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1.
The antipsychotic aripiprazole is a potent,partial agonist at the human 5-HT1A receptor 总被引:28,自引:0,他引:28
Jordan S Koprivica V Chen R Tottori K Kikuchi T Altar CA 《European journal of pharmacology》2002,441(3):137-140
Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer. 相似文献
2.
Dupuis DS Mannoury la Cour C Chaput C Verrièle L Lavielle G Millan MJ 《European journal of pharmacology》2008,588(2-3):170-177
Though 5-HT6 receptors are targets for the treatment of schizophrenia and other psychiatric disorders, the influence of drugs upon signal transduction has not been extensively characterized. Herein, we employed a Scintillation Proximity Assay (SPA)/antibody-immunocapture procedure of coupling to G alpha s to evaluate the interaction of a broad range of novel agonists, antagonists and antipsychotics at rat 5-HT(6) receptors stably expressed in HEK293 cells. Serotonin (pEC(50), 7.7) increased [35S]GTP gamma S binding to G alpha s by ca 2-fold without affecting binding to Gi/o or Gq. LSD (9.2), 5-MeODMT (7.9), 5-CT (7.0) and tryptamine (6.1) were likewise full agonists. In contrast, the novel sulfonyl derivatives, WAY181,187 (9.1) and WAY208,466 (7.8), behaved as partial agonists and attenuated the actions of 5-HT. SB271,046 and SB258,585 abolished activation of G alpha s by 5-HT with pKb values of 10.2 and 9.9, respectively, actions mimicked by the novel antagonist, SB399,885 (10.9). SB271,046 likewise blocked partial agonist properties of WAY181,187 and WAY208,466 with pKb values of 9.8 and 9.0, respectively. 5-HT-stimulated [35S]GTP gamma S binding to G alpha s was antagonised by various antipsychotics including olanzapine (7.8), asenapine (9.1) and SB737,050 (7.8), whereas aripiprazole and bifeprunox were inactive. Further, antagonist properties of clozapine (8.0) were mimicked by its major metabolite, N-desmethylclozapine (7.9). In conclusion, the novel ligands, WAY208,466 and WAY181,187, behaved as partial agonists at 5-HT6 receptors coupled to G alpha s, while SB399,885 was a potent antagonist. Though 5-HT6 receptor blockade is not indispensable for therapeutic efficacy, it may well play a role in the functional actions of certain antipsychotic agents. 相似文献
3.
In this study we have functionally characterized aripiprazole (OPC-14597; 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy-3,4-dihydro-2-(1H)-quinolinone), the prototype of a new generation antipsychotic drug termed dopamine-serotonin-system stabilizer, in cells expressing 5-hydroxytryptamine2 (5-HT2) receptor subtypes in comparison with olanzapine. In Chinese hamster ovary (CHO) cells stably expressing 5-HT2 receptors, aripiprazole displayed a dual agonist/antagonist profile for 5-HT2C receptor (VNI isoform) mediated calcium signaling (EC50 1070 nM, IC50 281 nM). It exhibited no appreciable 5-HT2A or 5-HT2B agonism, whereas it antagonized 5-HT-stimulated calcium increase at either 5-HT2A or 5-HT2B receptor expressed in CHO cells (IC50s of 369 and 0.46 nM, respectively). In comparison, olanzapine was devoid of agonism but was an antagonist at all three subtypes, with a potency rank order of 5-HT2A (IC50, 2.5 nM)>5-HT2B (47 nM)>5-HT2C (69 nM). In human embryonic kidney (HEK) cells transiently expressing 5-HT2C receptor isoforms, aripiprazole exhibited full agonism at the unedited INI, but partial agonism at the partially edited VNI and fully edited VSV isoforms (EC50s of 571, 1086 and 2099 nM, respectively). A partial antagonism was also observed for aripiprazole at the two edited isoforms (IC50s of 1138 and 1000 nM, respectively). In contrast, while lacking agonist activity at the VNI and VSV, olanzapine showed inverse agonism at the INI isoform (IC50 594 nM), reaching a maximal attenuation of 20%. In addition, olanzapine was a full antagonist at all three isoforms, with a rank order of potency of VNI (IC50, 79 nM)>VSV (101 nM)>INI (3856 nM). The modest 5-HT2A antagonism and 5-HT2C partial agonism, along with reported D2 and 5-HT1A partial agonism, may allow aripiprazole to stabilize the disturbed dopamine-serotonin interplay in schizophrenia with a moderate yet adequate pharmacological intervention. 5-HT2C agonism may also underlie the minimal weight gain seen with aripiprazole. 相似文献
4.
