Biomedical subjects

M-Y Ho

Publications and source records attributed to M-Y Ho.

9 recordsLinked to original sources

PubMed2004

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.

Adrenergic Agents↗

PubMed2004

Rapid development of an advanced squamous-cell carcinoma of the esophagus.

This report describes the case of a 42-year-old alcoholic man who developed advanced squamous-cell carcinoma of the esophagus following an endoscopic examination showing grossly normal mucosa only 8 months previously. We believe this is the first case report providing endoscopic images illustrating a progression from grossly normal mucosa to advanced carcinoma of the esophagus in only 8 months.

Adult↗

PubMed2003

Effects of 8-OH-DPAT and WAY-100635 on performance on a time-constrained progressive-ratio schedule.

RATIONALE: Performance on progressive-ratio schedules has been proposed as a means of assessing the effects of drugs on motivation. We have adopted a mathematical model proposed by Killeen to analyse the effects of drugs acting at 5-HT(1A) receptors on progressive-ratio performance. According to this model, the relationship between response rate and ratio size is described by a bitonic (inverted-U) function. One parameter of the function, a, expresses the motivational or "activating" effect of the reinforcer (duration of activation of responding produced by the reinforcer), whereas another parameter, delta, expresses the minimum time needed to execute a response and is regarded as an index of "motor capacity". OBJECTIVE: To examine the effect of the selective 5-HT(1A) receptor agonist 8-OH-DPAT [8-hydroxy-2-(di- n-propylamino)tetralin] and the antagonist WAY-100635 [ N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]- N-2-pyridinylcyclo-hexanecarboxamide] on progressive-ratio schedule performance. METHODS: Sixteen rats responded for a food-pellet reinforcer on a time-constrained progressive-ratio schedule (55-min sessions). In phase 1, they received single doses (s.c.) of 8-OH-DPAT (25, 50, 100, 200 microg kg(-1), four treatments at each dose) or the vehicle (0.9% saline solution). In phase 2, they received WAY-100635 (30, 100, 300 microg kg(-1)) according to the same regimen. In phase 3, they received 8-OH-DPAT (100 microg kg(-1)) alone or in combination with WAY-100635 (30 microg kg(-1)). 8-OH-DPAT dose dependently increased the value of a, significant increases being seen with the 50, 100 and 200 microg kg(-1) doses. The highest dose also increased delta. WAY-100635 did not significantly alter either a or delta. WAY-100635 significantly attenuated the effect of 8-OH-DPAT on both a and delta. CONCLUSIONS: The results suggest that 8-OH-DPAT enhanced the activating effect of the reinforcer (the highest dose may also have induced motor debilitation). The finding that the effect of 8-OH-DPAT on a was attenuated by WAY-100635 implicates 5-HT(1A) receptors in this effect. The results are consistent with previous reports that 8-OH-DPAT facilitates feeding and food-reinforced operant responding in rats and suggest that these effects may be brought about by an increase in food motivation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2003

Effects of a 5-HT2 receptor agonist, DOI (2,5-dimethoxy-4-iodoamphetamine), and antagonist, ketanserin, on the performance of rats on a free-operant timing schedule.

This experiment examined the effect of a 5-HT2 receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine), and antagonist, ketanserin, on temporal differentiation performance. Twelve rats were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials in which sucrose reinforcement (0.6 mol/l, 50 microl) was provided intermittently for responding on A during the first half, and on B during the second half of the trial. Psychometric curves were derived from percent responding on B (%B), recorded in successive 5-s epochs of the trials; logistic functions were fitted to these data for the derivation of timing indices (T50 [time corresponding to %B=50%], epsilon [slope of the logistic curve], Weber fraction). Cumulative probability of switching in successive 5-s epochs was used to estimate the mean switching time, S50. DOI (0.0625, 0.125 and 0.25 mg/kg, s.c.) dose-dependently reduced T50 and S50. These effects of DOI (0.25 mg/kg) were antagonized by ketanserin (1.0 mg/kg). The results show that DOI alters temporal differentiation in the free-operant psychophysical procedure. The antagonistic effect of ketanserin indicates that the effect of DOI was probably mediated by 5-HT2A rather than 5-HT2C receptors, since ketanserin is relatively selective for 5-HT2A receptors. Comparison of these results with our previous findings with a 5-HT1A receptor agonist indicates that 5-HT1A and 5-HT2A receptors mediate qualitatively similar effects on temporal differentiation.

Amphetamines↗

PubMed2002

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.

Animals↗

PubMed2002

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.

Animals↗

PubMed2002

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.

Animals↗

PubMed2002

Effect of 8-OH-DPAT on temporal discrimination following central 5-hydroxytryptamine depletion.

The 5-hydroxytryptamine (5-HT)(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) alters performance in discrete-trials timing schedules. 5-HT(1A) receptors occur both presynaptically and postsynaptically, but it is not known which receptor population mediates the effects of 8-OH-DPAT on timing. Rats received intra-raphe injections of 5,7-dihydroxytryptamine (n=16) or sham lesions (n=14). They were trained in a discrete-trials psychophysical procedure in which levers were presented at a predetermined time after the onset of each trial (2.5, 7.5,., 47.5 s). A response on lever A was reinforced if lever presentation occurred < 25 s after trial onset; a response on lever B was reinforced if lever presentation occurred >25 s after trial onset. After 70 preliminary sessions, the rats received 8-OH-DPAT (25, 50, 100, 200 microg kg(-1) sc) and saline vehicle. The percentage of responses on lever B (%B) increased as a function of time from trial onset. Under the baseline (vehicle-treatment) condition, performance did not differ between the two groups. 8-OH-DPAT did not alter the indifference point (time corresponding to %B=50%), but dose-dependently increased the Weber fraction in both groups. Forebrain concentrations of 5-HT and 5-HIAA in the lesioned group were approximately 10% of control levels. The results suggest that the effect of 8-OH-DPAT on performance on discrete-trials timing schedules is mediated by postsynaptic 5-HT(1A) receptors.

5,7-Dihydroxytryptamine↗

PubMed2002

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.

8-Hydroxy-2-(di-n-propylamino)tetralin↗