptor subtype-selective antagonists and agonists been identified. GTS-21 (also known as DMBX-anabaseine) is the only agent so far reported that selectively stimulates the α7 nicotinic receptor. Here GTS-21 was used to assess the possible mediation of the nicotine cue by this receptor subtype. Long–Evans rats were trained to discriminate between presession administration of 0.10 or 0.40 mg/kg (−)-nicotine bitartrate and its vehicle. GTS-21 did not substitute for nicotine, as all subjects consistently chose the vehicle lever after GTS-21 substitution. In another experiment, different doses of GTS-21 were administered prior to nicotine administration to investigate whether GTS-21 would antagonize the nicotine cue. Such was not the case. The lack of effect of GTS-21 upon the nicotine cue is consistent with the notion that the cue is mediated by nicotinic receptors other than the α7 receptor.

VAN HAAREN, F. AND K. G. ANDERSON. Avoidance of time-out from response- independent food presentation: Effects of chlordiazepoxide and buspirone. PHARMACOL BIOCHEM BEHAV 61 (2) 207–214, 1998.—Five male Wistar rats were exposed to a two- component multiple schedule. In one component, signaled by a tone, food pellets were presented on a random-time 120-s schedule. In the other component, food pellets were presented on a random-time 30-s schedule. Pellets were only presented during a 10-s time-in period that alternated with a 50-s time-out period, unless the subject pressed a lever to postpone time-out presentation by 20 s. Response-independent food pellets were never presented within 2 s of this avoidance response. For most subjects avoidance rates were consistently higher when response-independent food pellets were delivered infrequently than when they were delivered more often. The amount of time spent in time-in varied considerably between subjects but was not consistently related to the frequency of response-independent pellet presentation. Once stable response rates were established subjects were intraperitoneally injected with different doses of chlordiazepoxide (1, 3, 10, 17, or 30 mg/kg) or buspirone (0.1, 0.3, 1.0, 1.7, 3.0, or 4.2 mg/kg). Low doses of chlordiazepoxide either did not affect or slightly increased avoidance response rates, whereas higher doses (10 mg/kg and up) produced a dose-dependent decrease in avoidance responding. The time subjects spent in the presence of stimuli associated with the availability of response-independent food either did not change or increased slightly after the lower doses of chlordiazepoxide, while it decreased dose dependently following the higher doses. Low doses of buspirone increased avoidance rates in subjects first exposed to chlordiazepoxide, but did not alter rates in the remaining subjects. Intermediate doses of buspirone decreased avoidance rates more in the component with the lower frequency of pellet presentation, higher doses further decreased response rates. The amount of time spent in the presence of stimuli associated with pellet presentation was minimally affected by the lower doses of buspirone, but decreased dose dependently following the higher doses. The results of this experiment add further credence to the notion that the behavioral effects of drug administration may depend on nonpharmacological variables including, but not limited to, the nature of the consequent event.

Tail-tip plasma samples of intact and gonadectomized male and female Wistar rats were analyzed for cocaine and benzoylecgonine. The samples were obtained from immobilized subjects 10 and 30 min following the 1st and 22nd intraperitoneal injections of 10 mg/kg cocaine hydrochloride. Gender differences in plasma cocaine or benzoylecgonine levels were not observed after the first injection of cocaine because many of the samples were below the detection limit. Cocaine plasma levels were much higher after the 22nd injection, but gender differences were not observed either 10 or 30 min following cocaine administration. Plasma levels of benzoylecgonine were higher 30 min than 10 min after cocaine administration in intact and castrated male rats and ovariectomized female rats but not in intact female rats. These data show that, in rats, gender differences in cocaine metabolism may be observed after repeated cocaine administration, but the exact mechanism remains to be elucidated.

