Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on timing behaviour investigated with an interval bisection task

Seventeen rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei: 12 rats received sham injections. The rats were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus and to press lever B following an 8-s presentation of the same stimulus. Both groups learnt the task rapidly and maintained >90% accuracy throughout the experiment. When stable performance had been attained, probe trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. The bisection point (duration corresponding to 50% choice of lever B) was significantly shorter in the lesioned group than in the control group. There was no significant difference between the slopes of the psychophysical functions or the Weber fractions derived for the two groups. The levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results confirm the involvement of 5HTergic function in timing behaviour, but suggest that destruction of these pathways does not disrupt the capacity for temporal discrimination.     

Facilitated acquisition of a temporal discrimination following destruction of the ascending 5-hydroxytryptaminergic pathways

This experiment examined the effect of destroying the 5-hydroxytryptaminergic (5HTergic) pathways on the acquisition and performance of discrimination between two brief time intervals. 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 200-ms presentation of a light stimulus and lever B following an 800-ms presentation of the same stimulus. Both groups gradually acquired accurate performance, attaining 80%–85% accuracy by the end of 40 sessions. The lesioned group learnt the task significantly faster than the control group. When stable performance had been attained, probe trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. The bisection point (duration corresponding to 50% choice of lever B) did not differ significantly between the two groups; however, the Weber fraction was significantly smaller in the lesioned group than in the control group. The levels of 5HT and 5-hydroxy-indole-acetic acid were markedly reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. The results indicate that destruction of the 5HTergic pathways facilitates acquisition of a temporal discrimination. The lack of an effect of the lesion on the bisection point contrasts with our previous finding using longer stimulus durations; it is suggested that different behavioural processes may underlie millisecond-range and second-range temporal discrimination, and that these may be differently affected by 5HT depletion.     

Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on timing behaviour investigated with the fixed-interval peak procedure

Twelve rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 12 rats received sham lesions. The rats were then trained for 60 sessions under a discrete-trials fixed-interval schedule (peak procedure). In half the trials, a reinforcer became available 40 s after trial onset, and the trial was terminated upon reinforcer delivery; the remaining trials were 120 s in duration, and reinforcement did not occur in these trials. Performance during the 120-s trials was characterized by increasing response rate during the first 40 s of the trial, declining response rate between 40 s and 80 s, and a secondary increase in response rate during the final 40 s of the trial. The lesioned group showed a broader spread of the response rate function than the control group (time between attainment of 70% of the peak response rate and subsequent decline of response rate below this level); however, the peak response rate and the time from trial onset until attainment of the peak response rate did not differ significantly between the groups; the spread/peak-time ratio was significantly greater in the lesioned group than in the control group. The levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results confirm the involvement of 5HTergic function in timing behaviour.     

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     

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 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.     

Effects of desipramine and fluvoxamine on timing behaviour investigated with the fixed-interval peak procedure and the interval bisection task

Acute treatment with antidepressant drugs is known to increase the mean interresponse time (IRT) in the IRT >72-s schedule of reinforcement. In order to examine the possibility that this effect may reflect an action of the antidepressants on timing processes, we tested the effects of two antidepressants, desipramine and fluvoxamine, on behaviour maintained under two other timing schedules in rats. In the fixed-interval peak procedure (fixed-interval 30-s), acute treatment with desipramine (8 mg kg^–1) reduced response rate, whereas acute treatment with fluvoxamine (8 mg kg^–1) increased it. Neither drug significantly altered the time to attainment of peak response rate or the Weber fraction. In the interval bisection task (standard durations 2 s and 8 s), the bisection point was not significantly altered by acute treatment with either drug. Chronic treatment with desipramine (8 mg kg^–1 b.d.) had no effect on any of the indices of timing under either schedule. Chronic treatment with fluvoxamine (8 mg kg^–1 b.d.) reduced the time to attainment of peak response rate but had no effect on the Weber fraction under the fixed-interval peak procedure, and did not alter the bisection point or Weber fraction under the interval bisection procedure. The failure of desipramine and fluvoxamine to increase the time to peak response rate or the bisection point at doses that significantly altered operant response rate suggests that the effect of these drugs on IRT schedule performance is unlikely to reflect an interaction with timing processes.     

