共查询到20条相似文献,搜索用时 62 毫秒
1.
Serotonin autoreceptor in rat hippocampus: Pharmacological characterization as a subtype of the 5-HT1 receptor 总被引:3,自引:0,他引:3
G. Maura E. Roccatagliata M. Raiteri 《Naunyn-Schmiedeberg's archives of pharmacology》1986,334(4):323-326
Summary The 5-hydroxytryptamine (5-HT) autoreceptors mediating inhibition of [3H]5-HT release in rat hippocampus have been characterized pharmacologically in terms of 5-HT receptor subtype by using superfused synaptosomes depolarized with 15 mM KCl. Exogenous 5-HT inhibited in a concentration-dependent way (pEC30=8.74) the K+-evoked release of [3H]5-HT. Methiothepin shifted the concentration-response curve of 5-HT to the right (pA2=8.62). The 5-HT2 receptor antagonists, ketanserin, methysergide or spiperone were ineffective against 5-HT. The 5-HT1 receptor agonist, 5-methoxy-3-[1,2,3,6-tetra-hydropyridin-4-yl]-1H-indole (RU 24969) mimicked 5-HT and was equipotent as an inhibitor of the release of [3H]5-HT. In contrast, the putative 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was almost ineffective at 1 M. Finally, (–)propranolol, used as a non-selective 5-HT1A/5-HT1B receptor antagonist, shifted to the right (pA2=7.91) the concentration-response curve of 5-HT whereas the 5-HT1C receptor antagonist mesulergine was ineffective. In conclusion, 5-HT nerve terminals of rat hippocampus possess autoreceptors which appear to belong to the 5-HT1B subtype. 相似文献
2.
Guido Maura Alessandra Barzizza Susanna Folghera Maurizio Raiteri 《Naunyn-Schmiedeberg's archives of pharmacology》1991,343(3):229-236
Summary The effects of 5-hydroxytryptamine (5-HT) and of a number of 5-HT receptor agonists and antagonists on the release of endogenous aspartate were investigated in rat cerebellum slices and synaptosomes depolarized with high K+. The release of endogenous aspartate evoked from slices by 35 mmol/l KCl and from synaptosomes by 15 mmol/1 KCl was strongly (about 90%) calcium-dependent. In slices the release of aspartate was inhibited by exogenous 5-HT (0.1–100 nmol/1) in a concentration-dependent manner. The indoleamine was very potent, producing 30% inhibition at 0.1 nmol/l. The effect of 10 nmol/1 5-HT was partly but maximally counteracted by ketanserin (300–1000 nmol/1), a 5-HT2 receptor antagonist, but fully blocked by 300 nmol/1 of the mixed 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibited the K+-evoked release of endogenous aspartate in a concentration-dependent manner. The effect of 8-OH-DPAT was antagonized by methiothepin, but not by ketanserin which fully antagonized the inhibition produced by DOI. In cerebellar synaptosomes the release of endogenous aspartate evoked by 15 mmol/l K+ was inhibited by exogenous 5-HT and by 8-OH-DPAT, but not by DOI. Methiothepin (100–300 nmol/1) antagonized the inhibitory effects of 100 nmol/l 5-HT or 8-OH-DPAT. However, 1000 nmol/l of various 5-HT receptor antagonists [ketanserin, methysergide, (–)-propranolol, spiperone or ICS 205–930] did not counteract the effect of 100 nmol/15-HT.It is concluded that: (1) 5-HT projections to the rat cerebellum may exert a potent inhibitory action on the depolarization-evoked release of aspartate; (2) this inhi bition is mediated through receptors of both the 5-HT1 and the 5-HT2 type; (3) the 5-HT2 receptors appear to be sited on structures which do not survive the standard preparation of synaptosomes, while the 5-HT1 receptors are likely to be localized on Apartate-releasing nerve terminals; and (4) the 5-HT1 receptors do not conform to the pharmacological criteria defining the known subtypes of the 5-HT1-binding sites. 相似文献
3.
