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1.
Effects of 8-OH-DPAT and WAY-100635 on performance on a time-constrained progressive-ratio schedule 总被引:1,自引:1,他引:0
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-HT1A 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, δ, 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-HT1A 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 μg kg−1, four treatments at each dose) or the vehicle (0.9% saline solution). In phase 2, they received WAY-100635 (30, 100, 300 μg
kg−1) according to the same regimen. In phase 3, they received 8-OH-DPAT (100 μg kg−1) alone or in combination with WAY-100635 (30 μg kg−1). 8-OH-DPAT dose dependently increased the value of a, significant increases being seen with the 50, 100 and 200 μg kg−1 doses. The highest dose also increased δ. WAY-100635 did not significantly alter either a or δ. WAY-100635 significantly attenuated the effect of 8-OH-DPAT on both a and δ.
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-HT1A 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.
Electronic Publication 相似文献
2.
Newman-Tancredi A Rivet JM Cussac D Touzard M Chaput C Marini L Millan MJ 《Naunyn-Schmiedeberg's archives of pharmacology》2003,368(3):188-199
This study employed [35S]guanosine 5-O-(3-thiotriphosphate) ([35S]GTPS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT1A receptors with those of reference agonists at postsynaptic 5-HT1A receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, Emax, values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC50) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT1A receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100,635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT1A receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [35S]GTPS binding, consistent with partial agonist properties. In [35S]GTPS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT1A receptors, was more potent in the septum (pEC50~6.5) than in the dentate gyrus of the hippocampus (pEC50~5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 µM) did not enhance [35S]GTPS labelling in any structure, S16924 (10 µM) modestly increased [35S]GTPS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 µM)-stimulated [35S]GTPS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G protein activation at postsynaptic 5-HT1A receptors in the hippocampus. These data support a role of postsynaptic 5-HT1A receptors in the functional profiles of certain antipsychotic agents. 相似文献
3.
Reimold M Solbach C Noda S Schaefer JE Bartels M Beneke M Machulla HJ Bares R Glaser T Wormstall H 《Psychopharmacology》2007,190(2):241-249
Rationale Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine
D2, D1 and 5-HT2A receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative
symptomatology, which was implicated with flupentixol’s interaction with 5-HT2A and/or D1 receptors.
Objectives To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 ± 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 ± 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 ± 5.5 mg/day).
Materials and methods Each patient underwent two PET scans with 3-N-[11C]methylspiperone (target: frontal 5-HT2A), [11C]SCH23390 (striatal D1) or [11C]raclopride (striatal D2). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls.
Results D2-RO under FLX was between 50% and 70%, indicating an ED50 of about 0.7 ng/ml serum. 5-HT2A and D1-RO was 20 ± 10% and 20 ± 5% (mean, SEM). Under HAL, D1-RO was 14 ± 6% and under RIS not significantly different from zero.
Conclusions We were able to demonstrate a moderate 5-HT2A and D1 occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below
saturation. Therefore, if flupentixol’s efficacy on negative symptoms is based on its interaction with 5-HT2A and/or D1 receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest
that mechanisms other than D1 or 5-HT2A antagonism may contribute to flupentixol’s efficacy on negative symptoms. 相似文献
4.
Body S Asgari K Rickard JF Zhang Z Fone KC Bradshaw CM Szabadi E 《Psychopharmacology》2005,181(2):289-298
Rationale Temporal differentiation refers to animals’ ability to regulate their behaviour during an ongoing interval. Striatal dopaminergic
mechanisms are purported to be involved in temporal differentiation, and recent evidence also implicates 5-hydroxytryptaminergic
(5-HTergic) mechanisms, possibly mediated by 5-HT2A receptors. There is evidence that 5-HT3 receptors contribute to the regulation of dopamine release in the basal ganglia; however, it is not known whether 5-HT3 receptor stimulation can influence temporal differentiation.
Objective We examined the effects of a selective 5-HT3 receptor agonist m-CPBG, a mixed 5-HT2A/3 receptor agonist quipazine, and selective 5-HT3 and 5-HT2A receptor antagonists (MDL-72222 and ketanserin, respectively) on temporal differentiation in a free-operant psychophysical
procedure.