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 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 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.     

Impaired acquisition of temporal differentiation performance following lesions of the ascending 5-hydroxytryptaminergic pathways

Nineteen rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 16 rats received sham injections. The rats underwent 50 daily training sessions under an interresponse-time-greater-than-15-seconds (IRT >15 s) schedule of sucrose reinforcement. The lesioned group showed impaired acquisition of temporal differentiation, in that their response rates remained significantly higher and their obtained reinforcement frequencies significantly lower than those of the control (sham-lesioned) group. Comparison of the IRT frequency distributions obtained from the two groups during the last 5 days of training showed that the lesioned group produced a significantly higher proportion of very short IRTs (<3 s) than the control group; when these short IRTs were disregarded, the lesioned group displayed a significantly lower mean IRT and a significantly higher coefficient of variation than the control group. The levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results suggest that destruction of the ascending 5HTergic pathways may reduce animals' capacity to inhibit positively reinforced operant behaviour, and may impair temporal discrimination.     

Retarded acquisition of a temporal discrimination following destruction of noradrenergic neurones by systemic treatment with DSP4

This experiment examined the effect of destroying central noradrenergic neurones, using the selective neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) on the acquisition and performance of discrimination between two time intervals. Rats that had received systemic treatment with DSP4 and vehicle-treated 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. Both groups acquired the discrimination (>90% correct choices) within 15 sessions; however, the DSP4-treated group showed significantly slower acquisition than the control group. When stable performance had been attained, probe trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. Neither the bisection point (duration corresponding to 50% choice of lever B) nor the Weber fraction differed significantly between the DSP4-treated and control groups. The levels of noradrenaline were markedly reduced in the neocortex and hippocampus of the DSP4-treated group, but the levels of dopamine and 5-hydroxytryptamine were not altered. The results indicate that noradrenaline depletion induced by DSP4 retarded the acquisition of temporal discrimination, but did not impair steady-state discriminative precision.     

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 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     

5,7-Dihydroxytryptamine lesions of the ascending 5-hydroxytryptamine pathways: habituation, motor activity and agonistic behavior

Rats were injected stereotactically in mesencephalon with 5,7-dihydroxytryptamine (5,7-DHT) in the medial 5-hydroxytryptamine (5-HT) pathway (n = 8) and in the medial plus the lateral 5-HT pathways (n = 7) or injected with vehicle (n = 8), or sham-operated (n = 8). The 5,7-DHT lesions reduced the in vitro 3H-5-HT uptake in the hypothalamus and the cortex cerebri to 27-51% of control values, 3H-noradrenaline uptake was not significantly changed. 5,7-DHT lesions of the medial, and of the medial plus the lateral, 5-HT induced mouse killing behavior and increased number of boxing positions in the shock elicited fighting test. Both lesions also reduced the rate of habituation to touch, but only the lesion of the medial plus the lateral 5-HT pathway significantly reduced the rate of habituation to acoustic stimulation. Activity in the home cage was not significantly changed by the lesions. It was concluded that selective chemical lesions of the ascending 5-HT pathways result in prolonged habituation of the orienting response and increase in particular components of agonistic behavior. The increase in locomotor activity observed after electrolytic lesions of nucleus raphe medianus seems not to be due only to lesion of the 5-HT neurons ascending from this nucleus.     