Rudolf Markstein Machiko Matsumoto Christian Kohler Hiroko Togashi Mitsuhiro Yoshioka Daniel Hoyer 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(6):454-459
The pharmacological properties of 5-hydroxytryptamine (5-HT) receptors positively coupled to adenylyl cyclase in the rat hippocampus
were investigated using selective agonists and antagonists. 5-HT (0.008–125 μM) stimulated cyclic AMP formation in homogenates
of rat hippocampus in a concentration-dependent manner. The maximal increase in cyclic AMP formation occurred at 1 μM (141
± 6%) and the half-maximal effect (EC50) at 50 ± 22 nM. Cyclic AMP accumulation induced by 1 μM 5-HT was partly inhibited by the selective 5-HT1A receptor antagonist WAY 100,635 (1 μM), the selective 5-HT4 receptor antagonist SB 203,186 (1 μM), and the 5-HT2A/C/ 5-HT7 receptor antagonist mesulergine (25 μM). WAY 100,635, SB 203,186 and mesulergine inhibited the effect of 5-HT (1 μM) by 47%,
33% and 49%, respectively. The combination of WAY 100,635 (1 μM) with SB 203,186 (1 μM) or mesulergine (25 μM) resulted in
stronger inhibition than with each antagonist alone, and the combination of all three antagonists produced almost total blockade
(95%) of 5-HT-induced cyclic AMP accumulation. 5-Carboxamidotryptamine (5-CT; 0.008–125 μM), a 5-HT1/5-HT7 receptor agonist, and SDZ 216–454 (0.008– 125 μM), a selective 5-HT4 receptor agonist, concentration-dependently stimulated cyclic AMP formation, but the maximal effect of each agonist was smaller
than that of 5-HT alone. SDZ 216–454 (5 μM) and 5-CT (5 μM) in combination stimulated cyclic AMP formation in an additive
manner. 8-OH-PIPAT and 8-OH-DPAT, two selective 5-HT1A agonists, produced a small but significant increase in cyclic AMP formation at concentrations above 0.04 μM and 10 μM, respectively.
These findings suggest that at least three 5-HT receptor subtypes, i.e. 5-HT1A, 5-HT7 and 5-HT4 receptors, are involved in mediating 5-HT-induced cyclic AMP formation in rat hippocampus.
Received: 28 October 1998 / Accepted: 16 March 1999 相似文献
4.
Summary Peripheral 5-HT receptor-mediated responses were examined in pithed spontaneously hypertensive rats and normotensive wistar rats. Responses examined were: Pressor and depressor responses, tachycardia and inhibition of stimulation-evoked tachycardia. In pithed spontaneously hypertensive rats, 5-HT, but not the 5-HT1-selective agonist 5-carboxamidotryptamine, produced pressor responses, and these were potently antagonised by the 5-HT2-selective antagonists ketanserin and LY 53857. In pithed spontaneously hypertensive rats, the tachycardia to 5-HT was abolished by a combination of the 5-HT2 receptor antagonist LY 53857 and propranolol, suggesting that the tachycardia is mediated by 5-HT2 receptors and by release of noradrenaline. In pithed spontaneously hypertensive rats, 5-carboxamidotryptamine, 5-HT, and to a lesser extent the 5-HT1 receptor agonist RU 24969, but not the 5-HT1A receptor agonist 8-OH-DPAT, produced depressor responses which were antagonised by methysergide and metitepin, but which do not clearly fit with any of the 5-HT, ligand binding sites. In pithed normotensive wistar rat, 5-carboxamidotryptamine was approximately 100 times more potent than 5-HT and 8-OH-DPAT at inhibiting the cardio-acceleration produced by single pulse electrical stimulation and this inhibition was antagonised by metitepin, so that the response is mediated by 5-HT1 receptors. 相似文献
5.