Methods Twenty-four rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose
reinforcement (0.6 M, 50 μl) 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)], and quantitative indices of timing performance [T
50 (value of t corresponding to %B=50), Weber fraction, and mean time of switching from A to B, S
50] were derived.
Results Quipazine (0.5, 1, and 2 mg kg−1) altered timing performance, dose-dependently reducing T
50 and S
50; m-CPBG (2.5, 5, and 10 mg kg−1) had no significant effect. The effect of quipazine was antagonized by ketanserin (2 mg kg−1), but not by MDL-72222 (1 mg kg−1).
Conclusions The present results provide no evidence for the involvement of 5-HT3 receptors in temporal differentiation and indicate that the effect of quipazine on performance was mediated by 5-HT2A receptor stimulation. The results are consistent with previous evidence for the involvement of 5-HT2A receptors in interval timing behaviour.
Jonathan Francis Rickard (1977–2003), a gifted and dedicated PhD student, made a major contribution to this work. 相似文献
5.
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: |
6.
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
7.
McDonald LM Moran PM Vythelingum GN Joseph MH Stephenson JD Gray JA 《Psychopharmacology》2003,169(3-4):321-331
Rationale.
Clozapine-like atypical antipsychotic drugs, such as olanzapine, risperidone and sertindole, bind most strongly to 5-HT2A receptors, which may contribute to their antipsychotic effects. Antipsychotic drugs, such as clozapine and haloperidol, have
been found to enhance latent inhibition (LI) in humans and rats. LI is a process of learning to ignore irrelevant stimuli
that is disrupted in acute, positive-symptom schizophrenia, and can be modelled in animals.
Objectives.
The aim of this study was to determine the effects of two selective 5-HT2A receptor antagonists, SR 46,349B and ICI 169,369, on LI, as a test of their antipsychotic potential.
Methods.
Doses of the 5-HT2A receptor antagonists that were sufficient for receptor blockade were determined in 5-HT behavioural syndrome tests. SR 46,349B
and ICI 169,369 were then tested for enhancement of LI and reversal of amphetamine-induced attenuation of LI in a conditioned
suppression paradigm.
Results.
SR 46,349B (0.6–2.4 mg kg–1 i.p.) and ICI 169,369 (10–40 mg kg–1 i.p.) antagonised 5-hydroxytryptophan (5-HTP)-induced head twitches and wet dog shakes, which are mediated by 5-HT2A receptors, but had no effect on mCPP-induced hypolocomotion, which is mediated by 5-HT2C receptors. Neither SR 46,349B (1.2 mg kg–1 i.p.) nor ICI 169,369 (40 mg kg–1 i.p) affected 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced forepaw treading, suggesting that they were not in vivo 5-HT1A receptor antagonists. SR 46,349B (2.4 mg kg–1 i.p.) and ICI 169,369 (40 mg kg–1 i.p.) enhanced LI when given at both the pre-exposure and conditioning stages of the paradigm, but not when given at either
pre-exposure or conditioning only. Both drugs also reversed the disruption of LI induced by D-amphetamine (1 mg kg–1 i.p.).
Conclusions.
The profile of SR 46,349B and ICI 169,369 in LI differs from that of clozapine and haloperidol in LI, which both enhance LI
when given only at the conditioning stage of the paradigm. 相似文献
8.
Harvey MT Smith RL May ME Caruso M Roberts C Patterson TG Valdovinos M Kennedy CH 《Psychopharmacology》2004,176(2):123-128
Rationale REM sleep deprivation (REMSD) has been shown to increase rates of free-operant avoidance responding. Depletion of 5-hydroxytryptamine (5-HT, serotonin) levels produces similar effects on responding.Objective We studied whether the pharmacological activation of the 5-HT1A receptor would produce effects on avoidance responding similar to REMSD and depleted 5-HT levels.Methods Rats were trained to lever press on a free-operant avoidance task. Dose-effect functions were established for 8-OH-DPAT (a 5-HT1A receptor agonist) (0.1–1.0 mg/kg) and WAY 100635 (a 5-HT1A receptor antagonist) (0.1–1.0 mg/kg). Rats were then exposed to REMSD (48 h) or equivalent control conditions, and then administered 8-OH-DPAT (0.6 mg/kg) and/or WAY 100635 (0.025–0.1 mg/kg).Results Injections of 8-OH-DPAT increased rates of avoidance responding in a dose-dependent manner, while WAY 100635 did not alter responding. The effect of 8-OH-DPAT was antagonized by pre-injection of WAY 100635. REMSD and injections of 8-OH-DPAT increased rates of avoidance responding and the effects of both manipulations were reversed by pre-injection of WAY 100635.Conclusions Activation of the 5-HT1A receptor may be a mechanism by which REMSD increases rates of free-operant avoidance responding. 相似文献
9.