F. Tollens N. Gass R. Becker A.J. Schwarz C. Risterucci B. Künnecke P. Lebhardt J. Reinwald M. Sack W. Weber-Fahr A. Meyer-Lindenberg A. Sartorius 《European neuropsychopharmacology》2018,28(9):1035-1046
One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p?=?0.0004, r²?=?0.46; p?=?0.004, r²?=?0.33; p?=?0.002, r²?=?0.37; p?=?0.02, r²?=?0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics. 相似文献
5.
Rationale Aripiprazole is an atypical antipsychotic drug with high in vitro affinity for 5-HT1A, 5-HT2A and dopamine (DA) D2 receptors. However, its in vivo actions in the brain are still poorly characterized.
Objective The aim was to study the in vivo actions of aripiprazole in the rat and mouse brain.
Methods Brain microdialysis and single-unit extracellular recordings were performed.
Results The systemic administration of aripiprazole reduced 5-HT output in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus
of the rat. Aripiprazole also reduced extracellular 5-HT in the mPFC of wild-type (WT) but not of 5-HT1A (−/−) knockout (KO) mice. Aripiprazole reversed the elevation in extracellular 5-HT output produced by the local application
of the 5-HT2A/2C receptor agonist DOI in mPFC. Aripiprazole also increased the DA output in mPFC of WT but not of 5-HT1A KO mice, as observed for atypical antipsychotic drugs, in contrast to haloperidol. Contrary to haloperidol, which increases
the firing rate of DA neurons in the ventral tegmental area (VTA), aripiprazole induced a very moderate reduction in dopaminergic
activity. Haloperidol fully reversed the inhibition in dopaminergic firing rate induced by apomorphine, whereas aripiprazole
evoked a partial reversal that was significantly different from that evoked by haloperidol and from the spontaneous reversal
of dopaminergic activity in rats treated with apomorphine.
Conclusions These results indicate that aripiprazole modulates the in vivo 5-HT and DA release in mPFC through the activation of 5-HT1A receptors. Moreover, aripiprazole behaves as a partial agonist at DA D2 autoreceptors in vivo, an action which clearly distinguishes
it from haloperidol.
A. Bortolozzi and L. Díaz-Mataix have contributed equally to this study. 相似文献
6.
Rationale: Combining neuroleptics with 5-HT1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds
that have greater therapeutic potential and/or are better tolerated. Objective: To examine 1) the ability of 5-HT1A ligands to alter the effects of neuroleptics in preclinical models for antipsychotic potential (hindlimb retraction time
in the paw test) and extrapyramidal side-effects (forelimb retraction time in the paw test; catalepsy tests), 2) the role
of intrinsic activity at 5-HT1A receptors in the modulatory effects of 5-HT1A ligands, and 3) the generality of the interactions across neuroleptics. Methods: The effects of different doses of 5-HT1A ligands with intrinsic activity ranging from high (e.g., 8-OH-DPAT) to low (e.g., WAY 100135) administered together with
a fixed, high dose of the neuroleptics haloperidol, risperidone, and tropapride were examined in the paw test and on catalepsy.
Results: Firstly, the 5-HT1A agonists 8-OH-DPAT and ipsapirone attenuated the extrapyramidal-like effects of haloperidol and risperidone more than their
therapeutic-like effects; this was not observed for tropapride, where all of its effects were markedly attenuated. Secondly,
neither the weak 5-HT1A agonist WAY 100135 nor the silent antagonist WAY 100635 attenuated the effects of neuroleptics. Thirdly, neuroleptics apparently
differed in their sensitivity to interactions with 5-HT1A agonists inasmuch as 8-OH-DPAT and ipsapirone attenuated the effects of tropapride on hindlimb retraction times more than
those of haloperidol or risperidone. Conclusions: The present data suggest that 5-HT1A agonists with intermediate or high, but not low, intrinsic activity may abolish the extrapyramidal effects of neuroleptics.
Together with results of previous studies, it appears that 5-HT1A agonists alter the antipsychotic-like effects of neuroleptics, although this may depend on the neuroleptic studied.
Received: 29 June 1998/Final version: 6 November 1998 相似文献
7.
