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.     

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 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     

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. Accurate timing is still possible when this movement is suppressed by the introduction of a poke requirement; however, in this case timing is not affected by 5HT depletion.     

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 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.     

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure

Rational Psychostimulant injections in rats have been shown to alter future performance in natural reward conditioning. These effects may represent a persistent impact of drugs on neurocircuits that interface cognitive and motivational processes, which may be further altered in neuropsychiatric conditions that entail increased addiction vulnerability.Objective This study investigated whether a rat model of schizophrenia with cocaine addiction vulnerability shows altered natural reward conditioning with or without prior cocaine exposure.Methods Adult rats with SHAM or neonatal ventral hippocampal lesions were given cocaine (15 mg/kg per day for 5 days) or saline injections, followed 7 days later by natural reward-conditioned learning. Over ten daily sessions, water-restricted rats were assessed for durations of head entries into a magazine during random water presentations, a conditioning stimulus phase predictive of the water reward, and an inappropriate phase when conditioning stimuli were absent and reward presentation would be delayed.Results Over repeated sessions, lesioned and SHAM rats showed similar reductions in total magazine entry durations, with similar increases in the allocations of entry times during the water presentation. However, lesioned rats, especially those exposed to cocaine, demonstrated reduced allocations of magazine entry times during the conditioning stimulus phase, and increased allocations during the inappropriate phase.Conclusions Intact natural reward motivation accompanied by deficient learning of complex contingencies to guide efficient reward approach may represent a form of impulsivity as an addiction vulnerability trait marker in an animal model of schizophrenia.     

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 lesions of the orbitofrontal cortex on sensitivity to delayed and probabilistic reinforcement

RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size, delay and/or probability) has been proposed as a model of "impulsive choice" in animals. OBJECTIVE: The effect of lesions of the OPFC on rats' inter-temporal choice behaviour was examined in two experiments: (1) rats chose between a smaller immediate reinforcer and a larger delayed reinforcer; (2) rats chose between a smaller certain reinforcer and a larger probabilistic reinforcer. METHODS: Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 microl, two injections in each hemisphere), or sham lesions (injections of vehicle). They were trained to press two levers (A and B) for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, a press on A resulted in immediate delivery of one food pellet; a press on B resulted in delivery of two pellets, either following a delay ( d) (experiment 1), or with a probability ( p) <1 (experiment 2). The values of d and p were manipulated across phases of the experiments. The locations of the lesions were verified histologically at the end of the experiment. RESULTS: In experiment 1, both groups showed declining choice of lever B as a function of d. The lesioned rats showed significantly shorter indifference delays ( D50: the value of d corresponding to 50% choice of lever B) than the sham-lesioned rats. In experiment 2, both groups showed declining choice of lever B as a function of the odds against delivery of the two-pellet reinforcer, theta ( theta =[1/ p]-1). The lesioned rats showed lower indifference odds ( theta50: the value of theta corresponding to 50% choice of lever B) than the sham-lesioned rats. In both experiments, the lesioned rats showed extensive atrophy of the OPFC, with sparing of the dorsolateral prefrontal cortex. CONCLUSIONS: The results show that lesions of the OPFC can promote preference for the smaller and more immediate, and the smaller and more certain of two reinforcers. The results are consistent with two interpretations: the lesion may have altered (i) the rates of delay and odds discounting, and/or (ii) sensitivity to the ratio of the sizes of the two reinforcers.     

Effect of 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.     

The effects of chlordiazepoxide HCl administration upon punishment and conditioned suppression in the rat

Rats were trained to lever press for sucrose on a random interval (RI) 64-s schedule. During a 55 min session there were four 3 min intrusion periods signalled by a flashing house-light. In experiment 1 there were two groups matched for baseline response rate. During the intrusion periods one group received response-independent footshock on an independent RI64 schedule; the other group received responsecontingent shock on this schedule. Shock intensity was varied for each rat to match degree of response suppression between the two groups. Chlordiazepoxide HCl (CDP) in doses 0.5–5 mg/kg alleviated response suppression equally in both groups. Experiment II followed the same procedure, except that all animals had the same shock intensity, producing greater response suppression in the response-contingent shock groups. CDP alleviated response suppression more in the response-contingent shock groups, significantly so at 5 mg/kg, nonsignificantly at 1 mg/kg. These results suggest that previous reports that CDP differentially alleviates the response suppression produced by response-contingent shock are an artefact of rate dependency.     

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     

6-Hydroxydopamine lesion of the dopamine mesocorticolimbic cell bodies increases (+)-amphetamine self-administration

The effect of 6-OHDA lesions of the dopaminergic mesocorticolimbic cell bodies on intravenous (+)-amphetamine self-administration in the rat was assessed. An acquisition paradigm was used in which the rat had to discriminate between an active and an inactive lever. Each press on the active lever delivered 7.5 g/kg (+)-amphetamine. The lesioned animals acquired this discrimination faster and hence self-administered a larger amount of drug. Thus dysfunction of dopaminergic neurons can induce an enhanced vulnerability to drugs which may be abused by humans.     

