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1.
RATIONALE: The ascending 5-hydroxytryptaminergic (5-HTergic) pathways are believed to be involved in "impulse control". Rats whose 5-HTergic pathways have been destroyed are more liable than intact rats to select a smaller, immediate reinforcer rather than a larger, delayed reinforcer (impulsive choice), and recent evidence indicates that this effect of central 5-HT depletion reflects a change in the rate of time discounting (i.e. a change in the rate at which reinforcers become devalued as a function of delay). Delay of reinforcement and uncertainty of reinforcer delivery are believed to have equivalent effects on choice behaviour. However, it is not known whether central 5-HT depletion affects choice between probabilistic reinforcers. OBJECTIVE: We examined the effects of central 5-HT depletion on choice behaviour in two experiments: In experiment 1, rats chose between a smaller immediate reinforcer and a larger delayed reinforcer; in experiment 2, rats chose between a smaller certain reinforcer and a larger probabilistic reinforcer. METHODS: Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press two levers for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, selection of lever A resulted in immediate delivery of one food pellet; selection of lever B resulted in delivery of 2 pellets, either following a delay (dB) (experiment 1) or with a probability (pB) less than 1 (experiment 2). RESULTS: In experiment 1, both groups showed declining choice of lever B (%B) as a function of dB. The lesioned group showed shorter indifference delays (D50: the value of dB corresponding to %B=50) than the sham-lesioned group. In experiment 2, both groups showed declining choice of lever B as a function of the odds against delivery of the two-pellet reinforcer, thetaB (thetaB=[1/pB]-1). There was no difference between the "indifference odds" (theta50: the value of thetaB corresponding to %B=50) between the two groups. In both experiments, 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. CONCLUSIONS: These results provide additional evidence that central 5-HTergic mechanisms are involved in time discounting, but provide no evidence for a similar role of 5-HT in rats' sensitivity to probabilistic reinforcement. 相似文献
2.
Effects of quinolinic acid-induced lesions of the nucleus accumbens core on inter-temporal choice: a quantitative analysis 总被引:1,自引:1,他引:0
Bezzina G Cheung TH Asgari K Hampson CL Body S Bradshaw CM Szabadi E Deakin JF Anderson IM 《Psychopharmacology》2007,195(1):71-84
Rationale There 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.
Aim We 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 methods Sixteen 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
50 μl of the solution after a delay d
A; responses on B delivered 100 μl after d
B. d
B increased across blocks of trials, while d
A was manipulated across phases of the experiment. Indifference delay d
B(50) (value of d
B corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (d
B(50) vs d
A) derived.
Results
d
B(50) increased linearly with d
A (r
2 > 0.95 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.
Conclusions The 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. 相似文献
3.
Impulsive choice refers to the selection of small immediate gains in preference to larger delayed gains, or the selection of large delayed
penalties in preference to smaller immediate penalties. Current theoretical interpretations of impulsive choice are reviewed,
and a synthesis of these ideas, the ”multiplicative hyperbolic model of choice”, is presented. The model assumes that the
value of a positive reinforcer increases as a hyperbolic function of its size, and decreases as a hyperbolic function of its
delay and the odds against its occurrence. Each hyperbolic function contains a single discounting parameter which quantifies
the organism’s sensitivity to the variable in question. The hyperbolic discounting functions combine multiplicatively to determine
the overall value of the reinforcer. Equivalent functions are postulated to govern the (negative) value of aversive events,
the net value of an outcome reflecting the algebraic sum of the positive and negative values. The model gives rise to a quantitative
methodology for studying impulsive choice, based on a family of linear indifference (null) equations, which describe performance
under conditions of indifference, when the values of the reinforcers are assumed to be equal. This methodology may be used
to identify individual differences in sensitivity to the magnitude, delay and probability of reinforcement. The methodology
is also suitable for the quantitative evaluation of the effects of some pharmacological interventions on discounting parameters.
Recent psychopharmacological studies of impulsive choice are reviewed, and the utility of indifference equations for extending
this work, and developing a quantitative psychopharmacology of impulsive choice is discussed.
Received: 14 April 1999 / Final version: 6 May 1999 相似文献
4.