S. Kapur 《Psychopharmacology》1996,124(1-2):35-39
This article examines the hypothesis that 5-HT2 antagonism ameliorates extrapyramidal side effects (EPS) induced by the blockade of D2 dopamine receptors by antipsychotics. Neuroanatomical and neurophysiological data confirm the existence of pathways whereby 5-HT2 antagonism may influence EPS. The experimental data in rodents is marginally positive, but shows that the net effect of 5-HT2 antagonism is dependent upon the precise conditions under which catalepsy is induced. The data in monkeys are mainly negative. Studies in patients who have received adjunct 5-HT2 antagonists in addition to typical neuroleptics lend some support the the hypothesis, but are not conclusive. It is reasoned that 5-HT2 antagonism plays no role in clozapine's freedom from EPS, but it may be responsible for risperidone's decreased propensity to cause EPS. The article concludes that there is support for a conditional role of 5-HT2 in decreasing EPS: 5-HT2 antagonists may delay the onset and decrease the severity of EPS but cannot totally eliminate its occurrence. The implications of these findings for the next generation of combined 5-HT2/D2 antagonists are discussed. 相似文献
8.
Regulation by 5-HT1A receptors of the in vivo release of 5-HT and DA in mouse frontal cortex 总被引:3,自引:0,他引:3
This study examines the effects of serotonin (5-HT)1A receptor ligands on the in vivo release of 5-HT and dopamine (DA) in the prefrontal cortex of mice. Oral MKC-242 and 8-OH-DPAT, selective 5-HT1A receptor agonists, decreased cortical 5-HT release at low and high doses, while the receptor agonists increased cortical DA release only at a high dose. Local application of the selective 5-HT1A receptor antagonist, WAY100635, via a dialysis probe, antagonized oral MKC-242-induced increase in cortical DA release, but did not affect the decrease in cortical 5-HT release. Local application of 8-OH-DPAT at 100 and 300 nM via a dialysis probe increased cortical DA release, but did not affect cortical 5-HT release. The effects of oral MKC-242 and 8-OH-DPAT on 5-HT release were blocked by low and high doses of WAY100635, while blocking the agonist-induced increase in DA release required a high dose of WAY100635. These results suggest that 5-HT release and DA release in the frontal cortex of mice are regulated by pre- and postsynaptic 5-H1A receptors, respectively, and that the presynaptic 5-HT1A receptor-mediated response is more sensitive to inhibition by WAY100635 than the postsynaptic 5-HT1A receptor-mediated response in mice. 相似文献
9.
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
10.
The serotonin 5-HT2A receptor (5-HT2AR) and dopamine D2 receptor (D2R) are high-affinity G protein-coupled receptor targets for two different classes of antipsychotic drugs used to treat schizophrenia. Interestingly, the antipsychotic effects are not based on the regulation of same signaling mediators since activation of the 5-HT2AR and of the D2R regulate Gq/11 protein and Gi/o protein, respectively. Here we use radioligand binding and second messenger production assays to provide evidence for a functional crosstalk between 5-HT2AR and D2R in brain and in HEK293 cells. D2R activation increases the hallucinogenic agonist affinity for 5-HT2AR and decreases the 5-HT2AR induced inositol phosphate production. In vivo, 5-HT2AR expression is necessary for the full effects of D2R antagonist on MK-801-induced locomotor activity. Co-immunoprecipitation studies show that the two receptors can physically interact in HEK293 cells and raise the possibility that a receptor heterocomplex mediates the crosstalk observed. The existence of this 5-HT2AR-D2R heteromer and crosstalk may have implications for diseases involving alterations of serotonin and dopamine systems and for the development of new classes of therapeutic drugs. 相似文献
11.
