Effects of methylphenidate on impulsive choice in adult humans

Rationale Several studies with nonhumans and humans have shown that stimulants decrease impulsive choices on delay-to-reinforcement (self-control) procedures. Little is known, however, about the effects of the stimulant methylphenidate on choice for delayed reinforcers in humans.Objectives The present study was designed to investigate the effects of acute methylphenidate administrations on impulsive responding in adult humans on a delay-to-reinforcement task.Methods Eleven adult males with a history of criminal behavior but no history of attention–deficit hyperactivity disorder (ADHD) participated. Impulsive responding was measured using an adjusting-delay procedure in which subjects were presented with repeated choices between a small amount of money delivered after a short delay and a larger amount of money delivered after a delay that adjusted as a function of previous choices. Subjects were exposed to four experimental sessions each day of participation and 60 min prior to the first daily session received placebo or 0.15, 0.30, or 0.60 mg/kg methylphenidate. Stable choice patterns were re-established between each methylphenidate dose.Results Individuals differed in their sensitivity to methylphenidate, but in over half of the subjects methylphenidate decreased impulsive (i.e., increased the number of self-control choices) and increased the delay to the large reinforcer. The largest increases in self-control choices tended to occur at the 0.30-mg/kg and 0.60-mg/kg doses, and the effects often persisted across multiple daily sessions. In six subjects, under at least one methylphenidate dose, the number of impulsive choices decreased to zero.Conclusions Acute methylphenidate administrations tended to decrease the number of impulsive choices in adult humans on an adjusting-delay procedure, although there were substantial individual differences in the sensitivity of choice to methylphenidate. In no case, however, did methylphenidate increase impulsive choices. These results are consistent with several recent laboratory studies with nonhumans and humans showing that stimulants increase preference for large, delayed reinforcers.     

Strain differences in delay discounting between Lewis and Fischer 344 rats at baseline and following acute and chronic administration of d-amphetamine

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.     

Delay discounting of food and remifentanil in rhesus monkeys

Rationale

Drug abuse can be conceptualized as choice between drug and nondrug reinforcers in which drug choice is excessive; factors impacting drug taking can be examined using procedures in which subjects choose between drug and an alternative reinforcer.

Objective

This experiment examined the effects of delayed reinforcement on choice between food and the mu-opioid receptor agonist remifentanil.

Methods

Rhesus monkeys responded under a concurrent fixed-ratio 5, fixed-ratio 5 schedule in which responding on one lever delivered one food pellet and responding on another lever delivered an i.v. infusion.

Results

With no delay, monkeys responded predominantly for food rather than saline or small doses of remifentanil; as the dose of remifentanil increased (0.1–1.0 μg/kg/infusion), monkeys responded more for drug. Delaying delivery (30–240 s) of 0.32 and not 1.0 μg/kg/infusion of remifentanil (food delivered immediately) decreased responding for drug and increased responding for food, resulting in a rightward shift in the remifentanil dose–effect curve. Delaying delivery of food (60–240 s) when doses of remifentanil smaller than 0.32 μg/kg/infusion (but not saline) were available decreased responding for food and increased responding for drug, resulting in a leftward shift in the remifentanil dose–effect curve.

Conclusion

These results provide evidence that delaying the delivery of a mu-opioid receptor agonist reduces its potency as a positive reinforcer; more importantly, delaying the delivery of an alternative nondrug reinforcer (e.g., food) enhances the reinforcing potency of the agonist. Thus, understanding the factors that control substance abuse requires examination of contingencies for both drug and nondrug reinforcers.     

Effects of acute and chronic methylphenidate on delay discounting

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 (1.0-10.0 mg/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 16 s). 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 (3.0 mg/kg) decreased mean impulsive choice at one delay (8 s) 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 (4 s). Chronic administration of MPH did not show any negative indicators (e.g., an increase in impulsive choice) when administration was discontinued.     