前期研究表明粉防己碱增强戊巴比妥钠诱导的催眠作用与5-HT系统相关。本研究采用戊巴比妥钠(45 mg/kg,i.p.)诱导的小鼠翻正反射消失和恢复实验方法,对粉防己碱与不同5-HT受体在增强戊巴比妥钠诱导睡眠中的相互作用进行了探讨。结果表明粉防己碱分别与选择性5-HT1A受体拈抗剂p-MPPI(1 mg/kg,i.p.),选择性5-HT2A/2C受体拮抗剂ketanserin(1.5 mg/kg,i.p.)合用可以显著增强戊巴比妥钠诱导的催眠作用。选择性5-HT1A受体激动剂8-OH-DPAT(0.1 mg/kg,s.c.)或5-HT2A/2C受体激动剂DOI(0.2mg/kg,i.p.)能够显著减少戊巴比妥钠诱导的小鼠睡眠时间,而粉防己碱(60 mg/kg,i.g.)可以显著拮抗这种睡眠抑制作用。此结果提示,粉防己碱增强戊巴比妥钠诱导的催眠作用可能与5-HT1A受体和5-HT2A/2C受体有关。 相似文献
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.
We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization
(USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1B/1D, 5-HT2A, 5-HT3 or 5-HT4 receptors. The SSRIs, paroxetine (ED50 in mg/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (>30), dose dependently reduced shock-induced USV.
The effects of paroxetine (3.0 mg/kg, IP) were not blocked by the selective 5-HT1A receptor antagonist, WAY-100635 (3.0 mg/kg, IP), the 5-HT1B/1D receptor antagonist, GR 127935 (30 mg/kg, IP), the nonselective 5-HT2A receptor antagonists, ritanserin (3.0 mg/kg, IP) and ketanserin (1.0 mg/kg, IP), the 5-HT3 receptor antagonist, ondansetron (0.1 mg/kg, IP), or the 5-HT4 receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the selective 5-HT2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IP), completely prevented the paroxetine-induced reduction of USV. Under similar
conditions, WAY-100635 blocked the anxiolytic-like effects of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(±)-8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg, IP], and ritanserin, ketanserin, and MDL 100,907 blocked the anxiolytic-like effects of
the mixed 5-HT2A/2C receptor agonist, DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 3.0 mg/kg, IP]. WAY-100635 (1.0 mg/kg, IP) in combination
with ritanserin (3.0 mg/kg, IP), but not ondansetron (0.1 mg/kg, IP), GR 125487D (3.0 mg/ kg, SC), or GR 127935 (30 mg/kg,
IP), attenuated the USV reducing effects of paroxetine. Although the results suggest that selective stimulation of 5-HT1A and 5-HT2A receptors produces a decrease of USV, we postulate that only 5-HT2A receptors play a pivotal role in the effects of SSRIs in this model of anxiety.
Received: 19 May 1997 / Final version: 21 July 1997 相似文献
8.
It has recently been shown that the increase in external carotid blood flow (external CBF) produced by 5-hydroxytryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine, potently blocked by methiothepin and resistant to blockade by ritanserin and MDL 72222, is mediated by 5-HT1-like receptors. In the present investigation, we have further characterized these 5-HT1-like receptors. Like 5-HT, 1 min intracarotid (i.c.) infusions of the 5-HT1A receptor agonist, indorenate, produced an increase in external CBF without modifying mean arterial blood pressure or heart rate. Contrasting with indorenate, 1 min i.c. infusions of the 5-HT1A receptor agonists, 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone, or the 5-HT1A/5-HT1B receptor agonist, 5-methoxy-3-[1,2,3,6-tetrahydro-4-pyridinyl]-1-H-indol succinate (RU 24969), resulted in dose-dependent decreases in external CBF; furthermore, both the 5-HT1C/5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl-)-aminopropane (DOI) and the 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), were essentially inactive. Thus, only indorenate increased the external CBF in the dog; this effect of indorenate was not antagonized by intravenous (i.v.) administration of the 5-HT1 and 5-HT2 receptor antagonist, methiothepin, or completely abolished after sympathectomy. Unlike methiothepin, the 5-HT1A and 5-HT1B receptor antagonist, (±)-pindolol, did not block indorenate-induced external carotid vasodilatation. Together, the above results support the notion that indorenate is acting on the 5-HT1-like receptors involved in the increase in external CBF in the dog. These receptors, which are probably located on carotid sympathetic nerve endings, do not seem to correspond to either the 5-HT1A, 5-HT1B, or 5-HT1C binding sites. © 1993 Wiley-Liss, Inc. 相似文献
9.