Low doses of the atypical antipsychotic drug risperidone are effective in patients with obsessive compulsive disorder (OCD)
not responding to serotonin (5-HT) reuptake inhibitors, although higher doses have been reported to induce OCD symptoms in
psychotic patients. Since such atypical antipsychotics exert, in addition to dopamine, 5-HT2 receptor antagonistic properties, it was deemed essential to investigate the electrophysiological effect of these agents
on 5-HT2 receptors in the rat orbito-frontal cortex (OFc), a brain region implicated in OCD. Microiontophoretic application of the
GABAA receptor antagonist bicuculline had no effect on the suppressant effect of neuronal activity in the OFc induced by microiontophoretic
application of the preferential 5-HT2A and 5-HT2C receptor agonists (+)-1-(4-iodo-2, 5-dimethoxyphenyl)-2-aminopropane (DOI) and m-chlorophenyl-piperazine (mCPP), respectively, but it antagonized the effect of GABA on the same neurons. These results indicate
a lack of involvement of GABA interneurons in the suppressant effect of DOI and mCPP. While the 5-HT2 receptor antagonist ritanserin (2 mg/kg, IV) attenuated the inhibitory effect of DOI and mCPP in the medial prefrontal cortex
(mPFc), the inhibition was unaffected in the OFc. In the mPFc, the effect of DOI and mCPP was blocked by both clozapine (1.0
and 10 mg/kg, IV) and risperidone (0.1 and 1.0 mg/kg, IV). In the OFc, only the suppressant effect of mCPP was attenuated
by both doses of clozapine but only by the high dose of risperidone. These results suggest that the 5-HT2 response in the OFc is more akin to the 5-HT2C subtype and that the deleterious effect sometimes observed with high doses of risperidone and clozapine may be due to a decrease
in 5-HT neurotransmission. In contrast, the beneficial effect of low doses of risperidone may be due, in part, to the antagonism
of dopamine receptors.
Received: 22 June 1998/Final version: 8 October 1998 相似文献
12.
Aripiprazole is the first dopamine D2/D3 receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D2 and serotonin 5-HT1A receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D2S, D2L, D3 Ser-9 and D3 Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D2/D3 receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D2S and D2L receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D3 Ser-9 and D3 Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D2/D3 receptors for clinical efficacy and safety. 相似文献
13.
Rationale Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to ì-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms.Objectives The present study was undertaken to evaluate the potential role of 5-HT1A and 5-HT1B receptors on the analgesic and antidepressant-like effect of tramadol.Methods The effect of either a selective 5-HT1A receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2–0.8, 8 mg/kg) or a selective 5-HT1B receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1′-biphenyl)-4-carboxamide; 0.2–0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants.Results The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol.Conclusions These findings suggest that 5-HT1A receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT1A autoreceptors from the raphe nuclei and spinal 5-HT1A receptors in the antinociceptive effect. In contrast, the 5-HT1A receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT1B receptors seem not to modify these effects in the models investigated. 相似文献
14.
Jones HM Travis MJ Mulligan R Bressan RA Visvikis D Gacinovic S Ell PJ Pilowsky LS 《Psychopharmacology》2001,157(1):60-66
BACKGROUND: Atypical antipsychotic drugs are thought to show a high degree of 5-HT2A receptor blockade, which may prevent the emergence of extrapyramidal symptoms. METHOD: 5-HT2A binding was estimated using 123I-5-I-R91150 and single photon emission tomography (SPET) in six schizophrenic subjects treated with quetiapine at a mean (+/-SD) daily dose of 350+/-123 mg for at least 5 weeks and a matched sample of six healthy volunteers. Clinical and side-effect ratings were performed at baseline and at the time of SPET scanning. The reference region approach was used to define a 5-HT2A binding index in the frontal and temporal cortex. Results: Quetiapine treatment resulted in a significant decline in 5-HT2A receptor availability in the frontal cortex (mean 0.98+/-0.09) relative to healthy volunteers (mean 1.33+/-0.16). All patients showed improvements in clinical symptom or side-effect ratings. The mean frontal cortex:cerebellum ratio after quetiapine treatment was significantly negatively correlated with reduction in the Abnormal Involuntary Rating scale and Simpson-Angus scores (P<0.05 Bonferroni corrected), but not with the reduction in the scores from the scale for the assessment of positive symptoms, the scale for the assessment of negative symptoms, the Montgomery-Asberg depression rating scale or patient age. CONCLUSION: Quetiapine treatment results in significant in vivo blockade of cortical 5-HT2A, similar to other atypical antipsychotic drugs. This effect may contribute to its placebo level extrapyramidal side-effect profile. 相似文献
15.
目的评价阿立哌唑治疗精神分裂症的临床疗效及安全性。方法将62例首发精神分裂症患者随机分为两组,各31例,研究组口服阿立哌唑治疗,对照组口服氯氮平治疗,疗程8周。于治疗前及治疗第2、4、8周末采用阳性与阴性症状量表评定临床疗效,副反应量表评定不良反应。结果治疗8周末,研究组总有效率为86.1%,对照组为90。3%,两组比较差异无统计学意义(P〉0.05)。阳性与阴性症状量表评分两组治疗第2周末起总分与因子均较治疗前有极显著性下降(P〈0.01);两组间周期评分比较轻微,组研究组总不良反应发生率显著低于对照组(P〈0.05)。结论阿立哌唑治疗首发精神分裂症疗效显著,与氯氮平相比,不良反应轻微,安全性更高。 相似文献
16.
