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.     

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 performance in the “time-left” procedure: further evidence for a role of the 5-hydroxytryptaminergic pathways in behavioural “switching”

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on performance in a free-operant timing schedule: 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, 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 60-t s. The value of d _A was varied between 1 and 8 s in different phases of the experiment. Both groups showed decreasing response rates on lever A and increasing response rates on lever B as a function of time within the trial. An index of timing (T ₇₅: the time within the trial at which relative response rate on B attained a value of 75%) was systematically related to the value of d _A, but did not differ significantly between lesioned and control rats. However, the lesioned group showed significantly higher rates of switching between response alternatives than the sham-lesioned group at all values of d _A. 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 that the ascending 5HTergic pathways may contribute to the inhibitory regulation of switching between behavioural states. Received: 27 March 1997 /Final version: 19 May 1997     

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.     

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     

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     

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 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     

Choice under concurrent VI schedules: comparison of behavior maintained by cocaine or food

 Previous research has shown that concurrent schedule responding maintained by cocaine under short variable-interval (VI) schedules is well described by the generalized matching law. That is, drug-maintained behavior was apportioned in accordance with relative frequency of reinforcement. The purpose of the present experiment was to examine the ability of the generalized matching law to account for choice under longer VI schedules of cocaine availability, and to compare cocaine-maintained to food-maintained behavior in this regard. One group of rhesus monkeys (n=4) was prepared with indwelling IV catheters and allowed to respond under concurrent VI (conc VI) schedules of cocaine delivery (0.025, 0.05 or 0.1 mg/kg per injection) with an average inter-reinforcer interval (IRI) of 10 or 30 min. In a second group of monkeys (n=4), a comparable experiment was conducted but with responding maintained by different amounts of food (one, two, or four 1-g banana-flavored pellets). For both groups, the same reinforcer followed responding on either lever, the only difference between the options being the VI schedule, i.e., frequency of reinforcement. The behavior of the cocaine-maintained group was well predicted by the generalized matching law. While both groups evidenced undermatching of both response and time allocation, lever pressing of monkeys whose behavior was maintained by food showed more undermatching than that of the cocaine-maintained group. In addition, a consistent and unexplained bias in responding toward the right lever developed in the food-maintained, but not the cocaine-maintained monkeys. Considering the present results with those of previous experiments, it appears that food-, but not cocaine-maintained behavior, deviates increasingly from strict matching as the IRI is extended. This difference across reinforcers could be due to differences between cocaine and food in the mechanisms by which they maintain behavior, or a direct effect of cocaine on choice performance. Received: 9 February 1998 / Final version: 4 June 1998     

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

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

The pharmacology of impulsive behaviour in rats VII: the effects of serotonergic agonists and antagonists on responding under a discrimination task using unreliable visual stimuli

Rationale: The serotonergic systems have been implicated in the pathological impulsive behaviour on the basis of both clinical and preclinical data. However, impulsivity is probably made up of several independent factors, and the involvement of the diverse regulatory mechanisms of the serotonergic systems has not been widely studied. Objective: The influence of a range of serotonergic agents on impulsivity was examined using a procedure designed to test the dimension of impulsivity termed ”reflection-impulsivity” in rats. Methods: An operant procedure was used in which the need to wait before responding was made explicit by using a signal which increased in predictive value the longer the subject waited before responding. First, the rats learned that a light signal indicated the availability of a food reinforcer if one of two levers was pressed. In the test procedure, on each trial, when the light was turned on it was only 50% likely to indicate the ”correct” lever. After a brief interval it was turned off and on again, this time with a slightly higher probability (>50%) of indicating the correct lever. Over a period of a few seconds the probability that the light indicated the correct lever increased to almost 100%. Thus a quick response to the light would result in many errors, whereas a slow response could always result in food delivery. Once trained the rats were treated with a series of drugs: citalopram, (selective serotonin reuptake inhibitor), p-chloramphetamine (PCA, serotonin releaser), 8-OH-DPAT (5-HT_1A agonist), RU24969 (primarily a 5-HT_1B receptor agonist), DOI, (5-HT₂ agonist), WAY-100,635 (5-HT_1A antagonist), ritanserin (5-HT₂ antagonist), and MDL-72222, (5-HT₃ antagonist). Results: Of the test compounds, PCA, DOI and 8-OH-DPAT increased reaction times, whereas ritanserin reduced them. Citalopram and WAY-100,635 had no significant effects, RU-24969 appeared to disrupt responding, and MDL-72222 reduced premature responses and the number of short reaction times. Conclusions: Since agonists at the 5-HT_1A and 5-HT₂ receptors both reduced impulsivity in this procedure, these data suggest that serotonin may promote ”reflection” in this procedure via stimulation of these receptor subtypes. Received: 25 February 1999 / Final version: 4 June 1999     

Comparison of the effects of clozapine and 8-hydroxy-2-(di-<Emphasis Type="Italic">n</Emphasis>-propylamino)tetralin (8-OH-DPAT) on progressive ratio schedule performance: evidence against the involvement of 5-HT<Subscript>1A</Subscript> receptors in the behavioural effects of clozapine