Differential-reinforcement-of-low-rate-schedule performance and nicotine administration: a systematic investigation of dose, dose-regimen, and schedule requirement

Differential-reinforcement-of-low-rate (DRL) schedules have been used to evaluate the effects of a wide variety of drugs, including amphetamines, cannabanoids, and antidepressant medication. To earn a reinforcer, organisms operating under a DRL schedule are required to withhold a response for a predetermined amount of time before responding, and therefore this schedule maintains a low rate of responding and can be viewed as a response-inhibition task. In experiment 1, three different DRL schedules (4.5, 9.5, and 29.5 s) were used to evaluate systematically a range of nicotine doses (0.0, 0.1, 0.3, and 0.5 mg/kg). The dose-response effect of nicotine then was compared with the effects of increased reinforcer magnitude on responding. Both the administration of nicotine and increased reinforcer magnitude engendered less accurate DRL-schedule performance compared with baseline conditions, and the dose and magnitude-dependent shifts were most evident on the DRL 29.5-s schedule. Experiment 2 compared the differences between acute and chronic dosing regimens (0.3 mg/kg nicotine) on DRL 29.5-s schedule responding. After 20 consecutive sessions of nicotine dosing, accuracy deteriorated significantly, demonstrating that chronic nicotine dosing leads to a behavioral sensitization apparent on the DRL 29.5-s schedule. The results from both experiments suggest that responding on the DRL 29.5-s schedule is sensitive to both dose-response and regimen-dependent effects of nicotine.     

Effects of lesions of the orbitofrontal cortex on sensitivity to delayed and probabilistic reinforcement

RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size, delay and/or probability) has been proposed as a model of "impulsive choice" in animals. OBJECTIVE: The effect of lesions of the OPFC on rats' inter-temporal choice behaviour was examined in two experiments: (1) rats chose between a smaller immediate reinforcer and a larger delayed reinforcer; (2) rats chose between a smaller certain reinforcer and a larger probabilistic reinforcer. METHODS: Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 microl, two injections in each hemisphere), or sham lesions (injections of vehicle). They were trained to press two levers (A and B) for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, a press on A resulted in immediate delivery of one food pellet; a press on B resulted in delivery of two pellets, either following a delay ( d) (experiment 1), or with a probability ( p) <1 (experiment 2). The values of d and p were manipulated across phases of the experiments. The locations of the lesions were verified histologically at the end of the experiment. RESULTS: In experiment 1, both groups showed declining choice of lever B as a function of d. The lesioned rats showed significantly shorter indifference delays ( D50: the value of d corresponding to 50% choice of lever B) than the sham-lesioned rats. In experiment 2, both groups showed declining choice of lever B as a function of the odds against delivery of the two-pellet reinforcer, theta ( theta =[1/ p]-1). The lesioned rats showed lower indifference odds ( theta50: the value of theta corresponding to 50% choice of lever B) than the sham-lesioned rats. In both experiments, the lesioned rats showed extensive atrophy of the OPFC, with sparing of the dorsolateral prefrontal cortex. CONCLUSIONS: The results show that lesions of the OPFC can promote preference for the smaller and more immediate, and the smaller and more certain of two reinforcers. The results are consistent with two interpretations: the lesion may have altered (i) the rates of delay and odds discounting, and/or (ii) sensitivity to the ratio of the sizes of the two reinforcers.     

Measuring impulsivity in mice using a novel operant delayed reinforcement task: effects of behavioural manipulations and<Emphasis Type="Italic"> d-</Emphasis>amphetamine

Rationale The increasing use of genetically modified mice to probe genetic contributions to normal and abnormal behaviours requires the development of sensitive and selective behavioural tasks.Objectives To develop a discrete trial assay of impulsivity (delayed reinforcement) that is tractable in mice utilising a mouse operant nine-hole box apparatus and to specify the task with respect to behavioural and pharmacological manipulations.Methods Mice were trained to respond with a nose-poke to one of two visual stimuli; one response resulted in a small quantity of reinforcer, the other in a larger quantity of reinforcer. As the session proceeded increasing delay was introduced onto the response leading to the large reward. Hence, the nature of the choice was a small quantity of reinforcer immediately versus a larger but progressively delayed amount of reinforcer. At stable baseline performance the mice were challenged with a variety of task manipulations and systemic d-amphetamine in order to discern aspects of the underlying psychological and neurochemical substrates of the choice behaviour.Results The mice showed a systematic shift in responding away from the large reinforcer with increasing delay (0, 2, 4, 8, 12 s), such that at the longest delay >80% of nose-pokes were for the smaller, immediate reinforcer. Task manipulations indicated that behaviour was controlled in a trial discrete manner by the contingency between delay and reward and was not due to non-specific factors such as satiation. d-Amphetamine had complex, dose dependent effects on choice behaviour which revealed dissociations between impulsive choice and hyperactivity. Conclusions We have successfully developed an assay of impulsivity in mice that will be of utility to examine impulsive behaviours and their genetic substrates. In addition, our data provided evidence of distinct dopaminergic mechanisms mediating aspects of impulsivity and hyperactivity.     