The neurocognitive effects of aripiprazole: an open-label comparison with olanzapine 总被引:2,自引:0,他引:2
Kern RS Green MF Cornblatt BA Owen JR McQuade RD Carson WH Ali M Marcus R 《Psychopharmacology》2006,187(3):312-320
Rationale Cognitive deficits are a core feature of schizophrenia. As a target of intervention, improvements in cognition may lead to improvements in functional outcome.Objectives The present paper is the first report, to our knowledge, on the neurocognitive effects of aripiprazole. Unlike other second-generation antipsychotics, aripiprazole is a D2 and D3 receptor partial agonist. It is unknown what effects this unusual pharmacological profile may yield on neurocognition.Materials and methods The present open-label study included data on 169 patients with schizophrenia or schizoaffective disorder who were randomly treated with aripiprazole or olanzapine. Subjects received a neurocognitive battery at baseline, week 8, and 26.Results The aripiprazole group had a significantly greater dropout rate than the olanzapine group. Neurocognitive data were reduced through a principal components analysis that yielded a three-factor solution. The factors were general cognitive functioning, executive functioning, and verbal learning. For general cognitive functioning, both groups improved from baseline and the effects were relatively stable over the 26-week protocol. There were no differential treatment effects. For executive functioning, neither group improved significantly from baseline. For verbal learning, the aripiprazole group improved significantly from baseline to the 8th and 26th week of assessment, and there was a between-group effect favoring aripiprazole over olanzapine that was largely attributable to the differences in performance within the 8th week. Separate analyses were conducted for a measure of sustained attention (Continuous Performance Test–Identical Pairs). There were no differential treatment effects on this measure.Conclusions The findings from this open-label study suggest that the neurocognitive effects of aripiprazole are at least as good as those of olanzapine. 相似文献
17.
The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects ofm-chlorophenylpiperazine 总被引:4,自引:4,他引:0
m-Chlorophenylpiperazine (mCPP), a major metabolite of the atypical antidepressant trazadone, has been observed to produce marked physiological and behavioral effects in both humans and animals. These effects have been attributed to the interaction of mCPP with serotonergic receptors. The present study was designed to characterize those interactions of mCPP with central serotonergic receptors which mediate mCPP-induced stimulus control. A series of serotonergic antagonists (mesulergine, pizotyline, ketanserin, spiperone, risperidone, ritanserin, metergoline, pirenpirone, and LY53857) was tested for the ability to block the mCPP stimulus. The affinity of these antagonists for 5-HT2A and 5-HT2C receptors was then correlated with maximal percent inhibition of the mCPP stimulus. Kd at the 5-HT2C receptor was inversely proportional (r=–0.75,P<0.05), and Kd at the 5-HT2A receptor directly proportional (r=+0.67,P<0.05) to the maximal percent inhibition of the mCPP stimulus. The 5-HT2C selectivity ratio [Kd(5-HT2A)/Kd(5-HT2C)] of the antagonists was directly proportional (r=+0.86,P<0.01) to maximal percent inhibition of the mCPP stimulus. A multiple regressions analysis indicated that 81% of the variance in the ability of a given antagonist to block the mCPP stimulus could be predicted on the basis of its affinity for 5-HT2A and 5-HT2C receptors. It is concluded that the stimulus effects of mCPP are mediated predominantly by a combination of agonist activity at 5-HT2C receptors and antagonist activity at 5-HT2A receptors.This study was supported in part by U.S. Public Health Service grant DA 03385 (J.C.W., R.A.R.), by National Research Service Award MH 10567 (D.F.), and by a fellowship from Schering-Plough Research Institute (D.F.). Animals used in these studies were maintained in accordance with the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. 相似文献
18.