In delay discounting, choice is between two reinforcers that differ in amount and delay, and the subjective value of either reinforcer decreases as a function of delay to its receipt. The steepness of the discounting function is thought to reflect the degree of impulsive choice. Many factors can influence impulsive choice, including the addition of a constant delay or response requirement to the smaller sooner (SS) and larger later (LL) reinforcers. A delay-discounting procedure developed by Evenden and Ryan (1996) is commonly used in behavioral research, yet effects of adding a response requirement to both alternatives with this procedure has not been examined. If different delay-discounting procedures are measuring the same phenomenon, preference reversals should occur with the Evenden and Ryan procedure as they do with other procedures with an added response requirement. The current experiment used an Evenden and Ryan procedure, and choice was examined when the response requirement was a small, intermediate, and large fixed ratio (FR). Fewer LL choices occurred with the small FR, and more LL choices occurred with the intermediate and large FR. The present experiment extends preference-reversal findings to a different and commonly used delay-discounting procedure.

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.

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.

Stimulant drugs have been shown either to increase or decrease rates of delay discounting (impulsive choice). These mixed findings may result from genetic, neurochemical, or environmental factors. Lewis (LEW) and Fischer 344 (F344) rats have neurochemical and behavioral differences that may be relevant to delay discounting and were used to examine effects of acute and chronic administration of d-amphetamine (d-AMP) on impulsive choice using a within-session delay-discounting procedure. Male LEW (n=8) and F344 (n=8) rats chose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. Saline and d-AMP (0.1, 0.3, 1.0, and 1.7 mg/kg) were tested acutely and during chronic d-AMP exposure. Choice for the larger reinforcer decreased as the delay to its presentation increased for both strains at baseline. LEW rats made more impulsive choices than F344 rats as indicated by shorter indifference points, and this is consistent with previous research. Acute administration of d-AMP dose dependently increased larger-reinforcer choice and area under the curve (AUC) for LEW, but not F344 rats. During chronic exposure to d-AMP, larger-reinforcer choice and AUC increased relative to acute administration for F344 rats responding in shorter delay series, but not for F344 rats responding in longer delay series or for LEW rats. Differential effects of acute and chronic administration of d-AMP on impulsive choice in LEW and F344 rats may be a result of various factors, including genetic, neurochemical, and environmental variables. Future research should attempt to tease apart the relative contribution of each of these factors on impulsive choice.

Intact and gonadectomized male and female rats pressed a lever to obtain food on different fixed-ratio (FR) schedules in a three-component multiple schedule. The values of a small, intermediate and large FR schedule were individually determined and were higher for intact male rats than for most subjects in the other groups. Acute cocaine administration (1.0-30.0mg/kg) dose-dependently decreased response rates maintained by all three schedules, but responding maintained by the large FR schedule was more sensitive to the rate-decreasing effects of acute cocaine administration. Response rates of intact male rats were less sensitive to the rate-decreasing effects of cocaine than those of the other groups, at least at higher doses during the small and intermediate FR schedules. Cocaine's dose-effect curve was redetermined after chronic administration of a behaviorally active dose of cocaine. Differences between groups of subjects were not evident. Behavioral tolerance was consistently observed when responding was maintained by the small FR schedule. Effects varied between subjects within groups when responding was maintained by the intermediate FR schedule, but behavioral tolerance was frequently observed. Behavioral sensitization was evident during the large FR schedule, but these data were difficult to interpret because of a considerable shift in response rates after vehicle administration. The data suggest that the comparison of drug effects in male and female rats requires a systematic analysis of the contribution of behavioral parameters. They also provide additional evidence for the notion that reference to reinforcement-loss alone is not sufficient to explain the development of tolerance to the behavioral effects of cocaine.

Six female and five male Wistar rats obtained food by pressing a lever on a fixed-interval (FI) 60-s schedule in the presence of a sipper tube which allowed access to an alcohol solution. Systematic manipulation of the alcohol concentration revealed that male rats consumed higher alcohol concentrations (v/v) than female rats to obtain maximum alcohol intake (g ETOH/kg) during an experimental session. Males also reached higher blood alcohol levels (BALs) than females. Individual lick rates varied over a small range when the FI schedule parameter was manipulated (20 s and 180 s) during probe sessions. Very few licks were observed when all pellets were presented at the beginning of the session, during extinction, or during sessions in which only a few pellets were presented. Reduction of the solution's alcohol concentration to half the maximum concentration or presentation of distilled water resulted in increased lick rates at most values of the FI schedule in four of the five male subjects, but not in female subjects. Alcohol intake during sessions in which half the maximum alcohol concentration was available was lower than that observed during sessions in which subjects consumed the maximum alcohol concentration. The lick rate data in conjunction with those on alcohol intake suggest that male rats, but not female rats, maintained blood alcohol concentrations at levels which they had also reached during sessions in which the maximum alcohol concentration was available from the sipper tube.