Mature (3–4 months) and aged (18–19 months) Sprague-Dawley (SD) rats were treated with 5-HT receptor agonists and drug-induced behaviours monitored. The 5-HT2/1C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), induced wet dog shakes and back muscle contractions which were significantly increased in aged, compared to mature, rats, suggesting an age-related enhancement of 5-HT2 receptor function. In contrast, the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) induced forepaw treading, flat body posture, hypothermia and hyperactivity which were not significantly different in aged compared to mature rats. Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and frontal cortex were measured using high performance liquid chromatography with electrochemical detection. There were no age-related changes in hippocampal 5-HT or 5-HIAA. However both 5-HT and 5-HIAA were increased in the frontal cortex of aged SD rats. 8-OH-DPAT reduced 5-HIAA in both regions examined in mature rats, an effect which was attenuated in the aged rats, suggesting an age-related reduction in presynaptic 5-HT1A receptor function. DOI did not induce any changes in 5-HT or 5-HIAA in either of the regions examined. Radioligand binding studies with [3H] ketanserin showed there to be no significant age-related changes in cortical 5-HT2 receptor density or affinity. In the samples taken from mature rats GTP shifted the competition curve to DOI and reduced the proportion of high affinity agonist binding sites; this effect was not observed in the aged samples, suggesting that there may be age-related changes in G-protein-mediated receptor-effector coupling mechanisms. 相似文献
10.
Connie Snchez 《Basic & clinical pharmacology & toxicology》1995,77(1):71-78
Abstract A fully automated version of the black and white two-compartment box for mice is presented. The anxiolyticlike effects of the benzodiazepines, diazepam and chlordiazepoxide, were confirmed, and the involvement of serotonergic mechanisms was studied in this animal model of anxiety. The partial 5-HT1A receptor agonists, buspirone and ipsapirone showed anxiolytic-like effects in a limited dose interval. The full agonist hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) was inactive. The non-selective 5-HT1 receptor agonist, eltoprazine, induced marked increases of exploratory behaviour in the white compartment over a broad range of doses. Also pindolol a mixed 5-HT1A/1B and β-adrenergic receptor antagonist showed anxiolytic-like effects, whereas another compound with a similar profile (-)-, penbutolol and the β-adrenoceptor antagonist ICI 118,551, was inactive. The 5-HT2A/2C receptor antagonist, ritanserin, showed anxiogenic-like, and the 5-HT3 receptor antagonists, zacopride and ondansetron, showed anixiolytic-like effects. An overall increase of serotonergic activity by means of 5-HT uptake inhibition (citalopram), 5-HT release (fenfluramine) or administration of a 5-HT precursor (1–5-HTP) facilitated exploratory activity in the white compartment. Reduction of serotonergic activity by treatment with the 5-HT depletor p-chloro-phenylalanine methyl ester (PCPA) did not change the exploratory behaviour, but attenuated the response to fenfluramine significantly. 相似文献
11.
