5-hydroxytryptaminergic Pathways Research Articles

Effect of Ondansetron on Postoperative Shivering After Craniotomy

Postoperative shivering (POS) is an early complication after craniotomy. Preventive pharmacologic drugs are the mainstay of treatment. Meperidine is the drug of choice but with increased risk of apnea, nausea, and increased intracranial pressure. Some reports have suggested that ondansetron and meperidine have similar anti-shivering effects. To assess the preventive effect of ondansetron on POS after craniotomy. In a randomized, double-blind, placebo-controlled trial, 80 patients with American Society of Anesthesiologists status I to II between 20 and 60 years of age scheduled for elective craniotomy were enrolled in the study. Patients received either intravenous ondansetron 4 mg (n = 40) or saline (n = 40) 10 minutes before the end of surgery. POS was observed in 3 patients (7.5%) in the ondansetron group, significantly lower than in the control group (6 patients [15%]; P =0.048). Ondansetron decreased the relative risk of occurrence of POS after craniotomy from 4.42 (95% confidence interval [CI], 2.3-8.5; P = 0.0021) in the control group to 1.05 (95% CI, 0.76-2.20; P = 0.074). In the ondansetron group, the mean (± standard deviation) core temperature in the preoperative phase (36.6°C ± 0.66°C) was significantly higher than in the postoperative phase (34.2°C ± 0.56°C) (P = 0.001). In addition, the mean (± standard deviation) peripheral temperature in the preoperative phase (36.5°C ± 0.72°C) was significantly higher than in the postoperative phase (34.4°C ± 0.51°C) (P = 0.001). Ondansetron can effectively decrease POS after craniotomy. This effect is not mediated through maintenance of the core or peripheral temperature. Ondansetron probably acts by a central inhibitory mechanism on POS through 5-hydroxytryptaminergic pathways, not by changing thermoregulatory set points.

Synthesis of thiazolotriazine derivatives and their antinociceptive effects in mice.

Ans raci A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro -thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity. The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg(-1). Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg(-1), also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg(-1). Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of micro-receptors in the antinociceptive effects of this drug. In addition, a nonopioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives. These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.

Attenuation of the effects of d-amphetamine on interval timing behavior by central 5-hydroxytryptamine depletion

RationaleInterval 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-HT2A receptor antagonists. It is not known whether d-amphetamine’s effect requires an intact 5-hydroxytryptamine (5-HT) pathway.ObjectiveThe 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 methodsRats 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 (T50, 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.ResultsQuinpirole and SKF-81297 reduced T50 in both groups; d-amphetamine reduced T50 only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected.Conclusionsd-Amphetamine’s effect on performance in the free-operant psychophysical procedure requires an intact 5-HTergic system. 5-HT, possibly acting at 5-HT2A receptors, may play a ‘permissive’ role in dopamine release.

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

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. 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. 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). 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. 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.

Synthesis of New Pyridazinones Substituted by 4-Arylpiperazin-1-yl-carbonylalkyl Moieties and their Analgesic Properties in Mice

A new series of 4,6-diaryl pyridazin-3-ones substituted on the nitrogen atom in the 2-position have been prepared and evaluated for their analgesic activity in the phenylbenzo-quinone-induced abdominal constriction test. Most of the eighteen compounds displayed significant antinociceptive effects with ED50 ranging from 22-2 to 76-7 mg kg−1, intraperitoneally. Pyridazinones 4f and 5f were among the most interesting derivatives with marked analgesic properties associated to weak neurosedative activities (ED50 = 83-3 and 247-2 mg kg−1, i.p., respectively). Further investigations provided support for the hypothesis that the antinociceptive action of 4f and 5f probably resulted from interactions with opioidergic, 5-hydroxytryptaminergic and noradrenergic pathways.

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

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. 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. 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 (dA) followed by delivery of one pellet; selection of lever B resulted in a longer variable delay (dB) followed by delivery of two pellets; dB was adjusted in accordance with the subject's choices. The value of dA was varied (0.5-8.0 s) in successive phases of the experiment, and the indifference value of dB was determined in each case. In both groups, the indifference value of dB was linearly related to the value of dA, 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. 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.

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

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. 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. 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. 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. 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.

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.