阿立哌唑治疗女性精神分裂症的疗效和安全性 总被引:1,自引:0,他引:1
目的评价阿立哌唑治疗女性精神分裂症患者的临床疗效和不良反应。方法随机抽取60例女性精神分裂症患者,给予阿立哌唑10~30mg/d口服,治疗6周。采用PANSS、TESS评定疗效和不良反应。结果脱落例,纳入统计分析59例。治疗6周后的临床显效率为83.05%(49/59),总有效率为93.22%(55/59),不良反应的发生率为32.2%(19/59)。结论阿立哌唑能有效治疗精神分裂症的阳性症状、阴性症状和一般精神病理症状。不良反应轻微,有良好的安全性和耐受性。 相似文献
19.
A. Newman-Tancredi D. Cussac V. Audinot M. J. Millan 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(6):447-453
Roxindole is a potential antidepressant agent. The present study determined its affinity and agonist efficacy at recombinant
human (h) dopamine hD2, hD3 and hD4 and serotonin (5-HT) h5-HT1A, h5-HT1B and h5-HT1D receptors. Roxindole exhibited high affinity at hD3 as well as at hD2 (short isoform) and hD4 (4-repeat isoform) receptors (pK
i values 8.93, 8.55 and 8.23, respectively). Further, it displayed high affinity at h5-HT1A receptors (pK
i = 9.42) but modest affinity at 5-HT1B and 5-HT1D receptors (pK
i values 6.00 and 7.05, respectively). In [35S]GTPγS binding experiments, roxindole was >20-fold more potent in stimulating [35S]GTPγS binding at hD3 than at hD2 or hD4 receptors (pEC50 = 9.23 vs. 7.88 and 7.69). However, whereas roxindole exhibited partial agonist activity at hD3 and hD4 sites (E
max = 30.0% and 35.1%, respectively, relative to dopamine = 100%), it only weakly activated hD2 receptors (E
max = 10.5%). Roxindole potently blocked dopamine-stimulated [35S]GTPγS binding at hD2 receptors (pK
B = 9.05). In comparison, the dopamine receptor agonist, (-)quinpirole, acted as a partial agonist at hD3 and hD4 sites (E
max = 67.4% and 66.3%, respectively) but surpassed the efficacy of dopamine at hD2 receptors (E
max = 132%). At h5-HT1A receptors, roxindole behaved as a high affinity (pK
i = 9.42) partial agonist (E
max = 59.6%, relative to 5-HT = 100%), whereas (-)quinpirole had negligible activity. The selective 5-HT1A antagonist, WAY 100,635, blocked roxindole (100 nM)-stimulated [35S]GTPγS binding at h5-HT1A receptors in a concentration-dependent manner (pK
B = 9.28). Roxindole only weakly stimulated [35S]GTPγS binding at 5-HT1B and 5-HT1D receptors (E
max = 27.1% and 13.7%). The present data suggest that roxindole activates mainly D3 vs. D2 or D4 receptors and 5-HT1A vs. 5-HT1B or 5-HT1D receptors. Activation of D3 and/or 5-HT1A receptors may thus contribute to its potential antidepressant properties.
Received: 4 February 1999 / Accepted: 29 March 1999 相似文献
20.
Adaptive changes in serotonin2A (5-HT(2A)) receptor signaling are associated with the clinical response to a number of psychiatric drugs including atypical antipsychotics and selective serotonin reuptake inhibitors. The present study examined possible mechanisms of agonist-induced desensitization of 5-HT(2A) receptors in rat hypothalamic paraventricular nucleus (PVN) after 4 and 7 days of treatment with 1mg/kg (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The magnitude of 5-HT(2A) receptor-mediated oxytocin release decreased 78% after 4 days and 61% after 7 days of DOI treatment. Similarly, the magnitude of ACTH release following 1mg/kg DOI decreased by 31% after 4 days and 38% after 7 days of DOI treatment. Treatment with DOI for either 4 or 7 days caused a significant decrease (by approximately 50%) in the high-affinity 5-HT(2A) receptor binding as measured by (125)I-DOI binding compared to saline-treated control rats. In contrast, western blot analysis demonstrated a significant increase in 5-HT(2A) receptor protein levels with 4 or 7 days of DOI treatment to 167% and 191% of control levels, respectively. Real time quantitative RT-PCR analysis revealed a small but nonsignificant increase in the levels of 5-HT(2A) mRNA following treatment with DOI for 4 or 7 days. Taken together, the 5-HT(2A) receptor-stimulated hormone responses, agonist binding data and western blot data suggest that although agonist treatment increases the levels of 5-HT(2A) receptor protein in the cell membrane, there is a reduction in the population of 5-HT(2A) receptors capable of high-affinity binding and mediating a functional response. 相似文献