The "selective" dopamine D1 receptor antagonist, SCH23390, is a potent and high efficacy agonist at cloned human serotonin2C receptors

RATIONALE: The benzazepine and "selective" dopamine D1 receptor antagonist, SCH23390 [(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-benzazepine-7-ol], shows significant affinity at native serotonin (5-HT)2C receptors. OBJECTIVES: We examined its functional actions at cloned human (h)5-HT2C receptors (VSV isoform) stably expressed in CHO cells. METHODS: Since 5-HT2C receptors are positively coupled to phospholipase C (PLC), their activation was determined by depletion of membrane-bound pools of pre-labelled [3H]phosphotidylinositol ([3H]PI). RESULTS: SCH23390 showed high affinity (Ki, 9.3 nM) at h5-HT2C sites and depleted [3H]PI with an EC50 of 2.6 nM. Its efficacy was equivalent to that of 5-HT. [3H]PI depletion elicited by SCH23390 was concentration-dependently abolished by the selective 5-HT2C antagonist, SB242,084, with a K(B) of 0.55 nM. Further, in the presence of a fixed concentration of SB242,084 (10 nM), the concentration-response curve for SCH23390 was shifted to the right without loss of maximal effect, yielding a K(B) of 0.57 nM. CONCLUSIONS: SCH23390 is a potent and high efficacy agonist at h5-HT2C receptors. Activation of 5-HT2C receptors by SCH23390 may contribute to its functional properties both in animals and in humans.     

RU 24969-induced emesis in the cat: 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1c implicated

RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg. 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of non-specific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (−)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205 930, methiothepin, trimethobenzamide or BMY 7378. An indirect arguments is presented that implicates a role for 5-HT_1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.     

Catalepsy produced by striatal microinjections of the D1 dopamine receptor antagonist SCH 23390 in neonatal rats

Systemic injection of the D₁ dopamine receptor antagonist SCH 23390 produces catalepsy that is of lesser magnitude in neonatal than in adult rats. The present experiments were conducted in order to determine if SCH 23390 would produce catalepsy in neonatal rats following intrastriatal injection and if the ontogenetic pattern of catalepsy induced by intrastriatal SCH 23390 would be similar to the pattern observed with systemic injections. Rat pups (11 or 28 days of age) were microinjected unilaterally with SCH 23390 (0.2, 1, 5 or 10 μg) and tested for catalepsy using the forepow-on-horizontal-bar test. The results demonstrated that robust catalepsy occurred at both ages following intrastriatal injection and that catalepsy induced by 5 μg SCH 23390 was of lesser magnitude in 11-day-olds than in 28-day-olds. A separate study assessed the distribution of [³H]SCH 23390 (5 μg) following intrastriatal injection in 28-day-olds. Results of the distribution study indicated that [³H]SCH 23390 was localized primarily within the striatum. Taken together, these results suggest that the striatal mechanisms for catalepsy produced by D₁ receptor blockade are present, but not fully mature, in preweanling rat pups.     

Dopamine receptor agonists and antagonists both inhibit dopamine secretion in LLC-PK1 cells

A series of dopamine receptor agonists and antagonists were tested in a renal epithelial cell line (LLC-PK₁) for their ability to alter renal dopamine synthesis and secretion. LLC-PK₁ cells were incubated with L-3,4-dihydroxyphenylalanine (L-dopa) (250 μM) in the presence and absence of dopaminergic drugs known to be selective for dopamine receptor subtypes and total dopamine synthesis and dopamine secretion into the media were measured directly by high performance liquid chromatography (HPLC). Both dopamine receptor agonists and antagonists significantly inhibited dopamine secretion from LLC-PK₁ cells at concentrations between 10–100 μM. The phenothiazines, chlorpromazine and trifluoperazine, also significantly inhibited aromatic amino acid decarboxylase activity at 100 μM. The mechanism of action for these dopaminergic drugs appeared to involve the inhibition of dopamine secretion from LLC-PK₁ cells by direct competition for outward transport by an organic cation transporter. Inhibition of dopamine secretion by these drugs was usually accompanied by significant elevations of the intracellular stores of dopamine. The results of this study suggest that caution should be exhibited in the interpretation of experiments that employ high concentrations of dopamine drugs, in order to account for the potential interaction of these agents with the renal cation transport system.     