Stephan Hjorth Trevor Sharp Ye Liu 《Naunyn-Schmiedeberg's archives of pharmacology》1990,341(3):149-157
Summary The somatodendritic 5-HT1A autoreceptor regulating 5-HT neuronal activity is currently poorly defined pharmacologically because there are no specific antagonists, but also because potent and stereoselective agonists are scarce. Moreover, there have been few, if any, attempts to specifically investigate structure-activity relationships for agonists acting at this site. Employing brain microdialysis techniques, we have examined the effects of the enantiomers of cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (ALK-3; 0.01-0.3 mg/kg s.c.), its trans-1-methyl analogue (ALK-4; 0.3 mg/kg s.c.) and the pure enantiomers of the parent compound - 8-OH-DPAT (0.3 mg/kg s.c.) — in an attempt to address stereochemical agonist structure-activity requirements of 5-HT release-controlling 5-HT1A autoreceptors in brain. The cis-1-methylated 8-OH-DPAT analogue (+)ALK-3 was comparable to the parent compound in reducing the 5-HT output from rat ventral hippocampus. In comparison, both (–)ALK-3 and the racemic rans-diastereomer to ALK-3, ALK-4, were inactive, while the two stereoisomers of 8-OH-DPAT strongly reduced 5-HT release. Pretreatment with (–)pindolol (8 mg/kg s.c.), which has high affinity for 5-HT1A radioligand binding sites, blocked the reduction of hippocampal 5-HT release induced by a submaximally effective dose of (+)ALK-3. The direct intrahippocampal administration of (+)ALK3 (10 M) via the perfusion medium did not affect 5-HT output.In summary, the data indicate that (+)ALK-3, like 8-OH-DPAT, is a very potent 5-HT receptor agonist which inhibits terminal 5-HT release in rat hippocampus, probably via activation of somatodendritic 5-HT1A autoreceptors. However, unlike 8-OH-DPAT, (+)ALK-3 is highly stereoselective and may therefore represent a useful probe in the further characterization of 5-HT1A receptor-mediated mechanisms and function. The present study defines some of the stereochemical requirements for 5-HT1A receptor interaction, emphasizing the importance of the receptor region complementary to the C1 and C2 carbons of the 8-OH-DPAT molecule. These findings contribute to the establishment of structure-activity relationships for the cell body 5-HT1A autoreceptors and might be of value in resolving structural features that determine agonist/antagonist activity at central 5-HT1A receptors. Finally, in conjunction with our recent finding that (+)ALK-3 is a partial agonist at postsynaptic 5HT1A receptors, the present study extends previous observations suggesting that pre- and postsynaptic 5-HT1A receptor populations differ in their characteristics.
Send offprint requests to S. Hjorth at the above address 相似文献
12.
Rationale. Repeated withdrawals from chronic forced ethanol exposure sensitize animals to withdrawal-induced deficits in social interaction
behavior. The deficits in social interaction behavior following withdrawal from continuous ethanol exposure can be reduced
following acute treatments with 5-HT2C antagonists or 5-HT1A agonists.
Objectives. The present study investigated whether prior treatment with these serotonergic agents during early withdrawals in rats subjected
to repeated withdrawals from ethanol exposure would ameliorate the social interaction deficits observed following the final
withdrawal.
Methods. Sprague-Dawley rats were exposed to three cycles of 5 days forced ethanol (7%, w/v), with 2 days of control diet after the
first and second cycles. Drugs were administered IP 4 h after removal of ethanol on the first and second cycles but not the
third in one group and 4.5 h after removal of ethanol on the third cycle in another. The social interaction test was performed
5 h after removal of ethanol on the third cycle. Drugs tested included SB-242084, a 5-HT2C antagonist; buspirone, a 5-HT1A partial agonist; WAY-100635, a 5-HT1A antagonist; ketanserin, a 5-HT2A antagonist; ritanserin, a mixed 5-HT2A/2C antagonist; and Ro-601075, a 5-HT2C agonist.
Results. Both SB-242084 and buspirone reduced ethanol withdrawal-induced deficits in social interaction when given either acutely
30 min before the test or at 4 h after withdrawal from the first and second cycles. WAY-100635 and ketanserin were completely
ineffective regardless of mode of treatment. In contrast, the 5-HT2C agonist, Ro-601075, accentuated the withdrawal-induced deficit in social interaction behavior in rats exposed to either 4.5
or 7% ethanol diet.
Conclusions. These results support the utility of 5-HT1A agonists and 5-HT2C antagonists in reducing anxiety-like behavior induced by ethanol withdrawal and reducing the adaptive changes associated
with repeated withdrawals.
Electronic Publication 相似文献
13.
