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.     

Effect of central 5-hydroxytryptamine depletion on inter-temporal choice: a quantitative analysis

Rationale: It has been proposed that the ascending 5-hydroxytryptaminergic (5-HTergic) pathways are involved in ”impulse control”. Previous experiments have shown that 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). However, it remains unclear whether 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) or a change in sensitivity to reinforcer size. Objective: We examined the effect of central 5-HT depletion on time discounting using a quantitative model of inter-temporal choice (multiplicative hyperbolic model), which enables effects on time discounting to be differentiated from effects on sensitivity to reinforcer size. 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 a discrete-trials adjusting-delay schedule. In free-choice trials, selection of lever A resulted in a brief fixed delay (d _A ) followed by delivery of one pellet; selection of lever B resulted in a longer variable delay (d _B ) followed by delivery of two pellets; d _B was adjusted in accordance with the subject’s choices. The value of d _A was varied (0.5–8.0 s) in successive phasesof the experiment, and the indifference value of d _B was determined in each case. Results: In both groups, the indifference value of d _B was linearly related to the value of d _A ,in accordance with the multiplicative hyperbolic model. The lesioned group showed shorter indifference delays than the sham-lesioned group, this being reflected in a parallel displacement of the linear indifference function. In both experiments, the levels of 5-HT and 5-hydroxyindole-acetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. Conclusions: According to the multiplicative hyperbolic model, parallel displacement of the linear indifference function uniquely specifies a change in time discounting. Thus these results indicate that central 5-HT depletion results in an increase in the rate of time discounting for food reinforcers. Received: 19 October 1999 / Final version: 6 January 2000     

Effect of central 5-hydroxytryptamine depletion on changeover behaviour in concurrent schedules of reinforcement

  Rationale: Previous experiments have shown that rats whose 5-hydroxytryptaminergic (5-HTergic) pathways have been destroyed exhibit higher rates of switching between response alternatives on various temporal differentiation schedules. Objective: This paper reports two experiments investigating the effect of central 5-HT depletion on switching between concurrent schedules of reinforcement which do not entail temporal differentiation of behaviour. Methods: Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press levers for sucrose reinforcement. In experiment 1, the rats were exposed to concurrent pairs of variable-time (VT) schedules specifying equal inter-reinforcement intervals; responses on a single ”changeover lever” alternated between the two VT schedules. In experiment 2, the rats were exposed to concurrent pairs of variable-interval (VI) schedules specifying equal inter-reinforcement intervals; responses on one lever (”VI lever”) earned reinforcers, while responses on the other lever (”changeover lever”) alternated between the two VI schedules. Results: In experiment 1, both groups showed longer ”dwell-times” (intervals between successive changeover responses) when a reinforcer was delivered in the ”dwell” than when no reinforcer was delivered (”win-stay” effect). The lesioned rats showed higher rates of changeover responding and shorter dwell-times (with and without reinforcer delivery) than the sham-lesioned group. In experiment 2, the rate of responding on the VI lever did not differ significantly between the two groups; however, the lesioned rats showed higher rates of changeover responding, shorter dwell-times (with and without reinforcer delivery) and smaller numbers of inter-changeover responses on the VI lever than the sham-lesioned group. 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 further evidence for the involvement of the ascending 5-HTergic pathways in behavioural ”switching”, and indicate that this is not restricted to temporal differentiation schedules. Received: 28 September 1998 / Final version: 1 December 1998     

Effect of central 5-hydroxytryptamine depletion on performance in the free-operant psychophysical procedure: facilitation of switching, but no effect on temporal differentiation of responding

This experiment examined the effect of destroying the ascending 5-hydroxytryptaminergic (5-HTergic) pathways on timing and switching behaviour in the free-operant psychophysical procedure. Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press levers for sucrose reinforcement; sessions consisted of fifty 50-s trials in which reinforcers were available on a variable-interval 30-s schedule. In the first 25 s, of each trial, reinforcement was only available for responses on lever A; in the last 25 s, it was available only for responses on lever B. In phase 1 (70 sessions) repetitive switching between the levers was prevented by withdrawal of lever A after the first response on lever B in each trial; in phase 2 (40 sessions) this constraint on switching was removed; in phase 3 (40 sessions) the constraint was reinstated. Data were collected from probe trials (four per session) in which no reinforcers were delivered, during the last ten sessions of each phase. In all phases, both groups showed declining response rates on lever A and increasing response rates on lever B as a function of time from the onset of the trial. Response rate on lever B, expressed as percentage of overall response rate, could be described by a two-parameter logistic function. Removal of the constraint on switching reduced the slope of the function without changing the indifference point (time corresponding to 50% responding on lever B). The parameters of the timing function did not differ between the groups in any of the phases. However, the lesioned group showed a greater enhancement of switching rate during phase 2 than the control group. 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. The results provide further evidence for the involvement of the ascending 5-HTergic pathways in switching between response alternatives, but cast doubt on our previous suggestion that the effects of 5-HT depletion on temporal differentiation of behaviour are mediated by facilitated switching. Received: 12 July 1998/Final version: 9 October 1998     

