Short-term and long-term effects of diazepam on the memory for discrimination and generalization of scopolamine.

Benzodiazepines are among the most widely prescribed and misused psychopharmaceutical drugs. Although they are well-tolerated, they are also capable of producing amnestic effects similar to those observed after pharmacological or organic cholinergic dysfunction. To date, the effect of benzodiazepine diazepam on the memory for discrimination of anticholinergic drugs has not been reported. The aim of the present study was to analyze the immediate and long-term effects of diazepam on a drug discrimination task with scopolamine. Male Wistar rats were trained to discriminate between scopolamine and saline administration using a two-lever discrimination task. Once discrimination was acquired, the subjects were divided into three independent groups, (1) control, (2) diazepam, and (3) diazepam chronic administration (10 days). Subsequently, generalization curves for scopolamine were obtained. Additionally, the diazepam and control groups were revaluated after 90 days without having been given any other treatment. The results showed that diazepam produced a significant reduction in the generalization gradient for scopolamine, indicating an impairment of discrimination. The negative effect of diazepam persisted even 90 days after drug had been administered. Meanwhile, the previous administration of diazepam for 10 days totally abated the generalization curve and the general performance of the subjects. The results suggest that diazepam affects memory for the stimulus discrimination of anticholinergic drugs and does so persistently, which could be an important consideration during the treatment of amnesic patients with benzodiazepines.

Participation of the dorsal hippocampus in stimulus discrimination with scopolamine.

Stimulus discrimination is the capacity of an organism to differentiate between stimuli and emit associated responses. The administration of the muscarinic antagonist scopolamine can be used as a stimulus by mammals in a discrimination task. The present study analyzes the contribution of the hippocampus in scopolamine discrimination and generalization. Male Wistar rats, weighing 250-300 g at the beginning of the experiment, were trained to discriminate between scopolamine (1.0 mg/kg, i.p.) and saline administration using a two-lever operant task; rats had to respond differentially to each lever depending on the preceding drug or saline administration. Once stimulus control was attained, rats were tested with different scopolamine doses (0.0, 0.056, 0.091, 0.16, 0.31 and 1.0 mg/kg, i.p.) in order to obtain generalization curves. After generalization the rats were randomly assigned to hippocampal CA1 lesion or control groups. Hippocampus impairment produced a transient decrease in the capacity to discriminate between scopolamine and saline conditions; nonetheless, scopolamine correct responses were rapidly recovered after a few sessions and even maintained after 90 days. Correct responses for saline condition were never recovered. The generalization curve obtained after hippocampus lesion showed a response gradient severely flattened. Results suggest that the hippocampus participates as a neural system supporting the sensitivity to detect discrete changes in stimulus properties and relational memory, more than on the capacity to recall for simple associative responses.

Effects of orbital prefrontal cortex dopamine depletion on inter-temporal choice: a quantitative analysis.

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 and delay) has been proposed as a model of "impulsive choice" in animals. We recently found that destruction of the OPFC disrupted inter-temporal choice in rats. It is not known whether the dopaminergic projection to the OPFC contributes to the regulation of inter-temporal choice. OBJECTIVE: A quantitative method was used to compare inter-temporal choice in rats whose OPFC had been depleted of dopamine with that of sham-lesioned control rats. METHODS: Under halothane anaesthesia, rats received injections of 6-hydroxydopamine into the OPFC (2 microg microl(-1), 0.5 microl, two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 microl of the sucrose solution after a delay dA; a press on B resulted in delivery of 100 microl of the same solution after a delay dB. dB was increased progressively across successive blocks of six trials in each session, while dA was manipulated systematically across phases of the experiment. The indifference delay, dB(50) (value of dB corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of dB(50) versus dA were derived, and the parameters of the function compared between the groups. Concentrations of monoamines in the OPFC were determined by high-performance liquid chromatography at the end of the experiment. RESULTS: In both groups, dB(50) increased linearly with dA (r2>0.9 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. When delays of 4 or 8 s were imposed on the smaller reinforcer, the lesioned rats showed greater tolerance of delay to the larger reinforcer (i.e. they exhibited longer values of dB(50)) than the sham-lesioned rats. Dopamine, noradrenaline and 5-hydroxytryptamine levels in the OPFC of the lesioned group were 20, 75 and 98% of those of the sham-lesioned group. CONCLUSIONS: The results indicate that dopaminergic afferents to the OPFC contribute to the regulation of inter-temporal choice behaviour due to their role in determining organisms' sensitivity both to reinforcer size and to delay of reinforcement.