Effects of acute and chronic nicotine on responses maintained by primary and conditioned reinforcers in rats

There is growing recognition that nonnicotine factors, such as the sensory stimuli associated with smoking, can play a critical role in the maintenance of cigarette smoking. However, little is known about the effects of nicotine on responding maintained by these stimuli, which are assumed to be conditioned reinforcers. The authors used an animal model to examine the acute and chronic effects of nicotine on responses maintained by food and conditioned reinforcers (i.e., lights) and responses in the absence of programmed consequences (i.e., extinction). During the acute phase, 4 male rats received 5 doses of subcutaneous nicotine. One dose of nicotine was then administered for a minimum of 60 days. Food-maintained and extinction responses did not significantly increase during the acute phase; however, food-maintained responses did increase during the chronic phase. Relative to vehicle, intermediate doses increased responses maintained by conditioned reinforcers during both phases. The results suggest that nicotine enhances responding maintained by conditioned reinforcers and possibly by food.     

The development of pharmacological tolerance to the effect of nicotine on schedule-controlled responding in mice

The effects of nicotine in mice responding on a fixed-ratio schedule for a sweetened milk reinforcer were determined before, during, and after daily administration of the drug. Druing chronic treatment, responding was initially depressed in a group of mice given presession injections of nicotine and gradually returned to prechronic baseline levels. Responding to single doses of nicotine shifted to the right following chronic treatment for animals receiving either presession or postsession chronic injections of 1.2 mg/kg nicotine. Following termination of chronic treatment, both groups lost tolerance to the chronic dose at similar rates. These data indicate that animals given chronic pre- and postsession injections of nicotine develop tolerance to the pharmacological effects of the drug and that behavioral variables do not influence the development of tolerance to nicotine.     

The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of nicotine.

The primary reinforcing effects of nicotine are mediated by the drugs action at central nervous system nicotinic acetylcholine receptors (nAChRs). Although previous studies have demonstrated that nicotine potently enhances responding for non-pharmacological stimuli, the role of nAChRs in this reinforcement-enhancing effect is not known. The two reinforcement-related effects of nicotine can be dissociated in a paradigm that provides concurrent access to drug infusions and a non-pharmacological visual stimulus (VS). The present study characterized the role of nAChRs in the primary reinforcing effect of nicotine and the reinforcement-enhancing effect of nicotine. For rats with access to VS (VS-Only), nicotine (NIC-Only), both reinforcers contingent upon one response (NIC+VS) or both reinforcers contingent upon separate responses (2-Lever), unit dose-response relationships (0, 30, 60, or 90 microg/kg/infusion, free base) were determined over a 22-day acquisition period. Expression of the two reinforcement-related effects of nicotine was manipulated by pharmacological antagonism of nAChRs (1 mg/kg mecamylamine, subcutaneous, 5-min before the session) or by substituting saline for nicotine infusions (ie extinction) over a series of seven test sessions. Unit dose manipulations yielded an inverse dose-response relationship for active lever responding in the NIC+VS group. The dose-response relationships for rats with independent access to each reinforcer (2-Lever group) were relatively flat. For the 2-Lever group, acute mecamylamine challenge blocked the reinforcement-enhancing effects of nicotine, VS-lever responding decreased to basal levels on the first day of mecamylamine treatment or saline substitution (to the level of the VS-Only group). In contrast, nicotine-lever responding decreased gradually over the 7-day testing period (similar to saline extinction). The two reinforcement-related effects of nicotine are mediated by nAChRs but can be dissociated by acute and chronic profiles.     

Effects of altering reinforcer magnitude and reinforcement schedule on phencyclidine (PCP) self-administration in monkeys using an adjusting delay task

Compared to nondrug reinforcers, few studies have examined delay discounting for drug reinforcers. The purpose of the present study was to examine delay discounting in rhesus monkeys using orally delivered phencyclidine (PCP) as the reinforcer and to examine the effects of manipulating reinforcer magnitude and cost on delay discounting for PCP using an adjusting delay task. Monkeys could choose between a single delivery of PCP available immediately or a bundle of PCP deliveries available following a titrated delay. The average of the delays, or the mean adjusted delay (MAD), served as the quantitative measure of delay discounting. In Experiment 1, reinforcer magnitude was manipulated by varying the PCP concentration and the size of the delayed reinforcer (6 or 12 deliveries). The concentration-effect curve for PCP deliveries assumed an inverted U-shaped function, but varying PCP concentration had little effect on MAD values or the choice between immediate and delayed reinforcers. Increasing the size of the delayed reinforcer produced an upward and leftward shift in the concentration-effect curve. In Experiment 2, the cost of reinforcers was manipulated by increasing the fixed ratio (FR) requirement for each choice. Increasing the FR led to increased MAD values and decreased PCP self-administration.     

Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers

Rationale Nicotine has two effects on reinforcement in traditional self-administration paradigms. It serves as a primary reinforcer by increasing the probability of behaviors that result in nicotine delivery. However, nicotine also potently enhances behaviors that result in the delivery of nonpharmacological reinforcers. Objectives The present study sought to dissociate these two effects of nicotine on reinforcement. Methods For one group of rats (2 lever), a nonpharmacological reinforcer [visual stimulus (VS)] was available for pressing one lever. Nicotine infusions were available for pressing a different lever. A second group (NIC + VS) received more traditional self-administration training; both the VS and nicotine were delivered for pressing a single active lever. Control groups received either nicotine infusions (NIC only) or VS presentations (VS only) for pressing the active lever. Results Nicotine alone was a weak reinforcer; the VS alone was slightly more reinforcing than nicotine. When these two reinforcers were combined (NIC + VS), response rates were synergistically increased. For the 2-lever group, responding on the nicotine lever was weak, matching the response rates of rats receiving nicotine alone. However, responding on the VS lever was potently enhanced in this group; equaling the response rates for rats receiving both reinforcers for making a single response (NIC + VS). Conclusions These data indicate that the reinforcement-enhancing effects of nicotine are very potent even when only moderate quantities of the drug are self-administered. Moreover, they provide the first demonstration that the reinforcement-enhancing and primary reinforcing effects of nicotine can be dissociated behaviorally.     

Effects of altering reinforcer magnitude and reinforcement schedule on phencyclidine (PCP) self-administration in monkeys using an adjusting delay task

Compared to nondrug reinforcers, few studies have examined delay discounting for drug reinforcers. The purpose of the present study was to examine delay discounting in rhesus monkeys using orally delivered phencyclidine (PCP) as the reinforcer and to examine the effects of manipulating reinforcer magnitude and cost on delay discounting for PCP using an adjusting delay task. Monkeys could choose between a single delivery of PCP available immediately or a bundle of PCP deliveries available following a titrated delay. The average of the delays, or the mean adjusted delay (MAD), served as the quantitative measure of delay discounting. In Experiment 1, reinforcer magnitude was manipulated by varying the PCP concentration and the size of the delayed reinforcer (6 or 12 deliveries). The concentration-effect curve for PCP deliveries assumed an inverted U-shaped function, but varying PCP concentration had little effect on MAD values or the choice between immediate and delayed reinforcers. Increasing the size of the delayed reinforcer produced an upward and leftward shift in the concentration-effect curve. In Experiment 2, the cost of reinforcers was manipulated by increasing the fixed ratio (FR) requirement for each choice. Increasing the FR led to increased MAD values and decreased PCP self-administration.     

Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers

Rationale Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans.Objectives To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements.Methods Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1–20 min) and FR response requirement (10–1600) were varied in different subjects over consecutive sessions.Results Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings.Conclusions Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.Abstracts of these experiments previously appeared in Pharmacologist 25:219, 1983, and Neurosci Lett 14(Suppl):140, 1983.     

Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex

Rationale Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT_1A agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats.Objectives Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT_1A antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats.Methods In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex.Results Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT_1A receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition.Conclusions These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT_1A receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.     

The effects of d-amphetamine, chlordiazepoxide, α-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delayed reinforcement in rats

RATIONALE: Inability to tolerate delays to reward is an important component of impulsive behaviour, and has been suggested to reflect dysfunction of dopamine systems. OBJECTIVES: The present experiments examined the effects of signalling a delayed, large reward on rats' ability to choose it over a small, immediate reward, and on the response to amphetamine, a dopamine receptor antagonist, and a benzodiazepine. METHODS: Three groups of Lister hooded rats were tested on a two-lever discrete-trial delayed reinforcement task in which they chose one pellet delivered immediately or four pellets delivered after a delay. This delay increased from 0 to 60 s during each session. Trials began with illumination of a houselight: in the Houselight group, this remained on during the delay and feeding period. In the No Cue group, the houselight was extinguished at the moment of choice. In the Cue group, a stimulus light was illuminated during the delay. Once trained, the rats were challenged with d-amphetamine (0.3, 1.0, 1.6 mg/kg), chlordiazepoxide (1.0, 3.2, 5.6, 10 mg/kg), alpha-flupenthixol (0.125, 0.25, 0.5 mg/kg), and various behavioural manipulations. RESULTS: Subjects' choice became and remained sensitive to the delay; the cue speeded learning. Amphetamine decreased choice of the large reinforcer in the No Cue group and increased it in the Cue group. alpha-Flupenthixol and chlordiazepoxide generally decreased preference for the delayed reinforcer; flupenthixol reduced the cue's effects, but chlordiazepoxide did not interact with the cue condition. CONCLUSIONS: Signals present during a delay can enhance the ability of amphetamine to promote choice of delayed rewards.     

Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task

Rationale

Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward.

Objectives

To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward.

Materials and methods

Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays.

Results

Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine.

Conclusions

The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity.     

Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on choice between delayed reinforcers

The possible involvement of the ascending 5-hydroxytryptaminergic (5HTergic) pathways in determining the effectiveness of delayed positive reinforcers was investigated using Mazur's (1984) adjusting-delay paradigm. Fourteen rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 12 rats received sham lesions. The rats made repeated choices in a two-lever operant conditioning chamber between a smaller reinforcer delivered after a 2-s delay and a larger reinforcer delivered after a variable delay, the length of which was determined by the subject's previous choices. When the two reinforcers consisted of one and two food pellets, the indifference point (the delay to the larger reinforcer that rendered the two reinforcers equally effective) was shorter in the lesioned group than in the control group. Increasing the sizes of the reinforcers to three and six pellets reduced the indifference point in both groups and abolished the between-group difference. The levels of 5HT and 5-hydroxyindoleacetic acid (5HIAA) in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were greatly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected. The results are consistent with the suggestion that the 5HTergic pathways play a role in maintaining the effectiveness of delayed reinforcers.     

Cocaine decreases self-control in rats: a preliminary report

Cocaine abuse is often associated with behavior that takes into account short-term, but not long-term consequences. However, there has been no empirical research concerning the effects of cocaine on self-control (choice of a larger, more delayed reinforcer over a smaller, less delayed reinforcer). In the present research, when food-deprived rats repeatedly chose between a larger, more delayed food reinforcer and a smaller, less delayed food reinforcer, chronic intraperitoneal injections of 15 mg/kg cocaine (but not 10 mg/kg fluoxetine) decreased the rats' choices of the larger, more delayed reinforcer. Cocaine can decrease rats' self-control.     

Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement

RATIONALE: The ascending 5-hydroxytryptaminergic (5-HTergic) pathways are believed to be involved in "impulse control". Rats whose 5-HTergic pathways have been destroyed are more liable than intact rats to select a smaller, immediate reinforcer rather than a larger, delayed reinforcer (impulsive choice), and recent evidence indicates that this effect of central 5-HT depletion reflects a change in the rate of time discounting (i.e. a change in the rate at which reinforcers become devalued as a function of delay). Delay of reinforcement and uncertainty of reinforcer delivery are believed to have equivalent effects on choice behaviour. However, it is not known whether central 5-HT depletion affects choice between probabilistic reinforcers. OBJECTIVE: We examined the effects of central 5-HT depletion on choice behaviour in two experiments: In experiment 1, rats chose between a smaller immediate reinforcer and a larger delayed reinforcer; in experiment 2, rats chose between a smaller certain reinforcer and a larger probabilistic reinforcer. METHODS: Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press two levers for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, selection of lever A resulted in immediate delivery of one food pellet; selection of lever B resulted in delivery of 2 pellets, either following a delay (dB) (experiment 1) or with a probability (pB) less than 1 (experiment 2). RESULTS: In experiment 1, both groups showed declining choice of lever B (%B) as a function of dB. The lesioned group showed shorter indifference delays (D50: the value of dB corresponding to %B=50) than the sham-lesioned group. In experiment 2, both groups showed declining choice of lever B as a function of the odds against delivery of the two-pellet reinforcer, thetaB (thetaB=[1/pB]-1). There was no difference between the "indifference odds" (theta50: the value of thetaB corresponding to %B=50) between the two groups. In both experiments, the levels of 5-HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. CONCLUSIONS: These results provide additional evidence that central 5-HTergic mechanisms are involved in time discounting, but provide no evidence for a similar role of 5-HT in rats' sensitivity to probabilistic reinforcement.