- We have examined the effects of the systemic administration of the selective 5-HT1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated differentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus).
- Alnespirone (0.1–3 mg kg−1, s.c.) dose-dependently reduced extracellular 5-HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5-HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT1A antagonist WAY-100635 (0.5 mg kg−1, s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3 mg kg−1, s.c.) in frontal cortex.
- 8-OH-DPAT (0.025, 0.1 and 0.3 mg kg−1, s.c.) also reduced extracellular 5-HT in a regionally-selective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1 mg kg−1, s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nucleus at all doses examined.
- Doses of both compounds close to their respective ED50 values (0.3 mg kg−1 alnespirone, 0.025 mg kg−1 8-OH-DPAT) reduced 5-HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8-OH-DPAT.
- These data show that the reduction of 5-HT release elicited by alnespirone and 8-OH-DPAT is more important in forebrain areas innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by differences in the sensitivity of 5-HT1A autoreceptors controlling 5-HT release, given the dissimilar effects of these two 5-HT1A agonists in regions rich in cell bodies and nerve terminals. This suggests the presence of complex mechanisms of control of 5-HT release by 5-HT1A receptors.
10.
J. E. Barrett S. M. Hoffmann S. N. Olmstead M. J. Foust C. Harrod B. A. Weissman 《Psychopharmacology》1989,97(3):319-325
The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock (conflict procedure). Under the multiple schedule, spiroxatrine (0.3–1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01–1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component. 相似文献
11.
Jeltsch H Bertrand F Galani R Lazarus C Schimchowitsch S Cassel JC 《Psychopharmacology》2004,175(1):37-46
Rationale In rats, 5-HT1A receptors are present in the septal region, e.g. on cholinergic neurons of the medial septum, where they might be a substrate for cognitively relevant interactions between cholinergic and serotonergic systems.Objective The present experiment assessed the effects of the stimulation of septal 5-HT1A receptors on spatial working memory.Methods Stimulation of septal 5-HT1A receptors was carried out by infusions targetting the medial septum of the 5-HT1A/5-HT7 receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT; 0.5 or 4 µg). Spatial memory was assessed in a water maze using a protocol placing emphasis on spatial working memory. The location of the hidden platform was changed every day and performance was assessed on two consecutive trials each day.Results In comparison to vehicle injections, the intraseptal infusion of 4 µg 8-OH-DPAT impaired performance significantly: rats treated with 8-OH-DPAT exhibited increased distances to reach the hidden platform on both trials 1 and 2. Rats infused with 0.5 µg showed similar changes that failed to be significant. Such effects were not observed when the platform was visible.Conclusions These results extend those of a previous experiment which showed that intraseptal injections of 8-OH-DPAT impaired spatial reference memory. Based on the characteristics of the observed deficits, it is suggested that the 8-OH-DPAT-induced impairment, rather than being only the result of a true alteration of working memory, might reflect a more global cognitive deficiency in which alteration of general memory capacities may be biased by disrupted search strategies/exploration and/or dysfunctions of attention.H. Jeltsch and F. Bertrand contributed equally to the work. 相似文献
12.
Abstract
Rationale. Selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitors (SSRIs) such as fluoxetine produce a gradual desensitization
of hypothalamic post-synaptic 5-HT1A receptor systems. It is assumed that the effects of SSRIs on post-synaptic 5-HT1A receptors are mediated by 5-HT reuptake inhibition, leading to an increase of 5-HT in the synapse. However, there is no direct
evidence to support this hypothesis.
Objectives. The present study determined whether 5-HT1A receptor desensitization was mediated by fluoxetine's effects on serotonergic nerve terminals.