Role of the orbital prefrontal cortex in choice between delayed and uncertain reinforcers: a quantitative analysis.

'Inter-temporal choice' refers to choice between two or more outcomes that differ with respect to their sizes, delays, and/or probabilities of occurrence. According to the multiplicative hyperbolic model of inter-temporal choice, the value of a reinforcer increases as a hyperbolic function of its size, and decreases as a hyperbolic function of its delay and the odds against its occurrence. These functions, each of which contains a single discounting parameter, are assumed to combine multiplicatively to determine the overall value of the reinforcer. The model gives rise to a quantitative methodology for analysing inter-temporal choice, based on a family of linear null equations which describe performance under conditions of indifference, when the values of the reinforcers are assumed to be equal. This approach was used to examine the effect of lesions of the orbital prefrontal cortex (OPFC) on inter-temporal choice in rats. Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC or sham lesions. 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 delivery of a pellet after a delay d(A) with a probability P=0.5; a press on B resulted in delivery of a pellet with a probability P=1 after a delay d(B). d(B) was increased progressively across successive blocks of six trials in each session, while d(A) was manipulated systematically across phases of the experiment. The indifference delays, d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d(B(50)) versus d(A) were derived, and the parameters of the function compared between the groups. In both groups, d(B(50)) increased linearly with d(A). The slope of the linear function was significantly steeper in the lesioned group than in the sham-lesioned group, whereas the intercept did not differ significantly between the groups. Analysis based on the relevant null equation indicated that the lesion of the OPFC increased the rate of both delay and odds discounting. Possible implications of the results for interpreting the effects of OPFC lesions on inter-temporal choice behaviour in man are discussed.

Further evidence that the discriminative stimulus properties of indorenate are mediated by 5-HT 1A/1B/2C receptors.

Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors. Unlike other anxiolytics such as 5-HT receptor agonists, INDO may not share tolerance or dependency with the benzodiazepine anxiolytics. It has been reported that the discriminative stimulus properties of 5-HT(1A/1B/2C) agonists, but not those of 5-HT(3/4) agonists, generalize to INDO. Therefore, the aim of the present study was to obtain further evidence on the differential involvement of 5-HT(1A/1B/2C) receptors in the discriminative stimulus properties of INDO by evaluating its interactions with antagonists of the 5-HT(1A), 5-HT(1B), 5-HT(2C), and 5-HT(3/4) receptor subtypes. Rats were trained to discriminate INDO from saline in a conditioned taste aversion paradigm. For Group D(+)S(-), administration of INDO signalled that saccharin flavour was followed by LiCl, while injection of vehicle signalled safe consumption of saccharin solution. Group D(-)S(+) had the contingencies reversed. After this training, rats had generalization tests where INDO administration was preceded by different doses of the following antagonists: WAY100635 (5-HT(1A)), NAN190 (5-HT(1A)), methiothepin (5-HT(1A/1B/2C)), GR127935 (5-HT(1B/1D)), ketanserin (5-HT(2A/2C)), ritanserin (5-HT(2C/2A)), mesulergine (5-HT(2C/2A)), metergoline (5-HT(2C/2A)), SB206553 (5-HT(2B/2C)), and tropisetron (5-HT(3/4)). In Group D(+)S(-), the order of potency to block the discriminative stimulus properties of INDO was WAY100635>ketanserin>ritanserin>GR127935>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190, while in Group D(-)S(+), the order was WAY100635>GR127935>ketanserin>ritanserin>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190. Tropisetron did not produce any alteration of the discriminative control by INDO. These results suggest that the discriminative signal of INDO is mediated by 5-HT(1A/2C/1B) receptors and that blockade of any of its components produces a degradation of its discriminative effects.

Antagonism by WAY-100635 of the effects of 8-OH-DPAT on performance on a free-operant timing schedule in intact and 5-HT-depleted rats.

