共查询到20条相似文献,搜索用时 15 毫秒
1.
F. Borsini A. Ceci G. Bietti A. Donetti 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(3):283-290
BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT1A receptor agonist/5-HT2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1–10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1–1000 g/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1–10 g/kg and 0.1–3 g/kg i.v. respectively, and reduced it at higher doses, 30–300 g/kg and 10–30 g/kg i.v., respectively.The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 g/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OHDPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.These findings suggest that BIMT 17 directly inhibits the electrical activity of medial prefronto-cortical neurons through its dual mode of receptor interaction. 相似文献
2.
Rationale Tryptophan depletion is used to reduce central serotonergic function and to investigate its role in psychiatric illness. Despite
widespread clinical use, its effects on serotonin (5-HT) receptors have not been well characterized.
Objective The aim of this study was to examine the effect of acute (ATD) and chronic tryptophan depletion (CTD) on free-plasma tryptophan
(TRP), central TRP and 5-HT and brain 5-HT1A and 5-HT2A receptor binding in the rat.
Methods TRP and 5-HT were measured by high-performance liquid chromatography and receptor levels determined by homogenate radioligand
binding and in-vitro receptor autoradiography.
Results Free-plasma TRP, central TRP and central 5-HT levels were significantly and similarly reduced by ATD and 1- and 3-week CTD
compared to controls. ATD significantly reduced 5-HT1A binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT1A binding (frontal cortex, remaining cortex and hippocampus) or 5-HT2A binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT2A binding or postsynaptic 5-HT1A binding. Furthermore, 3-week CTD did not significantly alter 5-HT1A binding but significantly increased cortical 5-HT2A binding without affecting striatal or hippocampal levels. In the CTD 1 and 3-week groups, rat body weight was significantly
decreased as compared to controls. However, weight loss was not a confounding factor for decreased cortical 5-HT2A-receptor binding.
Conclusion ATD-induced reduction in somatodendritic 5-HT1A autoreceptor binding may represent an intrinsic ‘homeostatic response’ reducing serotonergic feedback in dorsal raphe projection
areas. In contrast, the increase in 5-HT2A receptor after CTD may be a compensatory response to a long-term reduction in 5-HT. 相似文献
3.
Delgado M Caicoya AG Greciano V Benhamú B López-Rodríguez ML Fernández-Alfonso MS Pozo MA Manzanares J Fuentes JA 《European journal of pharmacology》2005,511(1):9-19
S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety. 相似文献
4.
5.
Clinical studies have shown that triiodothyronine (T3) both augments and accelerates the therapeutic response to antidepressant drugs, particularly tricyclics. There is evidence that this effect is mediated by the serotonergic system. We show here that T3 administered daily for 7 days over the range 0.02-0.5 mg/kg increases basal serotonin (5-hydroxytryptamine, 5-HT) levels, as measured by in vivo microdialysis in rat cortex, in a dose-dependent fashion. All the doses of T3 examined reduced 5-HT(1A) autoreceptor activity, as measured by the effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) to decrease 5-HT levels in frontal cortex. T3 administered daily for 14 days at 0.02 mg/kg also reduced 5-HT(1B) autoreceptor activity, as measured by the effect of locally administered 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129, 10 microM) to decrease 5-HT levels. In animals administered imipramine (10 mg/kg/day by osmotic minipump) concurrently with T3 injections, no further changes in either 5-HT(1A) or 5-HT(1B) autoreceptor activity were seen. We suggest that the effect of T3 to accelerate the therapeutic actions of antidepressant drugs may be due to a combination of the actions of T3 at autoreceptors and the actions of the drugs at postsynaptic 5-HT(1A) receptors. 相似文献
6.
Philippe Schoeffter Daniel Hoyer 《Naunyn-Schmiedeberg's archives of pharmacology》1989,339(6):675-683
Summary The effects of several putative 5-HT1 receptorsubtype selective ligands were investigated in biochemical models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(mtrifluoromethylphenyl)piperazine), mCPP (1-m-chlorophe-nyl)piperazine, 1 CGS 12066 (7-trifluoromethyl-4-(4-methyl1-piperazinyl)-pyrrolo[1,2-a]quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine). Among reported 5-HT1B receptor selective drugs, TFMPP had similar potency at 5HT1A, 5-HT1B and 5-HT1C receptors, mCPP did not separate between 5-HT1B and 5-HT1C receptors, CGS 12066 was equipotent at 5-HT1B and 5-HT1D receptors, and isamoltane was only slightly 5-HTIB versus 5-HT1A selective. Quipazine showed equal potency at 5-HTIB and 5-HT1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT1A receptor selective, was equally potent at 5-HT1A and 5-HT1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT1 receptor subtype. Of interest were the properties of several of these drugs, which behaved as agonists at some receptors and as antagonists at others (e. g. quipazine, 1-NP, PAPP and isamoltane).