Methods. Serotonergic nerve terminals were destroyed by intracerebroventricular (i.c.v.) injection of the serotonin neurotoxin 5,7-dihydroxytryptamine
(5,7-DHT) combined with injection of the norepinephrine/dopamine reuptake inhibitor nomifensine. 5,7-DHT-induced loss of serotonergic
terminals was confirmed by a 95% reduction in the density of [3H]paroxetine-labeled 5-HT transporters in the hypothalamus and a 97% reduction in the levels of 5-HT and 5-hydroxyindoleacetic
acid in the cortex. Two weeks after the 5,7-DHT injections, rats were injected daily with fluoxetine (5 mg/kg or 10 mg/kg,
i.p.) or saline for 14 days.
Results. Injections of 10 mg/kg fluoxetine produced a significant decrease in body weight gain. Destruction of serotonergic nerve
terminals reduced body weight and potentiated the ability of fluoxetine to further inhibit body weight gain. Increases in
plasma levels of adrenal corticotrophic hormone (ACTH, corticotropin), corticosterone, and oxytocin after injection of the
5-HT1A agonist 8-hydroxy-2-dipropylaminotetralin [(±)8-OH-DPAT] were used as peripheral markers of 5-HT1A receptor function in the hypothalamus. In vehicle-pretreated rats, fluoxetine produced a dose-dependent reduction in the
(±)8-OH-DPAT-induced increase in plasma ACTH and oxytocin levels. Destruction of serotonergic nerve terminals blocked the
ability of fluoxetine to produce a desensitization in the ACTH, corticosterone, and oxytocin responses to (±)8-OH-DPAT.
Conclusions. The ability of fluoxetine to induce a desensitization of hypothalamic post-synaptic 5-HT1A receptor systems is dependent on the integrity of serotonergic nerve terminals in the hypothalamus, while its effect on body
weight is not mediated by serotonergic nerve terminals in the hypothalamus.
Electronic Publication 相似文献
13.
Enguix MJ Sánchez L Villazón M Brea J Tristán H Caruncho HJ Cadavid MI Loza MI 《Naunyn-Schmiedeberg's archives of pharmacology》2003,368(2):79-90
Most studies of 5-HT2 receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT2A and 5-HT2C receptors); very few in vitro studies have addressed the peripheral receptors 5-HT2A and 5-HT2B. The aim of this investigation was to compare the possible short- and long-term processes regulating these peripheral receptors in the rat.The in vitro contractile response elicited by serotonin (5-HT, 10 µM) in the rat gastric fundus (5-HT2B receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT2A receptor system), which was more stable, slower and sustained. To characterize drug-receptor interactions, cumulative concentration/response curves (CCRCs) for 5-HT were constructed ex vivo for rat tissues treated with drugs acting at these receptors. Rats were examined 4 or 24 h after a single, i.p. administration of (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI, 1 or 2.5 mg/kg], clozapine, cyproheptadine or rauwolscine (10 mg/kg), 48 h after a single i.p. administration of (±)DOI (2.5 mg/kg), clozapine or cyproheptadine (10 mg/kg) or 24 h after the last of with 15 daily i.p. administrations of (±)DOI (1 or 2.5 mg/kg), clozapine, cyproheptadine or rauwolscine (10 mg/kg). In the aorta, Emax (the maximum response elicited by 5-HT) was unchanged 4 h after a single dose of any of the drugs tested. However, 24 h after a single dose, Emax was lower in animals treated with (±)DOI (2.5 mg/kg), clozapine or cyproheptadine than in controls, whilst 48 h after a single dose of (±)DOI (2.5 mg/kg), clozapine or cyproheptadine there was no difference in Emax between experimental and control animals. After chronic treatment with (±)DOI (2.5 mg/kg), clozapine and cyproheptadine, Emax was lower than in controls. In the gastric fundus, Emax 4 h after a single dose of each drug was lower than in controls, and the response recovered by 24 or 48 h. Following chronic treatment, Emax was significantly lower than in controls for each drug used.These findings suggest first, that regulation of peripheral 5-HT2 receptors (5-HT2A and 5-HT2B) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT2 receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT2B receptors in rat gastric fundus are more sensitive to drug-induced regulation than the 5-HT2A rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer. 相似文献
14.