In this experiment we examined the effect of a serotonin receptor (5-HT1A) agonist and antagonist WAY-100635 (N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide) on temporal differentiation, in intact rats and rats whose serotonergic (5-HTergic) pathways had been destroyed by 5,7-dihydroxytryptamine (5,7-DHT). Thirteen rats received 5,7-DHT-induced lesions of the median and dorsal raphe nuclei; 14 rats received sham lesions. They were trained to press two levers (A and B) in 50-s trials, in which reinforcement was contingent upon responding on A in the first half, and B in the second half, of the trial. Logistic psychophysical curves were fitted to the relative response rate data (percent responding on B, %B), for derivation of timing indices [T50 (time corresponding to %B=50%), slope, Weber fraction] following WAY-100635, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], combinations of WAY-100635+8-OH-DPAT, and vehicle alone. WAY-100635 (30, 100 and 300 microg/kg, s.c.) did not affect the timing indices. 8-OH-DPAT (100, 200 microg/kg, s.c.) reduced T50 without affecting the Weber fraction. WAY-100635 (300 microg/kg) abolished the effect of 8-OH-DPAT on T50 in both the lesioned and sham-lesioned groups. 5-HT levels in the neocortex, hippocampus, amygdala, nucleus accumbens and hypothalamus of the lesioned group were <20% of those in the sham-lesioned group; catecholamine levels were unaffected. The results confirm that 8-OH-DPAT disrupts temporal differentiation in a free-operant psychophysical schedule, reducing T50, and indicate that this effect of 8-OH-DPAT is mediated by postsynaptic 5-HT1A receptors.

Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: a quantitative analysis.

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 and delay) has been proposed as a model of "impulsive choice" in animals. OBJECTIVE: A quantitative method was used to analyse inter-temporal choice in rats with lesions of the OPFC and sham-lesioned control rats. METHODS: Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 micro l; two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 micro l of the sucrose solution after a delay d (A); a press on B resulted in delivery of 100 micro l of the same solution after a delay d (B). d (B) was increased progressively across successive blocks of six trials in each session, while d (A) was manipulated systematically across phases of the experiment. The indifference delay, d (B(50)) (value of d (B) corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d (B(50)) versus d (A) were derived, and the parameters of the function compared between the groups. The locations of the lesions were verified histologically at the end of the experiment. RESULTS: In both groups, d (B(50)) increased linearly with d (A) ( r(2)>0.98 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. The brains of the lesioned rats showed extensive atrophy/gliosis of the OPFC, with sparing of the dorsolateral prefrontal cortex. CONCLUSIONS: The results indicate that lesions of the OPFC can alter inter-temporal choice, either promoting or suppressing "impulsive choice", depending upon the relative sizes and delays of the two choice alternatives. Theoretical analysis based on a quantitative model of inter-temporal choice indicates that the pattern of effect of the OPFC lesion is likely to reflect two actions: (i) an increase in the rate of time discounting; (ii) an increase in sensitivity to the ratio of the sizes of two reinforcers.

Full substitution of the discriminative cue of a 5-HT(1A/1B/2C) agonist with the combined administration of a 5-HT(1B/2C) and a 5-HT(1A) agonist.

The present study examined whether animals attend to the individual components of the cue produced by a drug that stimulates different 5-hydroxytryptamine (5-HT) receptor populations, using a drug discrimination task based on the conditioned taste aversion (CTA) procedure. The training drug was indorenate (5-methoxytryptamine beta-methylcarboxylate) (INDO) that has been described as a 5-HT(1A/2C/1B) agonist able to exert discriminative control in both operant and CTA procedures. The principal objective was to examine generalization with the combined administration of agonists for the different receptor sites that may mimic the mechanism of action of the training drug. Male Wistar rats, deprived of water, were trained to discriminate INDO from saline; during the drug trials, the administration of INDO preceded saccharin-LiCl pairings, while, during the saline trials, the administration of saline preceded the saccharin-saline pairings. In generalization tests, INDO, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT(1A) agonist), 1-(3-trifluoromethylphenyl)piperazine (TFMPP, a 5-HT(1B) agonist), alpha-methyl-5-HT (a 5-HT(2C) agonist) or 2-methyl-5-HT (a 5-HT(3) agonist), were administered alone or in combination. The results showed that 8-OH-DPAT, TFMPP and alpha-methyl-5-HT produced dose-dependent generalization, up to 88% in the case of 8-OH-DPAT. The combined administration of the following pairs of drugs, 8-OH-DPAT+TFMPP or 8-OH-DPAT+ alpha-methyl-5-HT, at doses that produced only 15-55% generalization when administered alone, produced greater than 80% generalization to INDO. However, the single administration of 2-methyl-5-HT produced only saline-like responding and its combined administration with 8-OH-DPAT did not modify the generalization produced by the single administration of 8-OH-DPAT. These results suggest that animals attend to the individual components of the drug cue; in the case of INDO, which has three elements, each mediated by a different receptor subpopulation (5-HT(1A), 5-HT(1B) and 5-HT(2C) ), the separate stimulation of at least two receptor subpopulations was 'interpreted' by the subject as the presence of the training drug.