A. S. A. Al-Ruwaitea T.-J. Chiang M.-Y. Ho C. M. Bradshaw E. Szabadi 《Psychopharmacology》1999,144(3):264-271
Rationale: Previous experiments have shown that rats whose 5-hydroxytryptaminergic (5-HTergic) pathways have been destroyed exhibit
higher rates of switching between response alternatives on various temporal differentiation schedules. Objective: This paper reports two experiments investigating the effect of central 5-HT depletion on switching between concurrent schedules
of reinforcement which do not entail temporal differentiation of behaviour. Methods: 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. In experiment 1, the rats were exposed to concurrent pairs of variable-time (VT)
schedules specifying equal inter-reinforcement intervals; responses on a single ”changeover lever” alternated between the
two VT schedules. In experiment 2, the rats were exposed to concurrent pairs of variable-interval (VI) schedules specifying
equal inter-reinforcement intervals; responses on one lever (”VI lever”) earned reinforcers, while responses on the other
lever (”changeover lever”) alternated between the two VI schedules. Results: In experiment 1, both groups showed longer ”dwell-times” (intervals between successive changeover responses) when a reinforcer
was delivered in the ”dwell” than when no reinforcer was delivered (”win-stay” effect). The lesioned rats showed higher rates
of changeover responding and shorter dwell-times (with and without reinforcer delivery) than the sham-lesioned group. In experiment
2, the rate of responding on the VI lever did not differ significantly between the two groups; however, the lesioned rats
showed higher rates of changeover responding, shorter dwell-times (with and without reinforcer delivery) and smaller numbers
of inter-changeover responses on the VI lever than the sham-lesioned group. In both experiments, 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. Conclusions: These results provide further evidence for the involvement of the ascending 5-HTergic pathways in behavioural ”switching”,
and indicate that this is not restricted to temporal differentiation schedules.
Received: 28 September 1998 / Final version: 1 December 1998 相似文献
5.
A. S. A. Al-Ruwaitea T.-J. Chiang S. S. A. Al-Zahrani M.-Y. Ho C. M. Bradshaw E. Szabadi 《Psychopharmacology》1999,141(1):22-29
This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on performance
on a new discrete-trials version of the “time-left” procedure. Rats received either injections of 5,7-dihydroxytryptamine
into the dorsal and median raphe nuclei or sham lesions. They were trained in a discrete trials schedule in which reinforcers
were provided for responding on either of two levers, A and B. At a random time point, t s after the start of each trial, the two levers were inserted into the operant chamber; a response on A resulted in the delivery
of one food pellet after d
A s, whereas a response on B resulted in the delivery of two pellets after 84-t s. The value of d
A was varied between 1 and 12 s in different phases of the experiment. Both groups showed an increasing tendency to respond
on lever B as a function of time within the trial. Logistic functions were fitted to the data from each group, and a value
of the “indifference point” (T
50: the time within the trial at which proportional choice of B attained a value of 50%) was derived for each rat. For each
value of d
A, the values of T
50 were significantly greater in the lesioned rats than in the control rats, reflecting a rightward shift of the logistic function
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 significantly altered. The results provide further evidence for the involvement
of the ascending 5HTergic pathways in the control of operant behaviour by delayed positive reinforcers.
Received: 12 January 1998/Final version: 6 May 1998 相似文献
6.
Rationale Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the efficacy
of reinforcers. A mathematical model (Killeen PR (1994) Mathematical principles of reinforcement. Behav Brain Sci 17:105–172)
affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. The model postulates a bitonic
function relating response rate and ratio size. One parameter of the function, a, expresses the motivational effect of the reinforcer, whereas another parameter, δ, expresses the minimum time needed to execute a response, and is regarded as an index of ‘motor capacity’. Previously we
found that the atypical antipsychotic clozapine increased a, indicating an increase in reinforcer efficacy; a similar effect was observed with the 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). It has been suggested that some of clozapine’s behavioural effects are mediated by agonistic
action at 5-HT1A receptors.
Objective This study was conducted to compare the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance.