Methylphenidate (MPH) is one of the most common therapeutics used for the treatment of attention-deficit/hyperactivity disorder (ADHD), which consists of symptoms of inattention, and/or impulsivity and hyperactivity. Acute administration of MPH has been found to decrease impulsive choice in both humans and nonhuman animals, however, little is known about potential long-term changes in impulsive choice due to chronic administration of MPH. In the present experiment, effects of acute and chronic MPH (1.0-10.0mg/kg) were assessed on impulsive choice in the adult male Spontaneously Hypertensive Rat (SHR) to determine the extent of behavioral changes after chronic MPH exposure. Subjects chose between an immediate single food pellet and three food pellets delivered after a delay that increased within session (0 to 16s). At relatively higher doses during acute and chronic administration, choice maintained by the larger reinforcer was disrupted when there was no delay to either outcome, suggesting that MPH may be affecting stimulus control under the current delay-discounting task. When this disruption was not observed, however, MPH effects were selective in that only one intermediate dose (3.0mg/kg) decreased mean impulsive choice at one delay (8s) following acute administration. The same effect was observed following chronic MPH administration except that the dose was higher (5.6 mg/kg) and the delay was shorter (4s). Chronic administration of MPH did not show any negative indicators (e.g., an increase in impulsive choice) when administration was discontinued.

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.

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.

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.

Although a delay between behavior and reinforcer has been shown to weaken behavior, little is known about the effects of delay on drug choice. 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. 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 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). 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.

Convergent lines of evidence support a dual deficit model of stimulant withdrawal, where reductions in synaptic dopamine (DA) and 5-hydroxytryptamine (serotonin) (5-HT) contribute to dysphoria, drug craving, and relapse. Thus, we predicted that a nonamphetamine compound with substrate activity at DA and 5-HT transporters (i.e., a dual DA/5-HT releaser) would be an effective medication for treating stimulant addictions. Ideally, this type of medication would alleviate withdrawal symptoms, suppress cocaine self-administration, and lack side effects commonly associated with central nervous system stimulants. In the present work, more than 350 compounds were screened in vitro for activity as substrate-type releasing agents at DA, 5-HT, and norepinephrine transporters. These efforts identified PAL-287 (1-napthyl-2-aminopropane) as a nonamphetamine compound with potent substrate activity at biogenic amine transporters. In vivo microdialysis in rats demonstrated that PAL-287 (1-3 mg/kg i.v.) increased extracellular DA and 5-HT in frontal cortex, but effects on 5-HT were somewhat greater. PAL-287 induced substantially less locomotor stimulation than (+)-amphetamine, a drug that increases only extracellular DA. Administration of high-dose (+)-methamphetamine or (+/-)-3,4-methylenedioxymethamphetamine to rats produced long-lasting depletion of cortical 5-HT, whereas PAL-287 (18 mg/kg i.p. x 3) did not. PAL-287 displayed little or no reinforcing properties in rhesus monkeys trained to self-administer cocaine, yet PAL-287 produced a dose-dependent decrease in responding for cocaine when infused at a dose of 1.0 mg/kg/h. Collectively, the findings reported here demonstrate that nonamphetamine monoamine releasing agents such as PAL-287 might be promising candidate medications for the treatment of stimulant dependence.

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.

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. The present study was designed to examine the generality of this finding to other behavioral conditions. 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. 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. 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.

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.