5-Hydroxytryptamine and interval timing behaviour.

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

Discriminative stimulus properties of indorenate in a conditioned taste aversion paradigm.

Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors. It possesses anxiolytic and antihypertensive actions mediated by 5-HT(1A) receptors and anorectic activity mediated by 5-HT(2C/1B) receptors. This study examined whether INDO may exert discriminative control using a conditioned taste aversion (CTA) paradigm, and whether differential participation of 5-HT receptor subtypes may be involved in its cue. Male Wistar rats trained to drink their daily water in a 30-min period were trained to discriminate INDO from saline. One group received the intraperitoneal administration of INDO (10.0 mg/kg) before saccharin-LiCl pairings; on alternate days, rats received saline before the saccharin-saline pairings (Group D(+)S(-)). The other group had the contingencies reversed (i.e., the administration of INDO preceded saccharin-saline pairings: Group D(-)S(+)). In two-bottle generalization tests (one bottle containing saccharin, the other plain water), the preference for saccharin was evaluated after different doses of INDO, [3H]-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) (5-HT(1A)), buspirone (5-HT(1A)), RU24969 (5-HT(1A/1B)), TFMPP (5-HT(1B/2C)), MK212 (5-HT(2C)), alpha-Me-5-HT (5-HT(2C/2A)), 2-Me-5-HT (5-HT(3)) and cisapride (5-HT(4)). The results showed that INDO, RU24969, TFMPP, alpha-Me-5-HT and MK 212 produced a dose-dependent generalization; 8-OH-DPAT and buspirone produced only partial generalization, while 2-Me-5-HT and cisapride did not produce generalization. The results indicate that INDO administration may exert discriminative control over saccharin preference mediated mainly by 5-HT(1B/2C) receptors, but with an important contribution of 5-HT(1A) receptors.

Discriminative stimulus properties of indorenate, a 5-HT1A, 5-HT1B and 5-HT2C agonist: a study in rats.

Indorenate (INDO), initially described as an antihypertensive agent, also has some effects on behaviour, with anxiolytic and anorectic actions being reported. The aim of the present experiment was to examine the activity of INDO at the behavioural level at various serotonin (5-hydroxytryptamine, 5-HT) receptor sites by comparing its stimulus properties with those of other 5-HT receptor agonists and by examining its interactions with some 5-HT antagonists. Rats were trained to discriminate between 10.0 mg/kg INDO (administered intraperitoneally (90 min before the start of the session) from saline. A Fixed Ratio 10 (FR10) schedule of reinforcement was in effect in each drug condition. During generalization test sessions, the discrimination index (DI, responses to drug lever/responses to drug + saline lever) was calculated from the responses emitted before the first reinforcer of the session. DI was a function of the dose of INDO employed. Generalization to the discriminative stimulus properties of INDO was observed with the 5-HT1A receptor agonist 8-OH-DPAT (1.0 mg/kg produced 90% generalization) and the 5-HT(1B/2C) receptor agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP) (3.0 mg/kg produced up to 75% generalization). Yohimbine (5.6 mg/kg), buspirone (1.0 mg/kg), 6-chloro-2-(1-piperaziny)pyrazine (1.0 mg/kg) and m-chlorophenylpiperazine (mCPP) (1.0 mg/kg) induced a DI of 70%, 50% and 48% and 55%, respectively. In generalization tests, ritanserin (0.01-1.0 mg/kg) induced saline-like responding. NAN-190 (3.0 mg/kg), a 5-HT1A receptor antagonist, was able to reduce the DI of INDO to 50%. Although the 5-HT(2C/2A) receptor antagonists cinanserin (10.0 mg/kg) and metergoline (0.3 mg/kg) were able to reduce the stimulus properties of INDO to 60% and 30%, respectively, only ritanserin (1.0 mg/kg) reduced the stimulus properties of INDO to 25% with a clear dose-response relationship. The results suggest that INDO acts as an agonist at 5-HT1A receptor sites, but its activity at 5-HT(1B/2C) receptor sites also contributes to its discriminative function.