Send offprint requests to D. Hoyer at the above address 相似文献
7.
Selective serotonin reuptake inhibitors (SSRI) are characterized by high clinical effectiveness and good tolerability. A 2-3 week delay in the onset of effects is caused by adaptive mechanisms, probably at the serotonergic (5-HT) receptor level. To analyze this in detail, we measured 5-HT(1A) and 5-HT(2A) receptor bindings in vitro after 3 weeks of citalopram treatment (20 mg/kg i.p. daily) in group-housed as well as isolation-housed mice, reflecting neurobiological aspects seen in psychiatric patients. Isolation housing increased somatodendritic (+52%) and postsynaptic (+30-95%) 5-HT(1A) as well as postsynaptic 5-HT(2A) receptor binding (+25-34%), which confirms previous findings. Chronic citalopram treatment did not induce alterations in raphe 5-HT(1A) autoreceptor binding, independent of housing conditions. Housing-dependent citalopram effects on postsynaptic 5-HT(1A) receptor binding were found with increases in group- (+11-42%) but decreases in isolation-housed (-11 to 35%) mice. Forebrain 5-HT(2A) receptor binding decreased between 11 and 38% after chronic citalopram administration, independent of housing conditions. Citalopram's long-term action comprises alterations at the postsynaptic 5-HT(1A) and 5-HT(2A) receptor binding levels. Housing conditions interact with citalopram effects, especially on 5-HT(1A) receptor binding, and should be more strongly considered in pharmacological studies. In general, SSRI-induced alterations were more pronounced and affected more brain regions in isolates, supporting the concept of a higher responsiveness in "stressed" animals. Isolation-induced receptor binding changes were partly normalized by chronic citalopram treatment, suggesting the isolation housing model for further analyses of SSRI effects, especially at the behavioral level. 相似文献
8.
Chilmonczyk Z Cybulski M Iskra-Jopa J Chojnacka-Wójcik E Tatarczyńska E Kłodzińska A Leś A Bronowska A Sylte I 《Il Farmaco; edizione pratica》2002,57(4):285-301
In the present paper, we describe affinities to 5-HT1A and 5-HT2A receptors of several new 1,2,4-trisubstituted piperazine derivatives. The affinities were compared with those described earlier for 1,4-disubstituted piperazines and the influence of the third (methyl) substituent on the affinity to both receptors is discussed. The difference between two- and three-substituted derivatives was rationalised in terms of molecular modelling of the respective ligand-receptor complexes. Additionally, the functional activity of some 1,2,4-trisubstituted piperazines for 5-HT1A receptor was examined in behavioural and biochemical models. The obtained results have shown that some trisubstituted compounds exhibited a higher affinity to 5-HT2A receptors than their respective disubstituted analogues (with the affinity to 5-HT1A receptors remaining the same or somewhat improving). The molecular dynamics simulations suggested that the presence of the third substituent in the piperazine ring of those compounds may induce stabilising effect on the ligand-receptor complexes. The results of the in vivo studies have shown that some of the examined trisubstituted piperazines (10-13, 16, 17) exhibited properties of postsynaptic 5-HT1A partial agonists. Moreover, compounds 13 and 16 exhibited features of 5-HT1A presynaptic agonists in in vitro test, and compound 16 also in in vivo tests. 相似文献
9.
5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion 总被引:4,自引:0,他引:4
Rationale Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT2A receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT2A and 5-HT2C receptors have opposing effects on behaviour, and that the 5-HT2C receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion.Objectives To assess the effects of 5-HT2A and 5-HT2C receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents.Methods The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats.Results ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls.Conclusions These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT2 receptor family is functionally heterogeneous. Although both 5-HT2A and 5-HT2C receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system. 相似文献
10.
