E. Szabadi

Effects of quinolinic acid-induced lesions of the nucleus accumbens core on inter-temporal choice: a quantitative analysis

RationaleThere is evidence that lesions of the nucleus accumbens core (AcbC) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms. It is not known whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both.AimWe examined the effect of AcbC lesions on inter-temporal choice using a quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size.Materials and methodsSixteen rats received bilateral quinolinic acid-induced lesions of the AcbC; 14 received sham lesions. They were trained under a discrete-trials progressive delay schedule to press two levers (A and B) for a sucrose solution. Responses on A delivered 50xa0μl of the solution after a delay dA; responses on B delivered 100xa0μl after dB. dB increased across blocks of trials, while dA was manipulated across phases of the experiment. Indifference delay dB(50) (value of dB corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (dB(50) vs dA) derived.ResultsdB(50) increased linearly with dA (r2u2009>u20090.95 in each group). The intercept of the indifference function was lower in the lesioned than the sham-lesioned group; slope did not differ between groups. The lesioned rats had extensive neuronal loss in the AcbC.ConclusionsThe results confirm that lesions of the AcbC promote preference for smaller, earlier reinforcers and suggest that this reflects an effect of the lesion on the rate of delay discounting.

Effects of lesions of the nucleus accumbens core on inter-temporal choice: Further observations with an adjusting-delay procedure

Previous experiments using progressive-delay schedules showed that destruction of the nucleus accumbens core (AcbC) altered rats choice between food reinforcers differing in size and delay. Application of a quantitative model of inter-temporal choice suggested that lesions of the AcbC increase the delay-dependent degradation of reinforcer value (delay discounting) without altering instantaneous reinforcer value. This experiment examined the effect of lesions of the AcbC on inter-temporal choice using an adjusting-delay schedule. Rats received excitotoxin-induced lesions of the AcbC or sham lesions. They were trained to press levers A and B for food-pellet reinforcers in an adjusting-delay schedule in which the delay to the larger reinforcer, d(B), varied in accordance with the rats choices between the two levers. In two experimental conditions, the reinforcers associated with levers A and B were 1 vs. 4 and 2 vs. 4 pellets. The AcbC-lesioned group showed shorter indifference delays to reinforcer B (d(B(50))) than the sham-lesioned group under both conditions. In confirmation of a prediction derived from the model of inter-temporal choice, the ratio of the indifference delays from the two conditions did not differ between the groups. Analysis of the cyclical changes in d(B) by Fourier transform showed that the period of oscillation and power within the dominant frequency band did not differ between the groups, suggesting that the lesion did not disrupt the rats ability to detect short-term changes in delay of reinforcement. The results are consistent with previous findings that indicate a role for the AcbC in delay discounting.

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

RationaleThe nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers.ObjectiveThis study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105–172).Materials and methodsRats with bilateral quinolinic acid-induced lesions of the AcbC (nu2009=u200915) or sham lesions (nu2009=u200914) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet.ResultsThe performance of both groups conformed to the model of progressive-ratio performance (group mean data: r2u2009>u20090.92). The motor parameter, δ, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group.ConclusionsThe results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.

Effect of quinolinic acid-induced lesions of the subthalamic nucleus on performance on a progressive-ratio schedule of reinforcement: A quantitative analysis

The subthalamic nucleus (STN), a major relay in the indirect striatofugal pathway, plays an important role in extrapyramidal motor control. Recent evidence indicates that it may also be involved in regulating the incentive value of food reinforcers. Objective To examine the effect of lesions of the STN on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes [Killeen PR. Mathematical principles of reinforcement. Behav Brain Sci 1994;17:105–72]. Rats with bilateral quinolinic acid-induced lesions of the STN (n = 14) or sham lesions (n = 14) were trained to press a lever for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions) it was two pellets; in Phase 3 (30 sessions) it was again one pellet. Results The performance of both groups conformed to the model of progressive-ratio schedule performance. The motor parameter, δ, was significantly higher in the STN-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was significantly higher in the STN-lesioned group than in the sham-lesioned group, consistent with enhanced reinforcer value in the STN-lesioned group compared to the sham-lesioned group. In both groups, a was sensitive to changes in reinforcer size, being significantly greater under the two-pellet condition (Phase 2) than under the one-pellet condition (Phases 1 and 3). The results suggest that destruction of the STN impairs response capacity and enhances the incentive value of food reinforcers.

Evidence for the sensitivity of operant timing behaviour to stimulation of D1 dopamine receptors.

RationaleTemporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Previous studies using the fixed-interval peak procedure implicated D2-like dopamine receptors in these effects. However, recent findings suggest that d-amphetamine alters timing performance on the free-operant psychophysical procedure via D1-like receptors. It is not known whether this effect of d-amphetamine is mimicked by direct D1-like receptor stimulation.ObjectiveThe effects of a D1-like receptor agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine (SKF-81297) on performance on the free-operant psychophysical procedure and the interaction between SKF-81297 and a D1-like receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566) and a D2-like receptor antagonist haloperidol, were examined.Materials and methodsRats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data (percent responding on B [%B] vs time from trial onset [t]) under each treatment condition, and quantitative indices of timing (T50 [value of t corresponding to %Bu2009=u200950] and the Weber fraction [(T75-T25)/2T50; T25 and T75 are values of t corresponding to %Bu2009=u200925 and %Bu2009=u200975] were compared among treatments.ResultsSKF-81297 (0.8xa0mg kg−1) reduced T50; this effect was antagonized by SKF-83566 (0.03xa0mg kg−1) but not by haloperidol (0.05, 0.1xa0mg kg−1).ConclusionsStimulation of D1-like dopamine receptors affects performance in the free-operant psychophysical procedure.