Methods Rats were trained under a time-constrained progressive ratio schedule (50-min sessions). In experiment 1, they received acute
doses of clozapine (4 mg kg−1) and 8-OH-DPAT (100 μg kg−1), alone and in combination with the 5-HT1A receptor antagonist N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-yridinylcyclohexanecarboxamide (WAY-100635; 30 μg kg−1). In experiment 2, the effects of clozapine (2, 4 and 8 mg kg−1) and 8-OH-DPAT (25, 50 and 100 μg kg−1) were compared between intact rats and rats whose 5-HTergic pathways had been ablated by 5,7-dihydroxytryptamine (5,7-DHT).
Results In both experiments, clozapine and 8-OH-DPAT increased a and δ. In experiment 1, WAY-100635 abolished the effect of 8-OH-DPAT on a and δ, but did not alter clozapine’s effects on these parameters. In experiment 2, the effects of clozapine and 8-OH-DPAT did not
differ between sham-lesioned and 5,7-DHT-lesioned rats.
Conclusions The results confirm previous findings on the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance.
8-OH-DPAT’s effects are probably mediated by post-synaptic 5-HT1A receptors; clozapine’s effects are mediated by a different mechanism, which does not appear to involve 5-HT1A receptors and which does not depend upon an intact 5-HTergic pathway.
Jonathan Francis Rickard (1977–2003), a gifted and dedicated Ph.D. student, made a major contribution to this work 相似文献
7.
S. Body T. H. C. Cheung C. L. Hampson F. S. den Boon G. Bezzina K. C. F. Fone C. M. Bradshaw E. Szabadi 《Psychopharmacology》2009,203(3):547-559
Rationale Interval 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.
Objective The 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 methods Rats 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 (T
50, time corresponding to %B = 50%; Weber fraction). The effects of d-amphetamine (0.4 mg kg−1 i.p.), quinpirole (0.08 mg kg−1 i.p.), and SKF-81297 (0.4 mg 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.
Results Quinpirole and SKF-81297 reduced T
50 in both groups; d-amphetamine reduced T
50 only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected.
Conclusions
d-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.
相似文献
S. BodyEmail: |
8.
Choice behaviour can be viewed as a response to reinforcement determined by an interaction between the quantities, delays and probabilities of two outcomes. The variation in the perceived value of a reinforcer with alteration of these factors (discounting) can be modelled mathematically by hyperbolic discounting functions. Making risky choices is a feature of impulsivity and has been associated with reduced serotonin (5-hydroxytryptamine, 5-HT) function. In this study, we investigated the possible role of 5-HT in modulating probability discounting using the technique of acute tryptophan (TRP) depletion in subjects undertaking an imaginary gambling task. The gambling task consisted of choosing between two 'roulette-like' dials: 'A' which provided a smaller but nearly certain 'win' and 'B' which gave a 'win' 2.5 times the amount with a probability that was systematically varied. A series of reward sizes on dial 'A' was presented ranging from 10 pence to 10,000 pounds. The probability of winning on dial 'B' at which the subjects valued the two dials equally (indifference point) was determined as a measure of willingness to take a risk. Subjects were more likely to take a risk for smaller rewards but the indifference points in the 15 subjects who received TRP depletion did not differ from 13 who had the control drink. On a surprise retesting 1 week later there was a trend (p < 0.07) for subjects to be more willing to take risks the second time, particularly in the case of small rewards. This study does not support a role for 5-HT in modulating probabilistic choice in agreement with recent evidence from experiments with animals; however, the imaginal nature of the task and modest numbers may have influenced the result. 相似文献
9.
Rationale Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T
50. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation.Objective We examined whether fenfluramines effect on temporal differentiation can be antagonised by the 5-HT1A receptor antagonist N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine.Methods Rats were trained under the free-operant psychophysical procedure to press 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 psychophysical curves were fitted to the data for derivation of timing indices (T
50, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT1A and 5-HT2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography.Results Experiment 1: fenfluramine (2 mg/kg) reduced T
50; this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-100635 (100 g/kg). Experiment 2: 8-OH-DPAT (100 g/kg) and DOI (250 g/kg) reduced T
50 in both groups; fenfluramine reduced T
50 only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected.Conclusions The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT2A receptors. 相似文献
10.