Kitamura Y Araki H Shibata K Gomita Y Tanizaki Y 《European journal of pharmacology》2003,481(1):75-77
We examined the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after administration of the 5-HT(1A) receptor agonist, 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT). Imipramine (3-30 mg/kg, i.p.) or 8-OH-DPAT (0.1-1 mg/kg, s.c.) significantly decreased the duration of immobility in normal rats. The immobility-decreasing effect of imipramine was blocked when ACTH was administered for 14 days. On the other hand, the immobility-decreasing effect induced by 8-OH-DPAT was not blocked by chronic administration of ACTH for 14 days. These findings indicate that 8-OH-DPAT can be useful in an animal model of depressive conditions resistant to antidepressant treatment. 相似文献
11.
Centenaro LA Vieira K Zimmermann N Miczek KA Lucion AB de Almeida RM 《Psychopharmacology》2008,201(2):237-248
Rationale Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to
that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation
with an intruder. Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the
ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive
and impulsive behavior.
Objectives The objectives of the study are to assess the anti-aggressive effects of 5-HT1A and 5-HT1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and CP-93,129] in the VO PFC of socially provoked male mice. To confirm the
specificity of the receptor, 5-HT1A and 5-HT1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist
effects.
Results 8-OH-DPAT (0.56 and 1.0 μg) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 μg) also decreased the
number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive
activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the
1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 μg)
and SB-224,289 (1.0 μg).
Conclusions The decrease in aggressiveness observed with microinjections of 5-HT1A and 5-HT1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates
high levels of aggression in a behaviorally specific manner. 相似文献
12.
Effects of novel antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCP-induced social interaction deficits in the rat 总被引:8,自引:0,他引:8
Considerable interest has arisen in identifying antipsychotic agents with improved efficacy against negative symptoms, such as social withdrawal. In rats, a social interaction deficit can be induced by the NMDA antagonist phencyclidine (PCP). Here, we examined the effects of antipsychotics, reported to exert dual 5-HT(1A)/D(2) actions, on PCP-induced social interaction deficits. Drugs were administered daily for 3 days in combination with either vehicle or PCP (2.5mg/kg, SC) and social interaction was measured on the last day of drug treatment. Pairs of unfamiliar rats receiving the same treatment were placed in a large open field for 10 min and the number of social behaviors were scored. The results indicate that: (1) PCP significantly reduced social interaction by over 50% compared with vehicle-treated controls; (2) haloperidol (0.0025-0.16 mg/kg, SC) and clozapine (0.04-10mg/kg, IP) did not reverse PCP-induced social interaction deficits; (3) the substituted benzamide remoxipride reversed PCP-induced deficits at 0.63 and 2.5mg/kg (4) the 5-HT(1A) agonist 8-OH-DPAT was inactive (at 0.01-0.63 mg/kg, SC); (5) among compounds reported to exert dual 5-HT(1A)/D(2) actions, SSR181507 (at 0.16 mg/kg, SC) and aripiprazole (at 0.04 and 0.16 mg/kg, IP), but not ziprasidone (0.04-2.5mg/kg, IP), SLV313 (0.0025-0.16 mg/kg, SC) or bifeprunox (0.01-0.63 mg/kg, IP), significantly reversed PCP-induced social interaction deficits; and (6) the 5-HT(1A) receptor antagonist WAY100635 blocked the effects of SSR181507 and aripiprazole. These findings indicate that the balance of activity at 5-HT(1A) and D(2) receptors profoundly influences the activity of antipsychotics in this model of social withdrawal, and their potential benefit on at least some of the negative symptoms of schizophrenia. 相似文献
13.