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on performance on two operant timing schedules

RATIONALE: Previous experiments have shown that the disruptive effect of central 5-HT depletion on interval timing behaviour is critically dependent upon the particular timing schedule used. However, it is not known how acute disruption of 5-HTergic function brought about by drugs acting at 5-HT receptors affects timing. OBJECTIVE: To examine the effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on performance on two quantitative timing schedules, a free-operant schedule in which rats were trained to distribute their responses differentially between two levers during the course of a 50-s trial (free-operant psychophysical procedure) and a discrete-trials schedule in which rats were trained to discriminate the durations of light stimuli (interval bisection task). METHODS: In experiment 1, rats were trained under the free-operant psychophysical procedure to respond on two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half, of the trial. For one group, repetitive switching between levers was permitted; for another group, it was prevented. In experiment 2, rats were trained to press lever A after a 2-s stimulus and lever B after an 8-s stimulus, and were then tested with stimuli of intermediate durations. For one group, a 'poke response' (depression of a central tray flap) was required after stimulus presentation to effect lever presentation; for the other group this requirement did not operate. In both experiments, quantitative indices of timing were derived from the psychophysical functions (%B responding vs time). RESULTS: In experiment 1, 8-OH-DPAT (25, 50, 100 and 200 microg kg(-1) s.c.) displaced the psychophysical curve to the left in both versions of the schedule. In experiment 2, 8-OH-DPAT increased the Weber fraction in both versions of the task without displacing the curve. CONCLUSIONS: These results show that 8-OH-DPAT disrupts timing behaviour. The results of experiment 1 are consistent with the proposal that 5-HTergic mechanisms help to regulate the period of the hypothetical pacemaker. However, the results of experiment 2 do not support this suggestion. Taken together, the results support the notion that different neural mechanisms may be involved in timing tasks involving temporal distribution of responding and discrimination of the durations of exteroceptive stimuli.     

5-Hydroxytryptamine and interval timing behaviour

Interval timing behaviour is revealed by prospective, immediate and retrospective timing schedules. Prospective timing tasks are used to study intertemporal choice (choice between outcomes occurring after different delays), immediate timing tasks to study temporal differentiation (temporal regulation of the animal's behaviour) and retrospective timing tasks to study temporal discrimination (discrimination between the durations of external events). Central 5-hydroxytryptamine (5-HT) depletion promotes preference for small early reinforcers over large delayed reinforcers, possibly by facilitating the time-dependent degradation of reinforcer value. Central 5-HT depletion retards the learning of temporal differentiation, and increases the variability of timing in some immediate timing tasks; however, it does not impede (in some cases it facilitates) the acquisition of temporal discrimination. Attempts to ascribe all the effects of 5-HT depletion on timing to a single behavioural process have been unsuccessful, although disinhibition of switching between operant responses may account for some of the findings. Acute treatment with drugs affecting 5-HTergic mechanisms alters timing behaviour in qualitatively different ways in different timing schedules, casting doubt on the idea that the effects of these drugs are mediated by interaction with a unitary timing process. The receptors that mediate 5-HT's putative involvement in interval timing behaviour remain to be identified.     

Effects of fenfluramine on free-operant timing behaviour: evidence for involvement of 5-HT2A receptors

RATIONALE: Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T50. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation. OBJECTIVE: We examined whether fenfluramine's effect on temporal differentiation can be antagonised by the 5-HT1A receptor antagonist N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine. METHODS: Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data for derivation of timing indices (T50, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT1A and 5-HT2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography. RESULTS: Experiment 1: fenfluramine (2 mg/kg) reduced T50; this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-100635 (100 microg/kg). Experiment 2: 8-OH-DPAT (100 microg/kg) and DOI (250 microg/kg) reduced T50 in both groups; fenfluramine reduced T50 only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected. CONCLUSIONS: The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT2A receptors.     