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 dA s, whereas a response on B resulted in the delivery of two pellets after 84-t s. The value of dA 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" (T50: 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 dA, the values of T50 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.

5-hydroxytryptamine and impulse control: prospects for a behavioural analysis.

Impulsiveness is a significant clinical problem associated with a variety of psychiatric and neuropsychiatric disorders. Clinical and experimental studies have provided evidence that individuals displaying impulsive behaviour tend to show signs of deficient functioning of the ascending 5-hydroxytryptaminergic (5-HTergic) pathways of the brain. A persistent problem in investigations of the biological basis of impulsive behaviour has been the lack of a satisfactory definition of 'impulsiveness', as distinct from other behavioural features, such as aggression, which are often apparent in 'impulsive' individuals. Research in the experimental analysis of behaviour suggests that two important characteristics of 'impulsiveness' are (i) deficient tolerance of delay of gratification and (ii) inability to inhibit or delay voluntary behaviour; both of these characteristics are amenable to study in laboratory animals. We describe some delayed reinforcement and delayed response paradigms which purport to capture these behavioural characteristics, and review recent evidence that manipulation of 5-HTergic function alters behaviour in these paradigms. It is argued that the two characteristics of 'impulsiveness' are themselves the product of disturbance of more fundamental behavioural processes; the nature of these processes is considered.

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 dA s, whereas a response on B resulted in the delivery of two pellets after 60-t s. The value of dA 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 (T75: the time within the trial at which relative response rate on B attained a value of 75%) was systematically related to the value of dA, 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 dA. 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.

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.

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

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

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 acquisition 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 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. 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.

The role of the ascending 5-hydroxytryptaminergic pathways in timing behaviour: further observations with the interval bisection task.

This experiment examined the effect of destroying the 5-hydroxytryptaminergic (5HTergic) pathways on rats' ability to discriminate between two durations. Rats received injections of 5,7-dihydroxytryptamine into the median and dorsal raphe nuclei or sham lesions. They were trained to press lever A following a 2-s presentation of a light and lever B following an 8-s presentation of the light. For some rats, the levers were inserted into the chamber immediately after stimulus presentation ("no-poke-requirement"); for others, the levers were not inserted until a flap covering the food tray positioned midway between the levers had been depressed ("poke-requirement"). When stable performance was attained, "probe" trials were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to log stimulus duration. Under the "no-poke-requirement" condition, the bisection point (duration yielding 50% choice of lever B) was shorter in the lesioned rats than in the control rats. Under the "poke-requirement" condition, this effect of the lesion was attenuated. There was no effect of the lesion on the Weber fraction under either condition. 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. It is proposed that rats may attain accurate timing under the interval bisection task by moving from one lever to the other during stimulus presentation; this movement may be facilitated by destruction of the 5HTergic pathways.(ABSTRACT TRUNCATED AT 250 WORDS)

Central 5-hydroxytryptaminergic function in irritable bowel syndrome.

Psychological factors may contribute to the aetiology and exacerbation of symptoms in irritable bowel syndrome (IBS), suggesting that the central nervous system may be an important site of dysfunction in IBS. Hormonal responses after a serotonergic challenge assess the functional integrity of central 5-hydroxytryptaminergic pathways and are diminished in depression. The aim of this study was to determine whether hormonal responses in IBS after a serotonergic challenge would be decreased, as in depression, or exaggerated, as have been reported in another functional gastrointestinal disorder, nonulcer dyspepsia. Fourteen IBS patients, 16 healthy volunteers, and 9 patients with inflammatory bowel disease were given 30 mg d-fenfluramine, a selective stimulus to central 5-hydroxytryptaminergic pathways. Plasma prolactin and cortisol concentrations during the following 5 h increased to a similar extent in all three subject groups, despite increased levels of anxiety and depression (as scored on the Hospital Anxiety and Depression Scale and Beck Depression Inventory) in the IBS and inflammatory bowel disease patients compared with the healthy controls. Base-line cortisol concentration correlated with the magnitude of affective disorder. In contrast to the alterations of central 5-hydroxytryptamine receptor sensitivity seen in depression and non-ulcer dyspepsia, central 5-hydroxytryptaminergic pathways function normally in IBS.

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.

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 a longer mean IRT and a lower coefficient of variation.(ABSTRACT TRUNCATED AT 250 WORDS)

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.