T. Sharp R. McQuade S. Bramwell S. Hjorth 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(4):339-346
1. | Electrophysiological measurements of 5-HT neuronal activity report that repeated administration of 5-HT1A receptor agonists leads to desensitization of the 5-HT1A autoreceptor but this has not yet been detected in measurements of brain 5-HT synthesis or metabolism. Here we have determined the effect of repeated administration of 5-HT1A receptor agonists on brain 5-HT release using microdialysis. |
2. | Acute administration of the 5-HT1A receptor agonists buspirone (0.1–5 mg/kg s.c.) and ipsapirone (0.03–3 mg/kg s.c.) caused a dose-dependent decrease in 5-HT output in ventral hippocampus of the chloral hydrate anaesthetized rat. |
3. | The 5-HT response to buspirone (0.1 and 0.5 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was significantly inhibited by pre-treatment with the 5-HT1/-adrenoceptor antagonist pindolol (8–16 mg/kg s.c.). The 5-HT response to buspirone (0.1 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was not blocked by pretreatment with a combination of the 1 and 2-adrenoceptor antagonists metoprolol and ICI 118,551 (4 mg/kg s.c.). |
4. | The effect of an acute challenge of buspirone (0.5 mg/kg s.c.) on 5-HT output in ventral hippocampus was not attenuated in rats treated twice daily for 14 days with 0.5 or 5 mg/kg s.c. buspirone compared to saline-injected controls. Similarly, the decrease in 5-HT induced by an acute challenge of ipsapirone (0.5 mg/kg s.c.) was not attenuated in rats treated twice daily for 14 days with 5 mg/kg s.c. ipsapirone. |
5. | In further experiments it was shown that the decrease in 5-HT induced in both ventral hippocampus and striatum by an acute challenge of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.025 mg/kg s.c.), was not attenuated in rats treated twice daily for 14 days with 1 mg/kg s.c. 8-OH-DPAT. |
6. | Basal levels of 5-HT in hippocampal and striatal microdialysates of animals treated repeatedly with the 5-HT1A receptor agonists were not consistently altered relative to treatment controls. |
7. | In agreement with earlier studies measuring regional brain 5-HT synthesis and metabolism, the present microdialysis measurements of 5-HT release indicate that the inhibitory effect of 5-HT1A receptor agonists on presynaptic 5-HT function is maintained in rats treated repeatedly with the same drugs. |
14.
Wolfgang Löscher Ulrike Witte Gabriele Fredow Jörg Traber Thomas Glaser 《Naunyn-Schmiedeberg's archives of pharmacology》1990,342(3):271-277
Summary In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol-3(2H)one-1,1-dioxide), which act as partial agonists at 5-HT1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg/kg i. m., ipsapirone, 2–5 mg/kg i.m., and Bay Vq 7813, 0.5–2 mg/kg i.m. or i.v., were head shakes. The potency of the three drugs to induce this behaviour correlated with their activity at 5-HT1A receptors as determined by inhibition of forskolin-stimulated adenylate cyclase, substantiating that the head shake response has potential as a quantitative probe of in vivo receptor function. The 5-HT2/5-HT1C receptor antagonist ritanserin did not counteract the head shakes induced by ipsapirone, suggesting that neither 5-HT2 nor 5-HT1C receptors are involved in mediation of this response to this 5-HT1A receptor agonist in pigs. Once daily administration of Bay Vq 7813 or ipsapirone for 3–5 days led to a reduction in the head shake response. 1-Pyrimidinylpiperazine (1-PP), a pharmacologically active metabolite shared by ipsapirone, Bay Vq 7813, and related pyrimidinylpiperazine derivatives, did not induce behavioural alterations in pigs. The data provide further evidence that marked species differences exist in functional responses to 5-HT receptor ligands.
Send offprint requests to W. Löscher at the above address 相似文献
15.
Intracerebroventricular administration of selective agonist of serotonin 5-HT7 receptor LP44 (4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-pyperasinehexanamide hydrochloride; 10.3, 20.5 or 41.0 nmol) produced considerable hypothermic response in CBA/Lac mice. LP44-induced (20.5 nmol) hypothermia was significantly attenuated by the selective 5-HT7 receptor antagonist SB 269970 (16.1 fmol, i.c.v.) pretreatment. At the same time, intraperitoneal administration of LP44 in a wide range of doses 1.0, 2.0 or 10.0 mg/kg (2.0, 4.0, 20.0 μmol/kg) did not cause considerable hypothermic response. These findings indicate the implication of central, rather than peripheral 5-HT7 receptors in the regulation of hypothermia. The comparison of LP44-induced (20.5 nmol) hypothermic reaction in eight inbred mouse strains (DBA/2J, CBA/Lac, C57BL/6, BALB/c, ICR, AKR/J, C3H and Asn) was performed and a significant effect of genotype was found.In the same eight mouse strains, functional activity of 5-HT1A and 5-HT3 receptors was studied. The comparison of hypothermic responses produced by 5-HT7 receptor agonist LP44 (20.5 nmol, i.c.v.) and 5-HT1A receptor agonist 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg), 5-HT3 receptor agonist m-CPBG (40.0 nmol, i.c.v.) did not reveal considerable interstrain correlations between 5-HT7 and 5-HT1A or 5-HT3 receptor-induced hypothermia. The selective 5-HT7 receptor antagonist SB 269970 (16.1 fmol, i.c.v.) failed to attenuate the hypothermic effect of 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg) and m-CPBG (40.0 nmol, i.c.v.) indicating that the brain 5-HT7 receptor is not involved in the hypothermic effects of 8-OH-DPAT or m-CPBG. The obtained results suggest that the central 5-HT7 receptor plays an essential role in the mediation of thermoregulation independent of 5-HT1A and 5-HT3 receptors. 相似文献
16.
