T. H. C. Cheung

Effect of disconnecting the orbital prefrontal cortex from the nucleus accumbens core on inter-temporal choice behaviour: A quantitative analysis

Previous experiments showed that destruction of the orbital prefrontal cortex (OPFC) or the nucleus accumbens core (AcbC) in rats altered choice between two delayed food reinforcers. Application of a quantitative model of inter-temporal choice suggested that lesions of either structure increased the delay-dependent degradation of reinforcer value (delay discounting); destruction of the OPFC (but not the AcbC) also increased the relative value of the larger reinforcer. This experiment examined the effect of disconnecting the OPFC from the AcbC on inter-temporal choice. Rats received excitotoxin-induced contralateral lesions of the OPFC and AcbC (disconnection), severing of the anterior corpus callosum (callosotomy), a combined lesion (disconnection + callosotomy) or sham lesions. They were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 μl of the solution after a delay dA; responses on B delivered 100 μl after a delay dB. dB increased across blocks of trials; dA was manipulated across phases of the experiment. Indifference delay, dB(50) (value of dB corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (dB(50)vs. dA) were derived. The disconnection + callosotomy group showed a lower intercept of the indifference function (implying a higher rate of delay discounting) than the sham-lesioned group; the disconnection group showed a similar but less robust effect, whereas the callosotomy group did not differ significantly from the sham-lesioned group. The results suggest that OPFC–AcbC connections are involved in delay discounting of food reinforcers, but provide no evidence for an involvement of OPFC–AcbC connections in regulating sensitivity to reinforcer size.

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 (n = 15) or sham lesions (n = 14) 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: r2 > 0.92). 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.

Quantitative analysis of the effect of lesions of the subthalamic nucleus on intertemporal choice: further evidence for enhancement of the incentive value of food reinforcers.

Recent evidence suggests that the subthalamic nucleus (STN) is involved in regulating the incentive value of food reinforcers. The objective of this study was to examine the effect of lesions of the STN on intertemporal choice (choice between reinforcers differing in size and delay). Rats with bilateral quinolinic acid-induced lesions of the STN (n = 15) or sham lesions (n = 14) were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 μl of the solution after a delay dA; responses on B delivered 100 μl after a delay dB. dB increased across blocks of trials; dA was manipulated across phases of the experiment. Indifference delay, dB(50) (value of dB corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (dB(50) vs. dA) were derived. The STN-lesioned group showed a flatter slope of the indifference function (implying higher instantaneous reinforcer values) than the sham-lesioned group; the intercepts did not differ between the groups. The results agree with recent evidence for a role of the STN in incentive value. Unlike some earlier studies, these results do not indicate a role of the STN in delay discounting.

Evidence that the effect of 5-HT2 receptor stimulation on temporal differentiation is not mediated by receptors in the dorsal striatum

5-HT2 receptor stimulation alters temporal differentiation in free-operant timing schedules. The anatomical location of the receptor population responsible for this effect is unknown. We examined the effect of a 5-HT2 receptor agonist and antagonists, injected systemically and into the dorsal striatum, a region that is believed to play a major role in interval timing. Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50s 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 5s epochs of the trials; logistic functions were fitted to the data from each rat to derive timing indices (T50: time corresponding to %B = 50; Weber fraction: [T75-T25]/2T50, where T75 and T25 are the times corresponding to %B = 75 and %B = 25). Systemic treatment with the 5-HT(2A/2C) receptor agonist 2,5,-dimethoxy-4-iodo-amphetamine (DOI) (0.25 mg/kg, s.c.) reduced T50; the 5-HT2A receptor antagonist MDL-100907 (0.5 mg/kg, i.p.) did not affect performance, but completely blocked the effect of DOI. DOI (1 and 3 microg) injected bilaterally into the dorsal striatum did not alter T50. The effect of systemic treatment with DOI (0.25 mg/kg, s.c.) was not altered by intra-striatal injection of MDL-100907 (0.3 microg) or the 5-HT2C receptor antagonist RS-102221 (0.15 microg). The ability of systemically administered MDL-100907 to reverse DOIs effect on T50 confirms the sensitivity of temporal differentiation to 5-HT2A receptor stimulation. The failure of intra-striatal MDL-100907 to antagonize the effects of DOI suggests that 5-HT2A receptors in the dorsal striatum are unlikely to be primarily responsible for DOIs effects on timing. Furthermore, the results provide no evidence for a role of striatal 5-HT2C receptors in DOIs effect on timing.