DSP4 and Herrnstein's equation: further evidence for a role of noradrenaline in the maintenance of operant behaviour by positive reinforcement

The effect of the selective noradrenaline neurotoxin DSP4 on steady-state operant behaviour was examined using a quantitative behavioural paradigm based on Herrnstein's (1970) equation, which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Eleven rats received injections of DSP4 (two doses of 50 mg/kg, intraperitoneally), and 12 rats received injections of the vehicle alone. The rats were trained to steady state in a series of six variable-interval schedules of sucrose reinforcement, affording scheduled reinforcement frequencies of 4–360 reinforcers per hour. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value ofK _H (the parameter expressing the reinforcement frequency needed to maintain the half-maximal response rate) was higher in the DSP4-treated rats than in the control rats; the value ofR _max (the parameter expressing the maximum response rate) did not differ significantly between the two groups. At the end of the behavioural experiment the rats were sacrificed for determination of the concentrations of catecholamines in the brain by high-performance liquid chromatography. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum of the DSP4-treated rats were less than 20% of those of the control rats. The results provide further evidence that central noradrenergic neurones are involved in the maintenance of operant behaviour by positive reinforcement.     

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 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     

The effects of selected antidepressant drugs on timing behaviour in rats

It has been suggested that the increased reinforcement rate on a differential-reinforcement-of-low-rate of responding (DRL) schedule observed following acute antidepressant administration in the rat is due to an improvement in timing accuracy. The aim of the present work was to evaluate the effects of antidepressants in another schedule that requires accurate estimation of time intervals, the peak procedure. Three antidepressant drugs were tested, the tricyclic antidepressant imipramine (1.0–10.0 mg/kg, IP) and the 5-HT reuptake inhibitors, zimelidine (10.0–40.0mg/kg, IP) and clomipramine (1.0–10.0 mg/kg, IP). For reference, the full benzodiazepine receptor agonist, diazepam (1.0–5.0 mg/kg, IP) and the psychomotor stimulant, d-amphetamine (0.5–1.5 mg/kg, SC) were also tested. All doses of d-amphetamine tested significantly increased lever-pressing rates, whereas all the other compounds induced significant decreases in lever-pressing rates. Overall, the time at which the maximal lever-pressing rate occurred was not altered by any of the compounds, suggesting that timing accuracy was not significantly affected by any of the compounds administered. The only exception was zimelidine (40.0 mg/kg), which reduced the time at which the maximal lever-pressing rate occurred, although lever-pressing rates were also significantly reduced at this dose. These data suggest that previously reported antidepressant-induced improvement in performance on the DRL schedule may not have been due to improved timing accuracy per se but may have been due to a decrease in lever-pressing rates. Received: 5 December 1996/Final version: 17 June 1997     

Does the effect of central 5-hydroxytryptamine depletion on timing depend on motivational change?

In a previous experiment we found that destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways by microinjection of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei resulted in impaired acquisition of temporal differentiation under an interresponse-time-greater-than-15-s (IRT>15 s) schedule of sucrose reinforcement. This paper reports three experiments, the results of which bear on the interpretation of that finding. In Experiment 1, 32 rats were trained for 120 sessions under the IRT>15 s schedule; then 16 received lesions of the 5HTergic pathways and 16 received sham lesions. Comparisons of the IRT frequency distributions of the two groups showed that the lesion produced a significant reduction of the mean IRT and an increase in the dispersion of IRTs, as expressed by the coefficient of variation. Obtained reinforcement rates were significantly reduced in the lesioned group, but response rates were not significantly altered. Levels of 5HT and 5-hydroxyindoleacetic acid were markedly reduced in all forebrain areas examined, without significant change in noradrenaline and dopamine levels. The results indicate that destruction of the 5HTergic pathways disrupts performance as well as acquisition of temporal differentiation. Experiments 2 and 3 examined whether changes in deprivation level and reinforcer magnitude, which are known to affect reinforcer value, would influence temporal differentiation in a similar fashion to destruction of the 5HTergic pathways. In experiment 2, 20 rats were trained under the IRT>15 s schedule while maintained at 80% or 90% of free-feeding body weight; the more severe deprivation condition was associated with alonger mean IRT and alower coefficient of variation. In experiment 3, 16 rats were trained under the IRT>15 s schedule using 100 µl or 20 µl of a 0.6 M sucrose solution as the reinforcer; indices of temporal differentiation did not differ between the two conditions. These results indicate that the deleterious effect of destruction of the 5HTergic pathways upon timing behaviour is unlikely to be secondary to the motivation enhancing effect of the lesion.