The effects of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-1,2-benzoisothiazol-3(2H)one-1,1-dioxide hydrochloride (isapirone, TVX Q 7821), a putative 5-HT1 receptor antagonist, has been studied on various models of 5-HT receptor sub-type function. In mice TVX Q 7821 produced a dose-dependent inhibition of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) with an ED50 of 5.3 mg/kg suggesting that TVX Q 7821 was an antagonist of the presynaptic (possibly somato-dendritic) 5-HT1A receptor. TVX Q 7821 did not alter the locomotor response to the suggested 5-HT1B agonist RU 24969. The rate of mouse brain 5-HT synthesis was accelerated by TVX Q 7821 (10 mg/kg). 5-HT2 receptor-mediated head twitch behaviour induced by precursor loading with 5-HTP was unaffected by TVX Q 7821 (10 mg/kg) pretreatment 75 min earlier, but the head-twitch induced by the agonist 5-methoxy-N,N-dimethyltryptamine was enhanced by prior treatment with TVX Q 7821.In rats the hypothermia induced by 8-OH-DPAT was partially antagonised by TVX Q 7821 while the behavioural serotonin syndrome induced by 8-OH-DPAT (a possible post-synaptic 5-HT1B-mediated effect) was unaffected by TVX Q 7821 as was the locomotion induced by RU 24969.The data suggest that TVX Q 7821 is a good presynaptic 5-HT1A antagonist in mice, as indicated by the 8-OH-DPAT-induced hypothermia and 5-HT synthesis rate studies. It did not antagonise 5-HT1B-mediated behaviour in mice or rats and appeared to have an antagonist action at pre- but not post-synaptic 5-HT1A receptors in rats.
Offprint requests to: G.M. Goodwin 相似文献
17.
Desensitization of 5-HT(1A) and 5-HT(1B) autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin reuptake inhibitors when these are administered chronically. The blockade of 5-HT(1A) autoreceptors occurring on administration of a selective serotonin reuptake inhibitor together with a 5-HT(1A) autoreceptor antagonist is responsible for the acute increase in 5-hydroxytryptamine (serotonin, 5-HT) levels observed under these circumstances. The effects of repeated administration of selective serotonin reuptake inhibitors together with 5-HT(1A) receptor antagonists have not been widely studied. In this work, we found that the effects of fluoxetine (5 mg/kg, i.p., daily for 12 days) to desensitize 5-HT(1B) autoreceptors in the frontal cortex, as measured by the effect of the locally administered 5-HT(1B) receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129), and to desensitize 5-HT(1A) autoreceptors as measured by the action of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 50 microg/kg, s.c.) to reduce 5-HT levels in cortex, were prevented by concomitant administration of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635; 0.3 mg/kg, s.c.). 5-HT(1B) receptor activity in the hypothalamus, as measured by the effects of locally administered CP 93129, and 5-HT(1A) autoreceptor activity, as determined by the effects of subcutaneous 8-OH-DPAT to reduce 5-HT levels in hypothalamus, were not altered either by fluoxetine alone or by fluoxetine in the presence of WAY-100635. The data suggest that the regulation of extracellular levels of 5-HT in the cortex and hypothalamus is subject to different autoregulatory mechanisms. 相似文献
18.