Rationale Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the efficacy of reinforcers. A mathematical model (Killeen PR (1994) Mathematical principles of reinforcement. Behav Brain Sci 17:105–172) affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. The model postulates a bitonic function relating response rate and ratio size. One parameter of the function, a, expresses the motivational effect of the reinforcer, whereas another parameter, δ, expresses the minimum time needed to execute a response, and is regarded as an index of ‘motor capacity’. Previously we found that the atypical antipsychotic clozapine increased a, indicating an increase in reinforcer efficacy; a similar effect was observed with the 5-hydroxytryptamine (5-HT)_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). It has been suggested that some of clozapine’s behavioural effects are mediated by agonistic action at 5-HT_1A receptors. Objective This study was conducted to compare the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. Methods Rats were trained under a time-constrained progressive ratio schedule (50-min sessions). In experiment 1, they received acute doses of clozapine (4 mg kg⁻¹) and 8-OH-DPAT (100 μg kg⁻¹), alone and in combination with the 5-HT_1A receptor antagonist N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-yridinylcyclohexanecarboxamide (WAY-100635; 30 μg kg⁻¹). In experiment 2, the effects of clozapine (2, 4 and 8 mg kg⁻¹) and 8-OH-DPAT (25, 50 and 100 μg kg⁻¹) were compared between intact rats and rats whose 5-HTergic pathways had been ablated by 5,7-dihydroxytryptamine (5,7-DHT). Results In both experiments, clozapine and 8-OH-DPAT increased a and δ. In experiment 1, WAY-100635 abolished the effect of 8-OH-DPAT on a and δ, but did not alter clozapine’s effects on these parameters. In experiment 2, the effects of clozapine and 8-OH-DPAT did not differ between sham-lesioned and 5,7-DHT-lesioned rats. Conclusions The results confirm previous findings on the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. 8-OH-DPAT’s effects are probably mediated by post-synaptic 5-HT_1A receptors; clozapine’s effects are mediated by a different mechanism, which does not appear to involve 5-HT_1A receptors and which does not depend upon an intact 5-HTergic pathway. Jonathan Francis Rickard (1977–2003), a gifted and dedicated Ph.D. student, made a major contribution to this work     

Evidence for an involvement of 5-hydroxytryptaminergic neurones in the maintenance of operant behaviour by positive reinforcement

The possible involvement of the ascending 5-hydroxytryptaminergic (5HTergic) pathways in the maintenance of operant behaviour by positive reinforcement was examined using a quantitative paradigm based on Herrnstein's (1970) equation which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Nine rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 12 rats received sham injections. The rats were trained to steady-state in a series of variable-interval schedules of sucrose reinforcement affording a range of reinforcement frequencies. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value of K_H (the parameter expressing the reinforcement frequency needed to obtain the half-maximum response rate) was significantly lower in the lesioned group than in the control group; the values of R_max (the parameter expressing the maximum response rate) did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, nucleus accumbens and hypothalamus were markedly reduced in all four regions in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected. The results indicate that damage to the central 5HTergic pathways resulted in an increase in the “value” of the sucrose reinforcer, without affecting the animals' response capacity. The results are consistent with the suggestion that the 5HTergic pathways may exert some limiting control on the “values” of certain reinforcers.     

Effect of quinolinic acid-induced lesions of the nucleus accumbens core on performance on a progressive ratio schedule of reinforcement: implications for inter-temporal choice

Rationale The nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers. Objective This study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105–172). Materials and methods Rats with bilateral quinolinic acid-induced lesions of the AcbC (n = 15) or sham lesions (n = 14) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet. Results The performance of both groups conformed to the model of progressive-ratio performance (group mean data: r ²  > 0.92). The motor parameter, δ, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. Conclusions The results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.     

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

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

Exploratory studies in sensory reinforcement in male rats: effects of methamphetamine

Understanding sensory reinforcement and the effects of stimulant drugs on sensory reinforcers is potentially important for understanding their influence on addiction processes. Experiment 1 explored the reinforcing properties of a visual stimulus and the effects of methamphetamine (METH) on responding maintained by a visual reinforcer (VRF) in male rats. Snout poke responses to the active alternative produced the VRF according to variable interval (VI) schedules of reinforcement, and responses to an inactive alternative had no programmed effect. Experiment 2 explored the effects of METH on choice between the VRF and a water reinforcer (H2ORF) using concurrent VI schedules in male rats. In Experiment 1, response-contingent onset of the VRF produced an increase in both the relative frequency and absolute rate of active responding. The rate of both active and inactive responding declined across the 40-min test sessions. METH did not differentially enhance active responding for the VRF. Instead, METH nondifferentially increased the rate of responding and attenuated the within-session decline of responding. In Experiment 2, METH differentially increased the rate of responding for the VRF relative to the H2ORF. The results of these exploratory experiments indicate that the reinforcing effects of the VRF were weak and transient. In addition, METH treatment increased responding, and the specificity of the enhancement of METH was dependent upon the testing conditions. Potential explanations of these differences, such as novelty and reinforcer type, are discussed.     