Rationale Dopamine (DA) and glutamate (Glu) interactions in the mesocorticolimbic pathway may regulate motivation and reward and contribute
to schizophrenia and drug abuse. We have recently demonstrated synergistic effects of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA)/kainate receptor blockade and D2/3 DA receptor stimulation in brain stimulation reward (BSR).
Objectives This study was conducted to explore interactions between DA and Glu systems in BSR using the NMDA receptor antagonist MK-801
and the DA receptor agonists 7-OH-DPAT and apomorphine.
Methods Systemic effects of these compounds were measured in male Sprague–Dawley rats using rate–frequency threshold analysis of ventral
tegmental area (VTA) BSR (n=27). Effects of bilateral applications of MK-801 and 7-OH-DPAT into the nucleus accumbens (NAS) shell subregion were also
investigated (n=10).
Results MK-801 (0.03 or 0.13 mg kg−1 i.p. or 0.66 μg intra-NAS) reduced reward thresholds while 7-OH-DPAT (0.03 mg kg−1 s.c. or 5.0 μg intra-NAS) or apomorphine (0.05 mg kg−1, s.c.) increased this measure. MK-801 combined with apomorphine or with 7-OH-DPAT, systemically or in the NAS shell, induced
additive effects.
Conclusions Lack of interaction between DA agonists and MK-801 in this study contrasts with our previous work showing synergistic reward-decreased
effects of AMPA/kainate receptor blockade and D2/3 DA receptor stimulation in the NAS shell, and indicates possible independence of DA and N-methyl-d-aspartate (NMDA) receptor effects in VTA electrical self-stimulation. 相似文献
15.
Blessing WW 《Psychopharmacology》2005,181(3):518-528
Rationale Clozapine inhibits sympathetic outflow to the cutaneous vascular bed. Clozapine reverses hyperthermia and cutaneous vasoconstriction
induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) or by lipopolysaccharide (LPS). Clozapine also reverses cutaneous
vasoconstriction elicited by exposure to cold. These actions distinguish clozapine from haloperidol. Clozapine could also
inhibit sympathetic cutaneous vasomotor alerting responses (SCVARs), vasoconstrictor episodes that reflect emotional/psychological
function, and this property might also distinguish clozapine from haloperidol.
Objectives Experiments in rats determined whether clozapine and haloperidol inhibit SCVARs, and whether SR46349B (a 5HT2A receptor antagonist), 8-OH-DPAT (a 5-HT1A agonist), L741,626 (a dopamine D2 antagonist) or SCH23390 (a dopamine D1 antagonist) have clozapine-like effects on SCVARs.
Methods Mean level and pulse amplitude of the tail artery Doppler flow signal were recorded in conscious freely moving rats before
and after alerting stimuli (e.g. tapping the cage), and expressed as a SCVAR index (fall to zero flow implies SCVAR index
of 100%, no fall implies 0%).
Results Clozapine (0.0625–1.0 mg/kg, s.c.) dose-dependently increased resting tail blood flow. After 1 mg/kg, the SCVAR index was
18±1%, compared with 83±2% after vehicle. SR46349B (0.01–1.0 mg/kg) and 8-OH-DPAT (0.25 mg/kg) had similar but less potent
effects on cutaneous blood flow and on SCVARs. Haloperidol (0.005–0.5 mg/kg) and L741,626 (1 mg/kg) had no or little effect
on these variables. SCH23390 mildly inhibited SCVARs.
Conclusions Clozapine, but not haloperidol, increases resting cutaneous blood flow and decreases SCVARs. Antagonism at 5-HT2A receptors and agonism at 5-HT1A receptors could contribute to these actions. 相似文献
16.