Failure of central 5-hydroxytryptamine depletion to alter the effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on timing performance on the free-operant psychophysical procedure

RATIONALE: The 5-hydroxytryptamine (5-HT)(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) alters temporal differentiation of behaviour on the free-operant psychophysical procedure, displacing the psychophysical curve to the left, thereby reducing the indifference point T(50). However, it is not known whether this effect of 8-OH-DPAT is mediated by an action of the drug at somatodendritic autoreceptors or at postsynaptic receptors. OBJECTIVE: To compare the effects of 8-OH-DPAT on performance on the free-operant psychophysical procedure in normal (sham-lesioned) rats and in rats whose 5-HTergic pathways had been lesioned by means of intra-raphe injections of the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). METHODS: Twelve rats received 5,7-DHT-induced lesions of the median and dorsal raphe nuclei, and twelve received sham lesions. They were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials, during which reinforcement was provided intermittently for responding on A in the first half and B in the second half of the trial. Percentage responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data from each rat for the derivation of timing indices [T(50) (time corresponding to %B=50%) and Weber fraction] following treatment with acute doses of 8-OH-DPAT (25, 50, 100, 200 microg kg(-1), s.c.) and saline (vehicle-alone treatment). Levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline and dopamine were measured in forebrain regions after the completion of the experiment. RESULTS: Under the vehicle-alone condition, the lesioned group displayed a greater propensity for switching between the levers, but T(50) and the Weber fraction did not differ between the groups. In both groups, 8-OH-DPAT shifted the psychophysical curve to the left, significantly reducing T(50) at the 200-microg kg(-1) dose; the effect of 8-OH-DPAT did not differ significantly between the groups. Levels of 5-HT and 5-HIAA in the lesioned group were about 10% of those in the sham-lesioned group; there was no effect of the lesion on catecholamine levels. CONCLUSIONS: The results confirm that 8-OH-DPAT disrupts temporal differentiation in the free-operant psychophysical schedule, reducing the indifference time, T(50). The failure of central 5-HT depletion to alter the effect of 8-OH-DPAT suggests that this effect may be mediated by stimulation of postsynaptic 5-HT(1A) (or possibly 5-HT(7)) receptors rather than somatodendritic 5-HT(1A) autoreceptors.     

Effect of destruction of the 5-hydroxytryptaminergic pathways on behavioural timing and “switching” in a free-operant psychophysical procedure

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on performance in a free-operant timing schedule. Rats received either injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press levers for a sucrose reinforcer. Training sessions consisted of 40, 50-s trials in which reinforcers were available on a variable-interval 25-s schedule; in the first 25 s of each trial, reinforcers were only available for responses on lever A, where in the last 25 s reinforcers were available only for responses on lever B. Data were collected probe trials (four per session) in which no reinforcers were delivered, during the last ten of 50 training sessions. Both groups showed decreasing response rates on lever A and increasing response rates on lever B as a function of time from the onset of the trial. Response rate on lever B, expressed as a percentage of overall response rate, could be described by a two-parameter logistic function; neither the indifference point (i.e the time corresponding to 50% responding on lever B) nor the slope of the function differed between the two groups. However, the lesioned group showed a higher rate of switching between response alternatives than the sham-lesioned group. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not significantly altered. The results confirm previous findings that behaviour in timing schedules is sensitive to destruction of the central 5HTergic pathways, and suggest that these pathways may contribute to the inhibitory regulation of switching between behavioural states.     

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.     

Selective destruction of brain serotonin neurons by 5,7-dihydroxytryptamine increases responding for a conditioned reward