Decrease in bradycardic effect of AQ-A 39 and alinidine in guinea-pig sinoatrial node depolarized by high external K+-concentration

Summary The effects of the two specific bradycardic agents AQ-A 39 and alinidine on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated. At high external K⁺-concentrations (10.8 and 16.2 mmol/l) the bradycardic effect of the two drugs was diminished or abolished. In contrast, the negative chronotropic effect of the reference compound verapamil (Ca²⁺-antagonist) was enhanced. These results show that the bradycardic effects of AQ-A 39 and alinidine are diminished in depolarized preparations, which makes it unlikely that in intact sinus node preparations the mechanism of action is the same as that of Ca²⁺-antagonists.     

Destruction of central noradrenergic neurones with DSP4 impairs the acquisition of temporal discrimination but does not affect memory for duration in a delayed conditional discrimination task

This experiment examined the effect of destroying central noradrenergic neurones using the selective neurotoxin N-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP4) 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 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. Following stimulus offset, a response on a panel placed midway between the two levers was required 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 acquired accurate discrimination, achieving 90% correct choices within 50 sessions; the DSP4-treated group acquired accurate performance more slowly than the control group. In phase II, delays were interposed between stimulus offset and lever presentation in 50% of the trials. In the absence of a delay, discriminative accuracy was lower in the DSP4-treated group than in the control group. Accuracy declined as a function of post-stimulus delay in both groups; both groups showed a delay-dependent bias towards responding on lever A (“choose-short” bias). Neither of these effects differed significantly between the two groups. The concentrations of noradrenaline in the parietal cortex and hippocampus were reduced by 90% and 89% in the DSP4-treated group, compared to the levels in the control group, but the levels of dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid did not differ significantly between the groups. The results confirm the deleterious effect of DSP4 on the acquisition of temporal discrimination, but do not provide evidence for a role of the noradrenergic innervation of the hippocampus and neocortex in temporal working memory. Received: 8 July 1996/Final version: 2 October 1996     

Effect of ruthenium red on responses mediated by activation of capsaicin-sensitive nerves of the rat urinary bladder

Summary (1) Topical administration of Ruthenium Red (10–100 M in saline) to the serosal surface of the urinary bladder in urethane-anesthetized rats prevented the motor response of the urinary bladder to topical administration of capsaicin and protected the sensory fibers from capsaicin desensitization, but had no effect on the volume-evoked contractions (micturition reflex). At 1 mM increased bladder capacity and decreased amplitude of micturition contraction were observed. (2) At 100 M, topical Ruthenium Red prevented the blood pressure rise produced by topical administration of capsaicin onto the bladder but did not affect the blood pressure rise produced by sudden bladder distension in spinal rats. (3) After intrathecal administration, Ruthenium Red (80–800 ng/rat) produced a long lasting inhibition of the micturition reflex in urethane-anesthetized rats, this effect being evident in both vehicleor capsaicin- (50 mg/kg s. c. 4 days before) pretreated rats. At 800 ng/rat, intrathecal Ruthenium Red did not affect the blood pressure rise produced by topical administration of capsaicin onto the rat bladder nor that produced by bladder distension. (4) These findings provide further evidence that Ruthenium Red acts quite selectively as a capsaicin antagonist preventing both reflex and efferent responses activated by peripherally administered capsaicin. By contrast, sensory impulse generation by a natural stimulus such as bladder distension is apparently unaffected by Ruthenium Red. The marked inhibition of the micturition reflex observed after intrathecal administration of Ruthenium Red does probably not involve an interaction with primary afferents in the spinal cord.     

Intraventricular self-administration of morphine in naive laboratory rats

Male Wistar rats implanted with cannulae aimed at the left lateral cerebral ventricle were individually maintained in Skinner boxes for 11 consecutive days. Animals were neither predependent on morphine nor shaped to press the operant lever. Experimental animals (n=7) obtained intraventricular infusions of a 1% morphine HCl solution (2 l per 5-s infusion) for each lever press while control animals (n=7) received only the vehicle. Four animals were yoked to experimental animals and received equivalent but non-contingent morphine HCl infusions. The mean number of lever presses per day for the experimental group was significantly higher than for the vehicle control or yoked control groups suggesting that naive rats will work for the positive reinforcing properties of morphine when it is infused centrally.     

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

Abstract 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 μl; 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 μl of the sucrose solution after a delay d _A ; a press on B resulted in delivery of 100 μl 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. Electronic Publication     

Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys

Rationale Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour.Objectives The present study, using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S⁺) and a 1-s cue light (CS⁺) or for water in the presence of anise odour (S^–) and 1-s white noise (CS^–), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated.Results Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 g or 1.0 g N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 g of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/OFQ (1.0–2.0 g per rat) significantly inhibited the reinstatement of extinguished ethanol responding under an S⁺/CS⁺ condition, whereas lever pressing under S^–/CS^– was not altered.Conclusions The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli.     

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 g l^–1, 0.5 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 l of the sucrose solution after a delay d _A; a press on B resulted in delivery of 100 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. Concentrations of monoamines in the OPFC were determined by high-performance liquid chromatography at the end of the experiment.Results In both groups, d _B(50) increased linearly with d _A (r ²>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 d _B(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.