J. Gommans J. A. Bouwknecht T. H. Hijzen H. H. G. Berendsen C. L. E. Broekkamp R. A. A. Maes B. Olivier 《Psychopharmacology》1998,140(4):496-502
A conditioned taste aversion (CTA) procedure in mice was used to investigate the stimulus effects of the serotonin reuptake
inhibitors (SSRIs) fluvoxamine and fluoxetine. Fluvoxamine elicited a reliable CTA (ED50 = 24 mg/kg, SC) and a number of drugs were tested as pre-exposure drugs. Pre-exposure to the serotonin (5-HT)1A receptor agonists flesinoxan and ±-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) prevented the CTA induced by fluvoxamine (50 mg/kg,
SC). Pre-exposure with the 5-HT2C receptor agonist MK 212 [6-chloro-2(1-piperazinyl)pyrazine] partially prevented the fluvoxamine-induced CTA, pre-exposure
with the 5-HT2A/2C receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] did not prevent the CTA induced by fluvoxamine.
Flesinoxan pre-exposure also prevented the taste aversion induced by fluoxetine (10 mg/kg, SC) completely. This contrasts
previous results obtained with fluoxetine, where was found that its stimulus is primarily mediated by 5-HT2C, and to a lesser degree by 5-HT1A receptors. Therefore, we compared the two SSRIs directly. Pre-exposure to fluvoxamine prevented the fluoxetine-induced CTA,
whereas pre-exposure to fluoxetine only partially prevented the fluvoxamine-induced CTA. We conclude that 5-HT1A receptors are involved in the stimulus properties of both fluvoxamine and fluoxetine, that 5-HT2C receptors are involved in fluvoxamine and especially fluoxetine, and , based primarily on the cross-comparison tests, that
the two SSRIs have somewhat different stimulus properties.
Received: 3 March 1998 / Final version: 26 May 1998 相似文献
14.
Marona-Lewicka D Kurrasch-Orbaugh DM Selken JR Cumbay MG Lisnicchia JG Nichols DE 《Psychopharmacology》2002,164(1):93-107
Abstract
Rationale. There is substantial evidence that lisuride can produce effects linked to 5-HT1A receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor
of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT2A/2C receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction
of lisuride with 5-HT1A receptors has been demonstrated in several different laboratories and that activation of 5-HT1A and 5-HT1B receptors can modulate dopaminergically mediated responses.
Objective. The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction
of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that
might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification
as a dopamine agonist in the literature.
Results. In drug discrimination studies, lisuride fully mimicked the 5-HT1A agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine. Lisuride produced
a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation
of behavior by action at central 5-HT1A receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective
5-HT1A antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect
on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that
of the selective 5-HT1A agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol.
Conclusion. We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT1A receptors.
Electronic Publication 相似文献
15.
The effects of chronic (10 days) treatment with serotonin (5-HT) receptor agonists on 5-HT1A receptor mediated lower lip retraction (LLR), 5-HT1C receptor mediated penile erections (PE) or 5-HT2 receptor mediated head shakes (HS) were studied in rats. It was found that the 5-HT1A and 5-HT2 receptor mediated behaviour could be attenuated after chronic treatment, whereas 5-HT1C receptor mediated behaviour remained unchanged. The ED50 for the 5-HT1A receptor mediated, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced LLR showed an increase from 0.07 mg/kg in placebo pretreated rats to 0.13 in 8-OH-DPAT (1mg/kg/day) pretreated rats. The number of 5-HT2 receptor mediated (±)-1-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.46 and 1 mg/kg)-induced HS was significantly reduced (67% and 50%, respectively) after 10 days' pretreatment with DOI (1 mg/kg/day). In the same animals the number of 5-HT1C receptor mediated PE was increased. Ten days' pretreatment with MK 212 (0.46 mg/kg/day) failed to affect MK 212 (0.22 and 0.46 mg/kg)-induced PE. In addition, the effects of chronic treatment with some antidepressants were studied. The monoamine oxidase (MAO) inhibitor tranylcypromine (4 mg/kg/day) given for 10 days caused an increase in the ED50 for 8-OH-DPAT induced LLR (ED50 values were 0.06 and 0.14 mg/kg, respectively, in placebo — and tranylcypromine — pretreated rats) and attenuated MK 212 (0.22 and 0.46 mg/kg)-induced PE. Chronic treatment with mianserin (10 mg/kg/day), a tetracyclic antidepressant with 5-HT1C and 5-HT2 receptor antagonistic properties, did not change PE induced by MK 212, but caused an increase of PE induced by DOI and a decrease of DOI-induced HS. Ten days' pretreatment with the 5-HT re-uptake inhibitor Org 6997 (5 mg/kg/day) had no effect on MK 212-induced PE. The results demonstrate that 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour can be attenuated by chronic treatment with agonists for these receptors. The 5-HT1C receptor mediated behaviour remains unchanged in response to chronic agonist treatment. Chronic treatment with antidepressants have differential effect on these behaviours. The possible implication for the mechanism of action of antidepressants is discussed. 相似文献
16.