Rationale: Previously, we have shown that increasing 5-hydroxytryptamine (5-HT) activity attenuates responding for conditioned reward (CR), and the response potentiating effect of d-amphetamine on this behaviour. Objectives: The present experiments examined the effects of reducing 5-HT function on responding for CR. Methods: In experiment 1, thirsty rats were trained to associate a CS+ with water delivery. The neurotoxin 5,7-DHT was then injected into the dorsal and median raphe nuclei. Subsequently, rats were treated with intra-accumbens d-amphetamine (1, 3, 10 μg) or saline and given access to two levers. One lever delivered the CS+ (now termed a CR), while the other was inactive. In experiment 2, the lesion was carried out prior to conditioning, and approach behaviour to the water magazine was measured during CS+ periods. Subsequently, rats were allowed to respond for the CS. In experiment 3, non-deprived rats learned to associate a CS+ with 10% sucrose; these animals also experienced a CS– which was not paired with sucrose. During a test phase responses on the two levers delivered either the CS+ or the CS–. Results: 5,7-DHT substantially reduced 5-HT levels in striatum and hippocampus. In experiment 1, responding for the CR was enhanced by both d-amphetamine and 5-HT depletion in an additive fashion. In experiments 2 and 3, the discriminative control over behaviour exerted by the CS+ was not affected by 5-HT depletion. However, compared to control animals 5-HT-depleted rats showed higher levels of operant responding for the CR. Conclusions: Serotonin depletion selectively enhances responding for CR. Although 5-HT depletion did not potentiate the effects of d-amphetamine, it is suggested that CRs activate the mesolimbic dopamine system, and that removal of an inhibitory influence of 5-HT on the activity of this system results in increased responding for CR in 5,7-DHT-treated rats. Received: 24 February 1999 / Final version: 16 June 1999     

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.     

Effect of central 5-hydroxytryptamine depletion on tolerance of delay of reinforcement: evidence from performance in a discrete-trials “time-left” procedure

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on performance on a new discrete-trials version of the “time-left” procedure. Rats received either injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained in a discrete trials schedule in which reinforcers were provided for responding on either of two levers, A and B. At a random time point, t s after the start of each trial, the two levers were inserted into the operant chamber; a response on A resulted in the delivery of one food pellet after d _A s, whereas a response on B resulted in the delivery of two pellets after 84-t s. The value of d _A was varied between 1 and 12 s in different phases of the experiment. Both groups showed an increasing tendency to respond on lever B as a function of time within the trial. Logistic functions were fitted to the data from each group, and a value of the “indifference point” (T ₅₀: the time within the trial at which proportional choice of B attained a value of 50%) was derived for each rat. For each value of d _A, the values of T ₅₀ were significantly greater in the lesioned rats than in the control rats, reflecting a rightward shift of the logistic function in the lesioned group. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not significantly altered. The results provide further evidence for the involvement of the ascending 5HTergic pathways in the control of operant behaviour by delayed positive reinforcers. Received: 12 January 1998/Final version: 6 May 1998     

Effects of acute and chronic nicotine on impulsive choice in rats

Impulsive choice, or preference for small immediate reinforcers over large delayed reinforcers, has been associated with cigarette smoking. The direct effects of nicotine on impulsive choice in laboratory animals are unknown. We examined the effects of acute and chronic nicotine injections, and the termination of injections, on impulsive choice in rats. Five rats made choices between a one- and a three-pellet reinforcer in a discrete trials procedure. The delay to the smaller reinforcer was always 1 s. A computer adjusted the delay to the larger reinforcer until the pattern of choices reflected indifference between the two alternatives. We assessed the effects of acute and chronic nicotine (vehicle, 0.03, 0.1, 0.3 and 1.0 mg/kg nicotine). The latency to make the first response of the session increased under the acute 1.0 mg/kg dose. There were no consistent differences in the effects of acute and chronic nicotine on response latency and lever pressing during the delays between choices. Acute injections of nicotine dose-dependently increased impulsive responding. After chronic injections, impulsive responding was increased equivalently regardless of dose, and it was increased even in the absence of nicotine. After drug injections were terminated, behavior remained impulsive for about 30 drug-free sessions, and then responding gradually returned to baseline levels. The results suggest that increases in impulsive choice were not due to anorectic effects, response biases or changes in conditioned reinforcement. Nicotine may have decreased the value of delayed reinforcers. Chronic nicotine exposure produced long-lasting but reversible increases in impulsive choice.     

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.     

Effect of destruction of the 5-hydroxytryptaminergic pathways on temporal memory: quantitative analysis with a delayed interval bisection task

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on memory for duration, using a delayed interval bisection task. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset a response on a panel placed midway between the two levers was required in order to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a ‘correct’ response, reinforcer delivery. When > 90% correct choices had been attained, an 8-s (phase I) or a 12-s (phase II) delay was interposed between stimulus offset and lever presentation in 50% of the trials, and probe trials (10% of both non-delay and delay trials) were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to stimulus duration. In both groups, the imposition of post-stimulus delays displaced the bisection point (duration yielding 50% choice of lever B) towards longer durations; this effect was significantly greater in the lesioned group than in the control group. Imposition of post-stimulus delays resulted in increases in the Weber fraction, which did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. Received: 30 April 1996 / Final version: 20 August 1996     

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 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.     