Nattaya Chairungsrilerd K.-I. Furukawa Tomihisa Ohta Shigeo Nozoe Yasushi Ohizumi 《Naunyn-Schmiedeberg's archives of pharmacology》1997,357(1):25-31
γ-Mangostin, purified from the fruit hull of the medicinal plant Garcinia mangostana caused a parallel rightwards shift of the concentration/response curve for the contraction elicited by 5-hydroxytryptamine
(5-HT) in the rabbit aorta (pA2 = 8.2) without affecting the contractile responses to KCl, phenylephrine (α1) or histamine (H1). The perfusion pressure response of rat coronary artery to 5-HT (5-HT2A) was reduced concentration dependently by γ-mangostin (IC50 = 0.32 μM). 5-HT amplified, ADP-induced aggregation of rabbit platelets (5-HT2A) was inhibited by γ-mangostin (IC50 = 0.29 μM), whereas that induced by thrombin was not affected, nor did γ-mangostin affect 5-HT-induced contraction of the
guinea-pig ileum (5-HT3)in the presence of 5-HT1, 5-HT2 and 5-HT4 receptor antagonists. Furthermore, 5-HT-induced contraction of the rat fundus (5-HT2B) and 5-HT-induced relaxation of the rabbit aorta in the presence of ketanserin (5-HT1) and carbachol-induced contraction of the guinea-pig ileum (muscarinic M3) were not affected by γ-mangostin (5 μM). γ-Mangostin inhibited [3H]spiperone binding to cultured rat aortic myocytes (IC50 = 3.5 nM). The K
d for [3H]spiperone binding was increased by γ-mangostin (3 nM) from 11.7 to 27.4 nM without affecting B
max. These results suggest that γ-mangostin is a novel competitive antagonist, free from a nitrogen atom, for the 5-HT2A receptors in vascular smooth muscles and platelets.
Received: 10 June 1997 / Accepted: 11 September 1997 相似文献
11.
A. S. A. Al-Ruwaitea S. S. A. Al-Zahrani M.-Y. Ho C. M. Bradshaw E. Szabadi 《Psychopharmacology》1997,134(2):179-186
This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on performance
in a free-operant timing schedule: the “time-left” procedure. Rats received either injections of 5,7-dihydroxytryptamine into
the dorsal and median raphe nuclei or sham lesions. They were trained in a discrete trials schedule in which reinforcers were
provided for responding on either of two levers, A and B. At a random time point, t s after the start of each trial, a response on A resulted in the delivery of one food pellet after d
A s, whereas a response on B resulted in the delivery of two pellets after 60-t s. The value of d
A was varied between 1 and 8 s in different phases of the experiment. Both groups showed decreasing response rates on lever
A and increasing response rates on lever B as a function of time within the trial. An index of timing (T
75: the time within the trial at which relative response rate on B attained a value of 75%) was systematically related to the
value of d
A, but did not differ significantly between lesioned and control rats. However, the lesioned group showed significantly higher
rates of switching between response alternatives than the sham-lesioned group at all values of d
A. 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 provide further evidence that the ascending 5HTergic pathways may
contribute to the inhibitory regulation of switching between behavioural states.
Received: 27 March 1997 /Final version: 19 May 1997 相似文献
12.
Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward 总被引:2,自引:2,他引:0
Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating
effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect
by investigating the effects of 5-HT agonists with differing affinities for 5-HT1 and 5-HT2 receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained to associate a light/tone stimulus (subsequently
the CR) with water delivery. In a test phase, they were allowed access to a lever delivering the CR, and an inactive (NCR)
lever. Responding on the CR lever was greater than responding on the NCR lever, indicating that the light/tone stimulus functioned
as a CR. Responding for the CR was selectively potentiated by injections of d-amphetamine (10 μg) into the nucleus accumbens. This effect was reduced by injections into the nucleus accumbens of 5-CT
(0.5 and 1 μg), RU24969 (10 μg), CP93,129 (1.25 and 2.5 μg) but not by DOI (10 μg) or 8-OH-DPAT (5 μg). The lower doses of
5-CT and CP93,129 did not reduce baseline responding for CR, or responding for water in a separate group of animals, indicating
that the effects of these drugs were behaviourally selective. The higher doses abolished the CR effect, and in the case of
5-CT and RU24969 also reduced responding for water. All of the effective drugs share in common the ability to stimulate 5-HT1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5-HT1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the5-HT1B/1D antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT1B receptors within the nucleus accumbens attenuates the effects of a dopamine-dependent behaviour, and that activation of these
receptors can oppose the behavioural effects of elevated mesolimbic dopamine transmission.