Veenema AH Cremers TI Jongsma ME Steenbergen PJ de Boer SF Koolhaas JM 《Psychopharmacology》2005,178(2-3):151-160
Rationale Male wild house-mice genetically selected for long attack latency (LAL) and short attack latency (SAL) differ in structural and functional properties of postsynaptic serotonergic-1A (5-HT1A) receptors. These mouse lines also show divergent behavioral responses in the forced swimming test (FST, i.e., higher immobility by LAL versus SAL mice).Objectives We investigated whether the line difference in 5-HT1A receptors is associated with a difference in brain 5-HT metabolism, and whether acute administration of a 5-HT1A receptor agonist could differentially affect the behavioral responses of LAL and SAL mice.Methods 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in homogenates of several brain regions using high-performance liquid chromatography. The behavioral effect of the full 5-HT1A receptor agonist, 8-OH-DPAT, and of the somatodendritic 5-HT1A autoreceptor agonist, S-15535, was examined in the FST. The effect of 8-OH-DPAT on forced swimming-induced 5-HT metabolism in brain homogenates was determined.Results In most brain regions, 5-HT and 5-HIAA levels and 5-HT turnover were not significantly different between LAL and SAL mice. 8-OH-DPAT abolished the behavioral line difference in the FST by reducing immobility in LAL mice and reducing climbing in SAL mice. S-15535 induced a similar behavioral effect to 8-OH-DPAT in SAL mice, but did not alter the behavior of LAL mice. Compared with LAL, forced swimming elicited in SAL mice a higher brain 5-HT turnover, which was potently attenuated by 8-OH-DPAT.Conclusions It is unlikely that the difference in 5-HT1A properties between LAL and SAL mice is an adaptive compensatory reaction to changes in 5-HT metabolism. Although unspecific motor effects, at least in SAL mice, cannot be ruled out, it is suggested that the behavioral effects of 8-OH-DPAT and S-15535 may be mediated by predominant activation of postsynaptic 5-HT1A receptors in LAL mice and by presynaptic 5-HT1A receptors in SAL mice. 相似文献
17.
Carlos Castillo Maximiliano Ibarra Js A. Terron Carlos M. Villaln Enrique Hong 《Drug development research》1994,33(1):20-25
Indorenate is a 5-HT1A receptor agonist with antihypertensive properties. This study was aimed to determine if indorenate, like other 5-HT1A receptor agonists, may also interact with α-adrenoceptors. Therefore, the effects of indorenate and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; which has affinity for 5-HT1A receptors and, to a lesser extent, for α1-adrenoceptors) on the blood pressure of pithed rats were compared. Both compounds produced dose-dependent increases in blood pressure; 8-OH-DPAT was the most potent whereas indorenate produced a higher maximum effect. Metitepine (a mixed 5-HT1/5-HT2 receptor antagonist), but not pindolol (a β-adrenoceptor and 5-HT1 receptor blocker), antagonized the pressor responses produced by both agonists; only the pressor effects of 8-OH-DPAT, however, were antagonized by prazosin (an α1-adrenoceptor antagonist). Interestingly, ketanserin (a 5-HT2 and α1-adrenoceptor blocker) strongly antagonized the pressor responses to indorenate whereas only a slight inhibition of 8-OH-DPAT responses was observed. Further, in pithed rats intravenously infused with norepinephrine (NE), 8-OH-DPAT, but not indorenate, produced dose-dependent hypotensive effects and both compounds were inactive in rats infused with quipazine. In conclusion, 8-OH-DPAT behaved as a partial agonist at α1-adrenoceptors whereas indorenate produced pressor effects probably due to stimulation of 5-HT2 receptors. Thus, 8-OH-DPAT, but not indorenate, showed activity at α1-adrenoceptors in the pithed rat. © 1994 Wiley-Liss, Inc. 相似文献
18.