It has previously been shown that self-administration of cocaine under concurrent variable-interval schedules is well described by the generalized matching law. That is, choice between two cocaine-maintained options was apportioned in accordance with relative frequency of reinforcement. However, the generality of this conclusion to drugs of other pharmacological classes has not been determined. In the present study, four male rhesus monkeys (Macaca mulatta) lever pressed under various pairs of concurrent variable-interval schedules with drug injection as the maintaining event. An opioid (alfentanil, 0.001 or 0.004 mg/kg/injection), a barbiturate (methohexital, 0.25 or 0.5 mg/kg/injection), and a psychomotor stimulant (cocaine, 0.05 mg/kg/injection) were selected as representatives of major classes of abused drugs and because of their relatively short duration of action. As has been found for cocaine, choice was well accounted for by the generalized matching law. There were no systematic differences in matching-law parameters across drugs and/or doses. As in earlier studies with drug and nondrug reinforcers, undermatching was a consistent finding. Therefore, the conclusion that relative reinforcement frequency is a crucial determinant of choice, as proposed by the generalized matching law, can be extended to behavior maintained by drugs from a variety of pharmacological classes.

Previously, sex differences have been observed in the behavioral effects of acute and chronic cocaine administration. In the present experiment, male and female rats were trained to discriminate intraperitoneal injections of 10.0 mg/kg cocaine from its vehicle. It was hypothesized that the subjective effects of cocaine might differ between male and female rats. It was further hypothesized that generalization gradients between male and female rats might differ as a function of the time since cocaine administration. In addition, we were interested to see whether multiple generalization gradients could be determined within the same experimental session. For that purpose, two different types of generalization tests were conducted in extinction, one in which subjects were tested both 10 min and 30 min following cocaine administration (vehicle, 1.0, 3.0, 5.6, 10 or 17 mg/kg) and one in which subjects were only tested 30 min after cocaine administration. The generalization gradients obtained 30 min following drug administration were shifted to the right of the gradient obtained 10 min following drug administration. The two 30-min gradients were not different from one another, showing that multiple generalization gradients can be obtained within the same experimental session.

Gender differences in anxiety have long been assumed to exist, but the experimental evidence is contradictory. It has also been suggested that antianxiety agents may have gender-dependent behavioral effects. The present experiment was designed to establish whether or not intact male and female rats behave differently when exposed to a Differential-Reinforcement of Low-Rate 72-s schedule of reinforcement (assumed to assess some of the inhibitory behavioral tendencies associated with anxiety), and whether or not the behavioral effects of acute chlordiazepoxide administration would differ between the sexes. There were no differences between male and female rats in the total number of responses, the total number of obtained reinforcers, or response efficiency in the absence of drug administration. Male and female Wistar rats were then challenged with different doses of chlordiazepoxide (vehicle, 1, 3, 10, 17, and 30 mg/kg). Low doses of chlordiazepoxide (1 and 3 mg/kg) decreased response efficiency, and medium doses (10 and 17 mg/kg) increased response efficiency in male and female rats. The highest dose of CDP (30 mg/kg) further increased response efficiency in male rats, but decreased response efficiency in female rats. These results suggest that the behavioral effects of chlordiazepoxide are dose dependent and that the effects of a large dose of chlordiazepoxide differ between male and female rats. Whether or not gender differences in drug metabolism or whether schedule contingencies played an important role in these observations remains to be determined in future experiments.

Three male and three female Wistar rats pressed a lever on a fixed-interval 60-s schedule of food reinforcement while they had simultaneous access to an alcohol solution. They were challenged with different doses of cocaine hydrochloride (vehicle, 1, 3, 10, and 30 mg/kg) once lever press rates and lick rates had stabilized. Low doses of cocaine (1 and 3 mg/kg) did not systematically affect lever press rates or lick rates. The administration of 10 and 30 mg/kg cocaine dose-dependently decreased lever press rates and schedule-induced licking to a greater extent in female than in male rats. Lick rates decreased even when cocaine administration did not affect the number of pellets obtained during an experimental session. Lever press rates accelerated throughout the interreinforcement interval during control sessions. Licking was mostly limited to the first 10 s (males) or 20 s (females) after pellet presentation. Cocaine administration did not affect the distribution of lever presses and licks during the interreinforcement interval. The results of the present experiment extend previous observations that cocaine's rate-dependent effects on lever press rates may be limited to situations in which changes in lever press frequency and/or distribution negatively affect reinforcement frequency and/or physiological consequences of schedule-induced behavior.