Attenuation of the effects of <Emphasis Type="Italic">d</Emphasis>-amphetamine on interval timing behavior by central 5-hydroxytryptamine depletion

Rationale  Interval timing in the free-operant psychophysical procedure is sensitive to the monoamine-releasing agent d-amphetamine, the D₂-like dopamine receptor agonist quinpirole, and the D₁-like agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzepine (SKF-81297). The effect of d-amphetamine can be antagonized by selective D₁-like and 5-HT_2A receptor antagonists. It is not known whether d-amphetamine’s effect requires an intact 5-hydroxytryptamine (5-HT) pathway. Objective  The objective of this study was to examine the effects of d-amphetamine, quinpirole, and SKF-81297 on timing in intact rats and rats whose 5-hydroxytryptaminergic (5-HTergic) pathways had been ablated. Materials and methods  Rats were trained under the free-operant psychophysical procedure to press 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. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data for derivation of timing indices (T ₅₀, time corresponding to %B = 50%; Weber fraction). The effects of d-amphetamine (0.4 mg kg⁻¹ i.p.), quinpirole (0.08 mg kg⁻¹ i.p.), and SKF-81297 (0.4 mg kg⁻¹ s.c.) were compared between intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Results  Quinpirole and SKF-81297 reduced T ₅₀ in both groups; d-amphetamine reduced T ₅₀ only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected. Conclusions   d-Amphetamine’s effect on performance in the free-operant psychophysical procedure requires an intact 5-HTergic system. 5-HT, possibly acting at 5-HT_2A receptors, may play a ‘permissive’ role in dopamine release.

Gestational exposure to methylmercury retards choice in transition in aging rats

Developmental exposure to methylmercury has behavioral effects that extend into adulthood and aging. In this study, methylmercury's prolonged effects on the acquisition of choice and sensitivity to changes in reinforcement rates were studied. Pregnant female rats were exposed to drinking water containing 0, 0.5, or 6.4 ppm Hg as methylmercury, resulting in about 40 and 500 microg/kg/day of mercury intake. Maternal exposure began at least 4 weeks before mating, and continued to postnatal day 16. Then all mercury exposure ended. The behavior of 1.7- and 2.3-year-old offspring was maintained under various concurrent schedules of reinforcement. Thus, one reinforcement schedule maintained left-lever responding and a separate one maintained right-lever responding. The animal could switch ("changeover") between the two levers at any time. For the first 30 min of a 3-h session, the left and right levers each produced reinforcement at the same rate and left:right response ratios were about 1:1. After 30 min, either the left lever became richer than the right; the right lever became richer than the left, or there was no change. Terminal reinforcer ratios (left:right) used were 9:1, 4:1, 3:1, 1:1, 1:3, 1:4, and 1:9. Response rates on the two levers were tracked continuously through a session. This novel procedure for examining choice, and its acquisition, in a single session, was validated through many comparisons with the extant literature. Both response rates and changeover rates were influenced by the reinforcer ratios for the 1.7-year-olds. Changeover rates were not influenced by reinforcement rate for their 2.3-year-old littermates. For the 1.7-year-olds, there was no effect of methylmercury on changeover or response rates and there was no interaction between exposure and reinforcer ratio. In controls and most methylmercury-exposed rats, response ratios (the measure of choice) approximately matched reinforcer ratios by the end of the single session. This is commonly interpreted as reflecting sensitivity to reinforcement rates. Methylmercury exposure did not affect this measure systematically. The single-session transition from baseline (response ratios about 1:1) to terminal performance was retarded in many methylmercury-exposed rats relative to controls, especially in the older rats. The 2.3-year-old control rats required about 20 to 25 reinforcers to complete one half of the 9:1 and 4:1 transitions, respectively, and exposed rats required about twice as many. Thus, prenatal methylmercury exposure specifically retarded the acquisition of choice in older rats. Methylmercury did not interfere with the final expression of choice. Moreover, two rate measures, lever-press rates and changeover rates, were not systematically affected by methylmercury. The acquisition of choice appears to be very sensitive to subtle consequences of developmental methylmercury exposure. The specific tactics greatly reduced the time required to study behavior in transition from a month in previous reports to a single session here.     

Effect of destruction of the 5-hydroxytryptaminergic pathways on the acquisition of temporal discrimination and memory for duration in a delayed conditional discrimination task

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on the acquistion of a temporal discrimination and on memory for duration, using a delayed conditional discrimination task. In phase I, rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and shamlesioned 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 intiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a correct response, reinforcer delivery. Both groups gradually acquired accurate discrimination, achieving >90% correct choices within 20–30 sessions; the lesioned group acquired accurate performance significantly faster than the control group. In phase II, delays were interposed between stimulus offset and lever presentation in 50% of the trials (2, 4, 8, 16 and 32 s; 10% of trials in each case). Accuracy declined as a function of post-stimulus delay in both groups, and there was no significant difference between the performances of the two groups. Both groups showed an increasing tendency to respond on lever A following longer post-stimulus delays (choose-short effect); this effect was somewhat enhanced 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 altered.     

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.