Received: 22 April 1998/Final version: 28 July 1998 相似文献
13.
Rationale: Tolerance to delay of reinforcement has been proposed as an important facet of self-control in both animals and man. Poor
self-control, leading to impulsive behaviour, can be a major problem if it reaches pathological levels. Objectives: The effects of five serotonergic drugs were compared to those of ethanol on a procedure for measuring tolerance to delay
of reinforcement in rats in order to elucidate further the role of the serotonin systems in the regulation of impulsive behaviour.
Methods: Rats were trained to choose between a single food pellet (small reinforcer) delivered immediately or five food pellets (large
reinforcer) delivered after programmed delays. At the start of each session, there was no delay between the response and delivery
of the large reinforcer, but this was increased stepwise during the session to delays of 10, 20, 40 and 60 s. Results: The rats showed consistent preference for the larger reinforcer when it was not delayed but showed a shift in preference
as the session continued, so that they preferred the small reinforcer when the large was delayed by 40 or 60 s. Ethanol at
a dose of 1.0 g/kg produced a significance increase in preference for the small, immediate reinforcer throughout the session,
although there were marked individual differences in the size of the effect. A similar, but somewhat smaller effect was seen
with the 5-HT2 agonist, DOI, at a dose of 1.0 mg/kg. In contrast, the 5-HT1A agonist, 8-OH-DPAT (0.3 mg/kg) reduced preference for the large reinforcer at the start of the session, and reduced preference
for the small reinforcer at the end of the session, i.e. produced a regression to indifference. Lower doses of these three
drugs, and treatment with the 5-HT receptor subtype selective antagonists WAY-100635 (5-HT1A: 0.01–0.1 mg/kg), ritanserin (5-HT2: 0.1 and 0.3 mg/kg) and MDL-72222 (5-HT3: 1.0 and 3.0 mg/kg) had no significant effects on reinforcer choice. Conclusion: These data show that ethanol and DOI increase preference for the immediate reinforcer, which can be construed as evidence
of an increase in impulsive behaviour (reduction in self control), whereas selective blockade of the 5-HT1A, 5-HT2 or 5-HT3 receptors using selective antagonists does not affect self-control.
Received: 24 October 1998 / Final version: 16 February 1999 相似文献
14.
T.-J. Chiang A. S. A. Al-Ruwaitea M.-Y. Ho C. M. Bradshaw E. Szabadi 《Psychopharmacology》1999,143(2):166-173
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 相似文献
15.
Fokko Bosker Dorien Vrinten André Klompmakers H. Westenberg 《Naunyn-Schmiedeberg's archives of pharmacology》1997,355(3):347-353
The modulation of extracellular 5-hydroxytryptamine (5-HT) in the central nucleus of the amygdala (CeA) by 5-HT1A receptors was studied by intracerebral microdialysis in awake and freely moving rats. Local administration of 1 μM tetrodotoxin
(TTX), 60 mM K+ and perfusion with Ca2+-free Ringer containing EGTA confirmed that the major part of dialysate 5-HT levels from the CeA is of neuronal origin. Administration
of 300 nM of RU 24969, a 5-HT1B receptor agonist, through the probe into the CeA decreased dialysate 5-HT levels to 67.2% of the baseline value. Systemic
administration of the 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan dose-dependently decreased 5-HT levels in the CeA. The effect of 0.3 mg/kg of
flesinoxan could be completely antagonized by systemic administration of 0.05 mg/kg WAY 100635, a 5-HT1A receptor antagonist. WAY 100635 alone had only minimal effects at this dose. These data show that a major part of the extracellular
5-HT in the CeA stems from 5-HT neurons and that the amount of 5-HT released into this brain region can be modulated by 5-HT1A receptors.