5-HT7 receptors are involved in REM sleep and possibly in mood disorders. REM sleep suppression and antidepressant-like behavior is observed in 5-HT7−/− mice and in rats treated with 5-HT7 receptor antagonists. We recently demonstrated that pharmacological blockade of 5-HT7 receptors enhances REM sleep suppression and antidepressant-like behavior induced by citalopram in rodents. It has been hypothesized that the effect of citalopram on sleep is essentially mediated by the activation of 5-HT1A receptors. The present study investigates the impact of 5-HT7 receptor gene deletion on the effect of various reuptake inhibitors on REM sleep and probes the role of 5-HT1A receptors in this response. Three SSRIs (citalopram, fluoxetine and paroxetine) but not the tricyclic antidepressant desipramine had a significantly stronger REM sleep suppressive effect in 5-HT7−/− mice compared to 5-HT7+/+ mice. In contrast, REM sleep was similarly reduced in 5-HT7+/+ mice and 5-HT7−/− mice after treatment with the 5-HT1A receptor agonist ipsapirone. Furthermore, both 5-HT7+/+ and 5-HT7−/− mice displayed the same increase in REM sleep duration produced by the 5-HT1A receptor antagonist WAY-100635. These findings indicate that 5-HT7 receptor deletion augments the effect of various SSRIs on REM sleep suppression and that this effect is distinct from those mediated via 5-HT1A receptors. 相似文献
19.
Previous work has shown that 5-HT2C receptor agonists and 5-HT2A receptor antagonists reduce impulsive action, as well as the locomotor stimulant effect of psychomotor stimulants. Since psychomotor stimulants also increase impulsive action we examined the effects of the 5-HT2C receptor agonist Ro60-0175, and the 5-HT2A receptor antagonist M100907 on impulsive action induced by amphetamine, cocaine and the NMDA receptor antagonist MK801 (dizocilpine). Impulsive action was measured in adult male Long-Evans rats as premature responding in the 5-choice serial reaction time (5-CSRT) test. Initially, we determined that amphetamine (0.3 mg/kg), cocaine (15 mg/kg) and MK801 (0.03 mg/kg) induced comparable premature response rates of approximately 50-70 per session, compared to 10-15 responses under baseline conditions. Each drug and its vehicle were then tested in combination with Ro60-0175 (0.1 and 0.6 mg/kg) or its vehicle, or M100907 (0.5 mg/kg) or its vehicle. At 0.1 mg/kg Ro60-0175 did not modify the effects of amphetamine, cocaine or MK801. In contrast, the 0.6 mg/kg dose reduced premature responses induced by amphetamine, cocaine and MK801. M100907 also reduced premature responding induced by all three of these drugs. In general, treatment with Ro60-0175 or M100907 by itself did not consistently alter any of the other aspects of task performance in the 5-CSRT test including number of trials completed, and accuracy of responding. These data show that activation of 5-HT2C receptors and blockade of 5-HT2A receptors have seemingly similar functional effects on a measure of impulsive action. 相似文献
20.
Attenuation by the 5-HT1A receptor agonist osemozotan of the behavioral effects of single and repeated methamphetamine in mice 总被引:1,自引:0,他引:1
This study examined the effects of the selective 5-HT1A receptor agonist osemozotan on repeated methamphetamine (METH)-induced behavioral sensitization and single METH-induced locomotor stimulant effect in mice, and then the neurochemical mechanisms using in vivo microdialysis. Repeated administration of METH for 7 days enhanced METH challenge-induced locomotor activity, and this sensitization was observed even after its withdrawal for 7-14 days. Administration of osemozotan to METH-sensitized mice inhibited the maintenance of behavioral sensitization. This effect was blocked by a low dose of WAY100635, a selective 5-HT1A receptor antagonist. A METH challenge increased the extracellular levels of dopamine (DA), 5-HT, and noradrenaline in the prefrontal cortex, but only the increase in 5-HT release was enhanced by repeated METH administration. This augmented response of 5-HT release was attenuated by osemozotan in a WAY100635-sensitive way. A single administration of osemozotan to drug na?ve mice inhibited METH-induced locomotor stimulant effect and reduced METH-induced increase in prefrontal 5-HT, but not DA, release. These results suggest that prefrontal 5-HT release is involved at least partly in the effects of osemozotan on single and repeated METH-induced behavioral effects in mice, and imply that the 5-HT1A receptors may have a potential therapeutic value in the remission of schizophrenia. 相似文献