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 %Bu2009=u200950%; Weber fraction). The effects of d-amphetamine (0.4xa0mg kg−1 i.p.), quinpirole (0.08xa0mg kg−1 i.p.), and SKF-81297 (0.4xa0mg 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.

Comparison of the effects of 2,5-dimethoxy-4-iodoamphetamine and D-amphetamine on the ability of rats to discriminate the durations and intensities of light stimuli

Rats ability to discriminate durations is disrupted by the monoamine-releasing agent D-amphetamine and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). It is unknown whether this effect is specific for temporal discrimination or reflects general disruption of stimulus control. This experiment addressed this question by comparing the effects of D-amphetamine and DOI on temporal discrimination and discrimination along a nontemporal dimension, light intensity. Twelve rats responded on a schedule in which a light (intensity 22u2009cd/m2) was presented for t seconds (2.5–47.5u2009s), after which levers A and B were presented. Responses on A were reinforced when t was less than 25u2009s, and responses on B were reinforced when t was greater than 25u2009s. Twelve rats responded on a similar schedule in which a light of intensity i (3.6–128.5u2009cd/m2) was presented for 25u2009s. Responses on A were reinforced when i was less than 22u2009cd/m2, and responses on B were reinforced when i was greater than 22u2009cd/m2. Logistic functions were fitted and psychophysical parameters estimated [T50, I50 (central tendency of temporal or light-intensity discrimination); Weber fraction (relative discriminative precision)]. D-Amphetamine (0.2–0.8u2009mg/kg) increased the Weber fraction for temporal and light-intensity discrimination; DOI (0.625–0.25u2009mg/kg) increased it for temporal discrimination only. Both drugs increased T50; neither altered I50. D-Amphetamine and DOI have similar effects on temporal discrimination but different effects on light-intensity discrimination. The increase in T50 may reflect the impairment of sustained attention during prolonged stimulus presentation.

Effects of amisulpride and aripiprazole on progressive-ratio schedule performance: comparison with clozapine and haloperidol.

Clozapine and some other atypical antipsychotics (e.g. quetiapine, olanzapine) have been found to exert a characteristic profile of action on operant behaviour maintained by progressive-ratio schedules, as revealed by Killeen’s Mathematical Principles of Reinforcement model of schedule-controlled behaviour. These drugs increase the value of a parameter that expresses the ‘incentive value’ of the reinforcer (a) and a parameter that is inversely related to the organism’s ‘motor capacity’ (δ). This experiment examined the effects of two further atypical antipsychotics, aripiprazole and amisulpride, on progressive-ratio schedule performance in rats; the effects of clozapine and a conventional antipsychotic, haloperidol, were also examined. In agreement with previous findings, clozapine (4, 8u2009mg kg−1) increased a and δ, whereas haloperidol (0.05, 0.1u2009mg kg−1) reduced a and increased δ. Aripiprazole (3,30u2009mg kg−1) increased δ but did not affect a. Amisulpride (5, 50u2009mg kg−1) had a delayed and protracted effect: δ was increased 3–6 hours after treatment; a was increased 1.5 hours, and reduced 12–24 hours after treatment. Interpretation based on Killeen’s model suggests that aripiprazole does not share clozapine’s ability to enhance reinforcer value. Amisulpride produced a short-lived enhancement, followed by a long-lasting reduction, of reinforcer value. Both drugs impaired motor performance.

New Findings on the Sensitivity of Free-Operant Timing Behaviour to 5-Hydroxytryptamine Receptor Stimulation

Timing performance maintained under the free-operant psychophysical procedure (FOPP) is sensitive to 5-hydroxytryptamine (5-HT)1A and 5-HT2A receptor stimulation. Agonists of these receptors displace the psychometric function towards shorter durations, reducing T50, the index of central tendency of timing. Here we report the effects of Ro-600175, a selective 5-HT2C receptor agonist, and mCPP, a 5-HT receptor agonist with high affinity for 5-HT2C receptors and lower affinity for 5-HT1A, 5-HT1B and 5-HT2A receptors, on timing behaviour. Rats were trained under the FOPP to press two levers (A and B) in 50-s trials in which reinforcers were 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 psychometric curves were fitted to the data from each rat under each treatment condition for derivation of timing indices [T50 (time corresponding to %B = 50%), Weber fraction]. The rats received systemic treatment with Ro-600175, mCPP, and mCPP in combination with antagonists of 5-HT1A (WAY-100635), 5-HT1B (isamoltane), 5-HT2A (MDL-100907) or 5-HT2C (SB-242084) receptors. mCPP (2.5xa0mg kg−1 i.p.), but not Ro-600175 (1, 2, 4xa0mg kg−1 i.p.), reduced T50. SB-242084 (0.6xa0mg kg−1 i.p.) potentiated mCPP’s effect on T50. mCPP’s effect on T50 was not altered by isamoltane (8.0xa0mg kg−1 i.p.), but was attenuated by MDL-100907 (1.0xa0mg kg−1 i.p.) and WAY-100635 (0.1xa0mg kg−1 s.c.). The results suggest that mCPP’s effect on timing is mediated by an agonistic action at 5-HT1A and 5-HT2A, but not 5-HT1B, receptors. The role of 5-HT2C receptors is unclear, in view of SB-242084’s ability to potentiate the effect of mCPP, while Ro-600175 had no effect on T50. The possibility is considered that 5-HT2C receptors may counteract 5-HT1A and/or 5-HT2A receptor-mediated effects on timing performance.