F. Chaouloff V. Baudrie D. Laude 《Naunyn-Schmiedeberg's archives of pharmacology》1990,341(4):381-384
Summary 8-Hydroxy-2-(di-n-propylamino)tetralin (8OH-DPAT) is a 5-HT1A receptor-selective agonist that has recently been reported to trigger adrenal catecholamine release and hyperglycemia. The aim of this study was to analyze in the conscious rat whether the 5-HT1A receptor subtype is involved in these effects.8-OH-DPAT (0.1–1 mg/kg, i.v.) evoked dose-dependent increases in plasma adrenaline and glucose concentrations. Increases in plasma adrenaline levels peaked 5 min after administration of 8-OH-DPAT; in contrast, plasma glucose levels rose throughout the 20 min period of analysis. Prior administration of (–)pindolol, a beta-adrenoceptor antagonist that blocks 5-HT1A receptors, markedly diminished the rise in plasma adrenaline levels and abolished the hyperglycemia triggered by 8-OHD-PAT. On the other hand, neither the selective beta 1-adrenoceptor antagonist, betaxolol, the selective beta 2-adrenoceptor antagonist, ICI 118.551, nor the 5-HT2 receptor antagonist, ketanserin, affected 8-OH-DPAT-induced increases in plasma adrenaline levels. In addition, except for ICI 118.551 pretreatment, which delayed the hyperglycemic effect of 8-OH-DPAT, none of these antagonists affected the rise in glycaemia evoked by 8-OHD-PAT.The data suggest that the adrenaline-releasing and a major part of the hyperglycemic effects of 8-OH-DPAT are mediated by activation of 5-HT1A receptors.
Send offprint requests to F. Chaouloff at the above address 相似文献
17.
Homberg JR De Boer SF Raasø HS Olivier JD Verheul M Ronken E Cools AR Ellenbroek BA Schoffelmeer AN Vanderschuren LJ De Vries TJ Cuppen E 《Psychopharmacology》2008,200(3):367-380
Rationale While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission,
the role of serotonin is not fully understood.
Objectives To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT−/−) rat and the involvement of compensatory changes in 5-HT1A receptor function are the objectives of the study.
Materials and methods The SERT−/− rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine
self-administration. In addition, the function and expression of 5-HT1A receptors was assessed using telemetry and autoradiography, respectively, and the effect of 5-HT1A receptor ligands on cocaine’s psychomotor effects were studied.
Results Cocaine-induced hyperactivity and conditioned place preference, as well as intravenous cocaine self-administration were enhanced
in SERT−/− rats. Furthermore, SERT−/− rats displayed a reduced hypothermic response to the 5-HT1A receptor agonist 8-OHDPAT. S-15535, a selective somatodendritic 5-HT1A receptor agonist, reduced stress-induced hyperthermia (SIH) in wild-type controls (SERT+/+), while it increased SIH in SERT−/− rats. As 5-HT1A receptor binding was reduced in selective brain regions, these thermal responses may be indicative for desensitized 5-HT1A receptors. We further found that both 8-OHDPAT and S-15535 pretreatment increased low-dose cocaine-induced locomotor activity
in SERT−/− rats, but not SERT+/+ rats. At a high cocaine dose, only SERT+/+ animals responded to 8-OHDPAT and S-15535.
Conclusion These data indicate that SERT−/−-associated 5-HT1A receptor adaptations facilitate low-dose cocaine effects and attenuate high-dose cocaine effects in cocaine supersensitive
animals. The role of postsynaptic and somatodendritic 5-HT1A receptors is discussed. 相似文献
18.
McClure EB Adler A Monk CS Cameron J Smith S Nelson EE Leibenluft E Ernst M Pine DS 《Psychopharmacology》2007,191(1):97-105
Rationale Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is an atypical centrally acting analgesic agent with weak opioid
receptor affinity that, like some antidepressants, enhances the extraneuronal concentrations of the monoamine neurotransmitters,
noradrenaline and serotonin, by interfering with their re-uptake and release mechanisms.
Objectives The present study was undertaken to evaluate the potential role of 5-HT1A receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either
a selective 5-HT1A receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT1A receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochloride dihydrate) was investigated
in combination with tramadol by means of the cold-plate test in the chronic constriction injury model in rats.
Results The results showed that WAY-100635 (0.8 mg/kg) significantly enhanced the antiallodynic effect of non-effective doses of tramadol
(5–10 mg/kg). In contrast, 8-OH-DPAT (0.5 mg/kg) counteracted the antiallodynic effect of an effective dose of tramadol (22 mg/kg).