Serotonin depletion attenuates cocaine seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats

RATIONALE: Acute serotonin (5-HT) depletion by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, attenuates cocaine seeking in rats. OBJECTIVE: The present study examined the effects of chronic 5-HT depletion on cocaine- and sucrose seeking using the 5-HT-selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). METHODS: Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for sucrose pellets (45 mg Noyes) on a fixed ratio (FR) 1 schedule of reinforcement during daily 2-h sessions. Subsequently, animals received i.c.v. infusions of either vehicle or 5,7-DHT (150 microg/6 microl or 200 microg/20 microl). After a minimum of 10 days post-lesion, cocaine- and sucrose seeking were measured as lever presses in the absence of reinforcement (extinction). Some cocaine-trained animals were also assessed for the re-establishment of self-administration and reinstatement of extinguished cocaine seeking by i.v. cocaine priming injections and response-contingent presentations of cocaine-paired stimuli. RESULTS: 5-HT depletion by the 150 microg/6 microl dose of 5,7-DHT failed to alter cocaine- and sucrose seeking despite producing a 42-77% depletion of 5-HT in limbic terminal regions. The 200 microg/20 microl dose of 5,7-DHT attenuated cocaine seeking but enhanced sucrose seeking during extinction and produced a 55-85% depletion of 5-HT. In addition, cocaine-paired cues and cocaine priming reinstated cocaine-seeking behavior, and responding was enhanced in 5,7-DHT-treated animals relative to vehicle-treated controls at the 1 mg/kg/0.1 ml priming dose. However, re-establishment of cocaine self-administration was not altered by 5,7-DHT. CONCLUSION: The results suggest that 5-HT depletion may attenuate cocaine seeking but may enhance sucrose seeking when animals are tested during extinction. Furthermore, 5-HT depletion may enhance cocaine seeking produced by cocaine itself. Together these findings suggest that 5-HT depletion may have opposite effects on incentive motivation for cocaine during abstinence versus relapse.     

The pharmacology of impulsive behaviour in rats VI: the effects of ethanol and selective serotonergic drugs on response choice with varying delays of reinforcement

Rationale: Tolerance to delay of reinforcement has been proposed as an important facet of self-control in both animals and man. Poor self-control, leading to impulsive behaviour, can be a major problem if it reaches pathological levels. Objectives: The effects of five serotonergic drugs were compared to those of ethanol on a procedure for measuring tolerance to delay of reinforcement in rats in order to elucidate further the role of the serotonin systems in the regulation of impulsive behaviour. Methods: Rats were trained to choose between a single food pellet (small reinforcer) delivered immediately or five food pellets (large reinforcer) delivered after programmed delays. At the start of each session, there was no delay between the response and delivery of the large reinforcer, but this was increased stepwise during the session to delays of 10, 20, 40 and 60 s. Results: The rats showed consistent preference for the larger reinforcer when it was not delayed but showed a shift in preference as the session continued, so that they preferred the small reinforcer when the large was delayed by 40 or 60 s. Ethanol at a dose of 1.0 g/kg produced a significance increase in preference for the small, immediate reinforcer throughout the session, although there were marked individual differences in the size of the effect. A similar, but somewhat smaller effect was seen with the 5-HT₂ agonist, DOI, at a dose of 1.0 mg/kg. In contrast, the 5-HT_1A agonist, 8-OH-DPAT (0.3 mg/kg) reduced preference for the large reinforcer at the start of the session, and reduced preference for the small reinforcer at the end of the session, i.e. produced a regression to indifference. Lower doses of these three drugs, and treatment with the 5-HT receptor subtype selective antagonists WAY-100635 (5-HT_1A: 0.01–0.1 mg/kg), ritanserin (5-HT₂: 0.1 and 0.3 mg/kg) and MDL-72222 (5-HT₃: 1.0 and 3.0 mg/kg) had no significant effects on reinforcer choice. Conclusion: These data show that ethanol and DOI increase preference for the immediate reinforcer, which can be construed as evidence of an increase in impulsive behaviour (reduction in self control), whereas selective blockade of the 5-HT_1A, 5-HT₂ or 5-HT₃ receptors using selective antagonists does not affect self-control. Received: 24 October 1998 / Final version: 16 February 1999