Received: 11 September 1996 / Accepted: 25 November 1996 相似文献
16.
T. Yamaguchi Masanori Suzuki Minoru Yamamoto 《Naunyn-Schmiedeberg's archives of pharmacology》1997,356(6):712-720
Effects of indeloxazine hydrochloride, an inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake with a facilitatory
effect on 5-HT release, on acetylcholine (ACh) output in frontal cortex of conscious rats were characterized using an in vivo
microdialysis technique. Systemic administration of indeloxazine (3 and 10 mg/kg, i.p.) increased ACh and 5-HT output in a
dose-dependent manner. Depletion of endogenous monoamines by reserpine and of 5-HT by p-chlorophenylalanine, but not that of catecholamines by α-methyl-p-tyrosine, significantly attenuated the facilitatory effect of indeloxazine on ACh release. When applied locally by reverse
dialysis, indeloxazine (10 and 30 μM) and the selective 5-HT reuptake inhibitor citalopram (10 μM), but not the NE reuptake
inhibitor maprotiline (30 μM), increased cortical ACh output. Indeloxazine (10 mg/kg)-induced increase in ACh release was
significantly inhibited by local application of the 5-HT4 receptor antagonists RS23597 (50 μM) and GR113803 (1 μM), while the 5-HT1A antagonist WAY-100135 (100 μM), 5-HT1A/1B/β-adrenoceptor antagonist (–)propranolol (150 μM), 5-HT2A/2C antagonist ritanserin (10 μM) and 5-HT3 antagonist ondansetron (10 μM) failed to significantly modify this effect. Neither depletion of monoamines nor treatment
with serotonergic antagonists significantly changed the basal ACh level, indicating that endogenous monoamines do not tonically
activate ACh release. These results suggest that indeloxazine-induced facilitation of ACh release in rat frontal cortex is
mediated by endogenous 5-HT and involves at least in part cortical 5-HT4 receptors.
Received: 22 May 1997 / Accepted: 26 August 1997 相似文献
17.
5-Hydroxytryptamine and interval timing behaviour 总被引:7,自引:0,他引:7
Ho MY Velázquez-Martínez DN Bradshaw CM Szabadi E 《Pharmacology, biochemistry, and behavior》2002,71(4):773-785
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. 相似文献
18.
Hughes ZA Starr KR Scott CM Newson MJ Sharp T Watson JM Hagan JJ Dawson LA 《Psychopharmacology》2007,192(1):121-133
Rationale The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors
has lead to new drug development strategies to produce agents with improved antidepressant efficacy.
Objectives We report the in vivo characterization of the novel 5-HT1A/1B autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B.
Materials and methods Ex vivo binding was used to ascertain 5-HT1A receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure
threshold were used as markers of central blockade of 5-HT1A and 5-HT1B receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs
and rats were used to evaluate the functional outcome of SB-649915-B.
Results SB-649915-B (1–10 mg/kg p.o.) produced a dose-related inhibition of 5-HT1A receptor radioligand binding and inhibited ex vivo [3H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1–10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor
activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT1A and 5-HT1B receptors, respectively. SB-649915-B (0.1–3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but
attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two-
to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs.
Conclusions Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have
therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current
selective serotonin reuptake inhibitors. 相似文献
19.