Naloxone (0.5 mg/kg) partially counteracted the antiallodynic effect of tramadol (22 mg/kg).
Conclusions These findings suggest the involvement of opioid and 5-HT1A receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds
having 5-HT1A antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain. 相似文献
19.
P. J. Pauwels Delphine S. Dupuis Michel Perez Serge Halazy 《Naunyn-Schmiedeberg's archives of pharmacology》1998,358(4):404-410
[35S]GTPγS binding responses can be used to measure differences between the intrinsic activity of ligands at human 5-hydroxytrypamine-1A (h 5-HT1A) receptors expressed in recombinant cell lines. The maximal [35S]GTPγS binding response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was lower than that to 5-HT in a recombinant C6-glial membrane preparation and dependent
on the GDP concentration: it was attenuated by about 60% vs 5-HT by increasing the concentration of GDP from 0.3 to 30 and
300 μM. Whereas dimerization of 8-OH-DPAT almost did not affect its potency at h 5-HT1A receptors (pEC50: 7.45 and 7.40 for 8-OH-DPAT and its dimer at 30 μM GDP), it increased efficacy at h 5-HT1A receptors. The maximal response to the 8-OH-DPAT dimer was systematically greater than the response to 8-OH-DPAT and identical
to that to 5-HT; moreover in contrast to the 8-OH-DPAT monomer, the maximal response to the dimer was unaffected by increasing
the GDP concentration. An enhanced [35S]GTPγS binding response (44 to 63% vs 8-OH-DPAT) was also observed in the hippocampus, lateral septum, dorsal raphe and cingulate
cortex of guinea-pig brain sections using autoradiography of 5-HT1A receptor-activated G-proteins. Hence, the 8-OH-DPAT dimer shows increased efficacy at 5-HT1A receptors compared to 8-OH-DPAT. The differential regulation of the maximal agonist responses by GDP suggests that the [35S]GTPγS binding responses to these two ligands could be mediated by different G-protein subtypes upon activation of the 5-HT1A receptor.
Received: 23 June 1998 / Accepted: 29 July 1998 相似文献
20.
Sánchez-López A Centurión D Vázquez E Arulmani U Saxena PR Villalón CM 《Naunyn-Schmiedeberg's archives of pharmacology》2004,369(2):220-227
Serotonin (5-hydroxytryptamine; 5-HT) is capable of inhibiting the tachycardic responses elicited by sympathetic stimulation, but not by exogenous noradrenaline, in pithed rats pre-treated with desipramine. More recently, it has been shown that this cardiac sympatho-inhibitory response to 5-HT, mediated by prejunctional 5-HT1 receptors as well as putative 5-ht5A/5B receptors, is mimicked dose-dependently by the agonists CP 93,129 (r5-HT1B), sumatriptan (5-HT1B/1D) and PNU-142633 (5-HT1D). This study analysed further the pharmacological profile of the above 5-HT1 receptors.Continuous i.v. infusions of CP 93,129, sumatriptan or PNU-142633 (30 µg kg–1min–1 each) failed to modify the tachycardic responses to exogenous noradrenaline but inhibited those elicited by preganglionic (C7–T1) stimulation of the cardiac sympathetic outflow. These sympatho-inhibitory responses were unaltered after i.v. administration of physiological saline (1 ml kg–1) or the 5-HT1A receptor antagonist WAY 100635 (10 µg kg–1). In contrast, the antagonist GR 127935 (5-HT1B/1D; 100 µg kg–1, i.v.) abolished the responses to CP 93,129, sumatriptan and PNU-142633, whilst SB224289 (5-HT1B; 300 µg kg–1, i.v.) abolished the responses to CP 93,129 without affecting those to sumatriptan and PNU-142633. Interestingly, BRL15572 (5-HT1D; 300 µg kg–1, i.v.) abolished the responses to PNU-142633 and attenuated those to sumatriptan, but not those to CP 93,129.WAY 100635, GR 127935, SB224289 and BRL15572, given alone at the above doses, failed to modify the sympathetically induced tachycardic responses. The 5-HT1 receptors producing cardiac sympatho-inhibition in pithed rats thus display the pharmacological profile of the 5-HT1B and 5-HT1D receptor subtypes. 相似文献