Pharmacological studies of performance on the free-operant psychophysical procedure

In the free-operant psychophysical procedure (FOPP), reinforcement is provided intermittently for responding on lever A in the first half and lever B in the second half of a trial. Temporal differentiation is measured from the psychometric function (percent responding on B, %B, versus time from trial onset, t), the index of timing being T50, the value of t at %B=50. T50 is reduced by acute treatment with 5-hydroxytryptamine (5-HT1A, 5-HT2A) and dopamine (D1-like, D2-like) receptor agonists. The effects of the agonists can be reversed by the respective antagonists of these receptors. Evidence is reviewed suggesting that the effect of endogenous 5-HT is mediated by 5-HT2A receptors and the effect of endogenous dopamine by D1-like receptors. Data are presented on the effects of lesions of the prefrontal cortex and corpus striatum on the sensitivity of performance on the FOPP to D1-like and D2-like receptor agonists. Lesions of the nucleus accumbens, but not the dorsal striatum or prefrontal cortex, attenuated the effects of a D1-like receptor agonist, 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine [SKF-81297], but not a D2-like receptor agonist, quinpirole, on T50. The results indicate that a population of D1-like receptors in the ventral striatum may contribute to the control of timing performance on the FOPP.

Evidence for a role of 5-HT2C receptors in the motor aspects of performance, but not the efficacy of food reinforcers, in a progressive ratio schedule.

Rationale5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathematical models can help to differentiate between these processes.ObjectiveThe effects of the 5-HT2C receptor agonist Ro-600175 ((αS)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine) and the non-selective 5-HT receptor agonist 1-(m-chlorophenyl)piperazine (mCPP) on rats’ performance on a progressive ratio schedule maintained by food pellet reinforcers were assessed using a model derived from Killeen’s Behav Brain Sci 17:105–172, 1994 general theory of schedule-controlled behaviour, ‘mathematical principles of reinforcement’.MethodRats were trained under the progressive ratio schedule, and running and overall response rates in successive ratios were analysed using the model. The effects of the agonists on estimates of the model’s parameters, and the sensitivity of these effects to selective antagonists, were examined.ResultsRo-600175 and mCPP reduced the breakpoint. Neither agonist significantly affected a (the parameter expressing incentive value), but both agonists increased δ (the parameter expressing minimum response time). The effects of both agonists could be attenuated by the selective 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carboxamide). The effect of mCPP was not altered by isamoltane, a selective 5-HT1B receptor antagonist, or MDL-100907 ((±)2,3-dimethoxyphenyl-1-(2-(4-piperidine)methanol)), a selective 5-HT2A receptor antagonist.ConclusionsThe results are consistent with the hypothesis that the effect of the 5-HT2C receptor agonists on progressive ratio schedule performance is mediated by an impairment of motor capacity rather than by a reduction of the incentive value of the food reinforcer.

Fos expression in the prefrontal cortex and ventral striatum after exposure to a free-operant timing schedule

It has been proposed that cortico-striato-thalamo-cortical circuits that incorporate the prefrontal cortex and corpus striatum regulate interval timing behaviour. In the present experiment regional Fos expression was compared between rats trained under an immediate timing schedule, the free-operant psychophysical procedure (FOPP), which entails temporally regulated switching between two operanda, and a yoked variable-interval (VI) schedule matched to the timing task for food deprivation level, reinforcement rate and overall response rate. The density of Fos-positive neurones (counts mm−2) in the orbital prefrontal cortex (OPFC) and the shell of the nucleus accumbens (AcbS) was greater in rats exposed to the FOPP than in rats exposed to the VI schedule, suggesting a greater activation of these areas during the performance of the former task. The enhancement of Fos expression in the OPFC is consistent with previous findings with both immediate and retrospective timing schedules. Enhanced Fos expression in the AcbS was previously found in retrospective timing schedules based on conditional discrimination tasks, but not in a single-operandum immediate timing schedule, the fixed-interval peak procedure. It is suggested that the ventral striatum may be engaged during performance on timing schedules that entail operant choice, irrespective of whether they belong to the immediate or retrospective categories.