Stenfors C Magnusson T Larsson LG Yu H Hållbus M Magnusson O Ross SB 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(2):110-116
The effects on 5-HT turnover (5-HIAA/5-HT ratio) and extracellular 5-HT and 5-HIAA levels (in vivo microdialysis in freely
moving animals) were analysed in guinea-pig brains following the 5-HT1B receptor antagonist, GR 127935 {N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide}, or the 5-HT1A receptor antagonist, WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride), administered alone or in combination. GR 127935, injected alone,
increased 5-HT turnover with maximal effects approximately 50% above the control levels in the four brain regions examined
(hypothalamus, hippocampus, striatum and frontal cortex). GR 127935 significantly increased extracellular concentrations of
5-HT and 5-HIAA in frontal cortex (40%), whereas 5-HIAA, but not 5-HT, was elevated in striatum (20–30%). WAY-100635 did not
significantly change 5-HT turnover but caused a small significant increase in the extracellular 5-HT and 5-HIAA concentrations
in both striatum and frontal cortex. The combined treatment with GR 127935 and WAY-100635 resulted in an increased 5-HT turnover
reaching maximal effects of 70–90% above the control values in all brain regions tested and produced a significant elevation
of striatal and frontal cortex extracellular 5-HT (40% and 60%, respectively) and 5-HIAA (60% and 70%, respectively) concentrations.
The synergistic effect of the two receptor antagonists on the 5-HT turnover and the terminal release of 5-HT indicate somatodendritic
5-HT release and stimulation of inhibitory 5-HT1A receptors at this level. Extracellular 5-HIAA seems to be a better marker than 5-HT itself for the evoked 5-HT release when
the reuptake mechanism is intact.
Received: 2 September 1998 / Accepted: 19 November 1998 相似文献
20.
David B. Wainscott D. A. Sasso J. David Kursar Melvyn Baez Virginia L. Lucaites D. L. Nelson 《Naunyn-Schmiedeberg's archives of pharmacology》1997,357(1):17-24
In previous reports, [3H]5-HT has been used to characterize the pharmacology of the rat and human 5-HT2B receptors. 5-HT, the native agonist for the 5-HT2B receptor, has a limitation in its usefulness as a radioligand since it is difficult to study the agonist low-affinity state
of a G protein-coupled receptor using an agonist radioligand. When using [3H]5-HT as a radioligand, rauwolscine was determined to have relatively high affinity for the human receptor (Ki human = 14.3 ± 1.2 nM, compared to Ki rat = 35.8 ± 3.8 nM). Since no known high affinity antagonist was available as a radioligand, these studies were performed
to characterize [3H]rauwolscine as a radioligand for the cloned human 5-HT2B receptor expressed in AV12 cells. When [3H]rauwolscine was initially tested for its usefulness as a radioligand, complex competition curves were obtained. After testing
several α2-adrenergic ligands, it was determined that there was a component of [3H]rauwolscine binding in the AV12 cell that was due to the presence of an endogenous α2-adrenergic receptor. The α2-adrenergic ligand efaroxan was found to block [3H]rauwolscine binding to the α2-adrenergic receptor without significantly affecting binding to the 5-HT2B receptor and was therefore included in all subsequent studies. In saturation studies at 37° C, [3H]rauwolscine labeled a single population of binding sites, Kd = 3.75 ± 0.23 nM. In simultaneous experiments using identical tissue samples, [3H]rauwolscine labeled 783 ± 10 fmol of 5-HT2B receptors/mg of protein, as compared to 733 ± 14 fmol of 5-HT2B receptors/mg of protein for [3H]5-HT binding. At 0° C, where the conditions for [3H]5-HT binding should label mostly the agonist high affinity state of the human 5-HT2B receptor, [3H]rauwolscine (Bmax = 951 ± 136 fmol/ mg), again labeled significantly more receptors than [3H]5-HT (Bmax = 615 ± 34 fmol/mg). The affinity of [3H]rauwolscine for the human 5-HT2B receptor at 0° C did not change, Kd = 4.93 ± 1.27 nM, while that for [3H]5-HT increased greatly (Kd at 37° C = 7.76 ± 1.06 nM; Kd at 0° C = 0.0735 ± 0.0081 nM). When using [3H]rauwolscine as the radioligand, competition curves for antagonist structures modeled to a single binding site, while agonist
competition typically resulted in curves that best fit a two site binding model. In addition, many of the compounds with antagonist
structures displayed higher affinity for the 5-HT2B receptor when [3H]rauwolscine was the radioligand. Typically, ∼ 85% of [3H]rauwolscine binding was specific binding. These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. This should provide a good tool for the study of both the agonist high- and low-affinity states of the human cloned
5-HT2B receptor.
Received: 26 June 1997 / Accepted: 30 August 1997 相似文献