One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly
via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist
WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan
result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during
5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic
reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1–0.3 mg/kg, IP) or flesinoxan
(0.1–1.0 mg/kg, IP). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with
the antagonist WAY 100635 (0.1 mg/kg, IP) shifted the agonist dose-effect curves for behavioral effects to the right. In a
further experiment, oral ethanol (1.0 g/kg, PO) increased the frequency of attacks in excess of 2 SD from their mean vehicle
level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03–0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg),
given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast,
these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity
of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic
5-HT1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission.
Received: 26 January 1998/Final version: 10 March 1998 相似文献
19.
In the present study, the effects of 5-HT1A receptor ligands with varying degrees of intrinsic activity at the 5-HT1A receptor were examined in the conditioned emotional response (CER) test and their effects compared to those of the benzodiazepine
receptor agonists, diazepam and chlordiazepoxide. Diazepam (3.0 mg/kg) and chlordiazepoxide (3.0 mg/kg), and the 5-HT1A receptor partial agonists, ipsapirone (10.0 mg/kg) and gepirone (3.0 mg/kg), alleviated conditioned suppression of lever
pressing. The 5-HT1A receptor partial agonist, buspirone (0.1–1.0 mg/kg), the 5-HT1A receptor agonist, 8-OH-DPAT (0.01– 0.10 mg/kg), and the 5-HT1A receptor antagonist, WAY-100635 (0.03–3.0 mg/kg), had no effects on conditioned fear. Neither enhancing the level of food
deprivation nor pretreatment with the amnesic agent scopolamine induced anxiolytic-like effects in the present CER test. The
anxiolytic-like effects of ipsapirone in this test were completely reversed by WAY-100635. These results indicate that 5-HT1A agonist, but not antagonist actions, induce an anxiolytic effect in the CER test in rats.
Received: 13 March 1996/Final version: 8 July 1996 相似文献
20.
Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro 总被引:4,自引:1,他引:4
The effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists were studied on the release of 5-HT from enterochromaffin
cells of incubated strips of porcine and human small intestine. Tetrodotoxin (1 μmol/l) was present in the incubation medium
to block neuronally mediated inputs to the enterochromaffin cells. The 5-HT1A receptor agonist (+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 1 μmol/l) and the 5-HT2 receptor agonist α-methyl-5-HT (1 μmol/l) increased 5-HT release by 40% in about 60% of the human preparations.These agonists
showed no effect on 5-HT release in porcine intestinal mucosa. The 5-HT3 receptor agonist 2-methyl-5-HT (3–100 μmol/l) increased 5-HT release in both species by 60% (pig) and 90% (man), respectively.
These stimulatory effects were antagonized by tropisetron (10 nmol/l). The 5-HT4 receptor agonist 5-methoxytryptamine (0.3–30 μmol/l) reduced 5-HT release by about 50% in both species. These inhibitory
effects were antagonized by tropisetron (3 μmol/l). The basal outflow of 5-HT from the intestinal mucosa was not significantly
affected by tropisetron (10 nmol/l; 3 μmol/l). The specific 5-HT4 receptor antagonist GR 113808 ((1-[2-methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate)
(0.1 μmol/l) which by itself did not significantly affect 5-HT release from human duodenal specimens blocked the inhibitory
effect of 5-methoxytryptamine (30 μmol/l).
These findings indicate that stimulatory 5-HT3 and inhibitory 5-HT4 receptors are present on enterochromaffin cells of the porcine and human intestinal mucosa. Under the present experimental
conditions endogenous 5-HT does not significantly activate these receptors. Stimulatory 5-HT1A and 5-HT2 receptors may additionally be present on human enterochromaffin cells.
Received: 19 September 1997/ Accepted: 29 January 1998 相似文献