Discriminative stimulus properties of indorenate, a serotonin agonist.

OBJECTIVE: To determine whether indorenate, a serotonin-receptor agonist, can exert discriminative control over operant responses, to establish the temporal course of discriminative control and to compare its stimulus properties to a (5-HT)IA receptor agonist. [3H]-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT). DESIGN: Prospective animal study. ANIMALS: Ten male Wistar rats. INTERVENTIONS: Rats were trained to press either of 2 levers for sucrose solution according to a fixed ratio schedule, which was gradually increased. Rats were given injections of either indorenate or saline solution during discrimination training. Once they had achieved an 83% accuracy rate, rats underwent generalization tests after having received a different dose of indorenate, the training dose of indorenate at various intervals before the test, various doses of 8-OH-DPT, or NAN-190 administered before indorenate or 8-OH-DPAT. OUTCOME MEASURES: Distribution of responses between the 2 levers before the first reinforcer of the session, response rate for all the responses in the session, and a discrimination index that expressed the drug-appropriate responses as a proportion of the total responses. RESULTS: Indorenate administration resulted in discriminative control over operant responses, maintained at fixed ratio 10, at a dose of 10.0 mg/kg (but not 3.0 mg/kg). When the interval between the administration of indorenate and the start of the session was varied, the time course of its cue properties followed that of its described effects on 5-HT turnover. In generalization tests, the discrimination index was a function of the dose of indorenate employed; moreover, administration of 8-OH-DPAT (from 0.1 to 1.0 mg/kg) fully mimicked the stimulus properties of indorenate in a dose-dependent way. The (5-HT)IA antagonist NAN-190 prevented the stimulus generalization from indorenate to 8-OH-DPAT. Also, NAN-190 antagonized the stimulus control of indorenate when administered 45 minutes before the session, but not when administered 105 minutes before the session (i.e., 15 minutes before the administration of indorenate). CONCLUSION: (5-HT)IA receptors are of relevance to the stimulus function of indorenate. However, other receptor subtypes may also be involved. Hence, other agonists and specific antagonists should be studied before definite conclusions are drawn.

Discriminative stimulus properties of amphetamine in a conditioned taste aversion paradigm.

It has been proposed that the conditioned taste aversion paradigm may be used to achieve rapid training of subjects in drug discrimination studies. We report here that amphetamine (1.0 mg/kg) may acquire discriminative control over the preference of rats for a distinctive flavour when its administration precedes access to a saccharin solution (0.15% w/v), versus the occasions when the injection of saline precedes no toxicosis after access to the same flavour. Other doses of amphetamine (0.18-1.0 mg/kg) or apomorphine (0.1-1.0 mg/kg) produced a dose-dependent generalization to the stimulus cue of amphetamine (1.0 mg/kg), and haloperidol (0.01-0.1 mg/kg) was able to prevent the stimulus control exerted by amphetamine. No stimulus control was seen in a control group where no distinctive outcomes followed the administration of either amphetamine or saline before the subjects had access to the saccharin-flavoured solution. In the experimental group only, changes in the preference for saccharin were observed, with no changes in the total amount of water and saccharin ingested. Taken together, the present results suggest the usefulness of the conditioned taste aversion procedure to train subjects in drug discrimination.

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, whereas in the last 25 s reinforcers were available only for responses on lever B. Data were collected from 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 different between the two groups. However, the lesioned group showed a higher rate of switching between response alternatives than the sham-lesioned group. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not significantly altered. The results confirm previous findings that behaviour in timing schedules is sensitive to destruction of the central 5HTergic pathways, and suggest that these pathways may contribute to the inhibitory regulation of switching between behavioural states.

Effects of desipramine and fluvoxamine on timing behavior 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.

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)

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.