Behavioral effects of selective and nonselective dopamine agonists on young rats after irreversible antagonism of D1 and/or D2 receptors

In general, preweanling and adult rats respond similarly when challenged with competitive dopamine (DA) agonists or antagonists. In contrast, results using a noncompetitive antagonist suggest that the D₁ and D₂ receptor systems of preweanling and adult rats differ in some critical way. To further assess this phenomenon, the behavioral effects of irreversible receptor blockade were assessed across 8 days in NPA (a nonselective DA agonist), quinpirole (a D₂ agonist), or SKF 38393 (a D₁ agonist) treated 17-day-old rat pups. The irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) did not block the locomotor activity and rearing of NPA- or quinpirole-treated rat pups, nor did EEDQ reduce SKF 38393-induced grooming. Moreover, pretreatment with EEDQ appeared to potentiate the normal increases in locomotor activity and rearing produced by NPA, but only when D₂ receptors were not protected by a previous injection of sulpiride (a D₂ antagonist). Taken together, these results are consistent with the presence of large reserves of D₁ and D₂ receptors in the preweanling rat pup.     

Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated

The 5-HT_2B receptor agonist, BW 723C86 (10, 30 mg/kg i.p. 30 min pre-test), increased the number of punishments accepted in a rat Vogel drinking conflict paradigm over 3 min, as did the benzodiazepine anxiolytics, chlordiazepoxide (2.5–10 mg/kg p.o. 1 h pre-test) and alprazolam (0.2–5 mg/kg p.o. 1 h pre-test), but not the 5-HT_2C/2B receptor agonist, m-chlorophenylpiperazine (mCPP, 0.3–3 mg/kg i.p) or the 5-HT_1A receptor agonist, buspirone (5–20 mg/kg p.o. 1 h pre-test). The effect of BW 723C86 was unlikely to be secondary to enhanced thirst, as BW 723C86 did not increase the time that rats with free access to water spent drinking, nor did it reduce sensitivity to shock in the apparatus. The anti-punishment effect of BW 723C86 was opposed by prior treatment with the 5-HT_2C/2B receptor antagonist, SB-206553 (10 and 20 mg/kg p.o. 1 h pre-test), and the selective 5-HT_2B receptor antagonist, SB-215505 (1 and 3 mg/kg p.o. 1 h pre-test), but not by the selective 5-HT_2C receptor antagonist, SB-242084 (5 mg/kg p.o.), or the 5-HT_1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test). Thus, the anti-punishment action of BW 723C86 is likely to be 5-HT_2B receptor mediated. This is consistent with previous reports that BW 723C86 exhibited anxiolytic-like properties in both the social interaction and Geller-Seifter conflict tests.     

Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents

The 5-hydroxytryptamine 5-HT_1A receptor has been the focus of considerable research effort for over a decade. However, the definitive classification of this receptor and the full characterization of its pharmacology have awaited the development of highly selective 5-HT_1A receptor antagonists. The only compounds available until recently have been either nonselective or partial 5-HT_1A receptor agonists (or a combination of both). Confusion has arisen owing to the use of different pharmacological models in examining the functional activity of 5-HT_1A receptor ligands. Several partial agonists display only antagonist activity in models of postsynaptic 5-HT_1A receptor function, whereas their agonist properties are revealed in models of presynaptic, somatodendritic 5-HT_1A autoreceptor function. In view of these considerations, the term ‘silent antagonist’ has been introduced to distinguish true 5-HT_1A receptor antagonists from partial agonists. Allan Fletcher and colleagues review the pharmacological properties of the first selective silent 5-HT_1A receptor antagonists that have been recently discovered and discuss the potential therapeutic utility of these novel compounds.     

Pharmacological studies in vivo with ICI 169,369, a chemically novel 5-HT2/5-HT1C receptor antagonist

ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) has been tested in vivo for its potency and selectivity as an antagonist at 5-HT₂ and 5-HT_1C receptors. It caused a 50% inhibition of 5-HTP-induced head twitches in mice and fenfluramine-induced hyperthermia in the rat at approximately 1 mg/kg following parenteral administration. Results showed that ICI 169,369 had good oral bioavailability, since in the fenfluramine test the oral and s.c. ID₅₀ values were similar. ICI 169,369 was a selective antagonist of 5-HT-induced bronhoconstriction in the guinea-pig and 5-HT-induced pressor effects in the anaesthetised dog. In a series of other test in vivo the compound was shown to be devoid of significant activity at α₂- and α₂-adrenoceptors, dopamine (D₂), muscarinic (M₁) and histamine (H₁) receptors at 30–100 times its ID₅₀ values used in the 5-HT tests. Thus, ICI 169, 369 is a selective, orally active 5-HT₂/5-HT_1C antagonist that should prove useful in the analysis of the role of 5-HT in physiological and pathological states.     

Behavioral and biochemical effects of the dopamine D3 receptor-selective ligand, 7-OH-DPAT, in the normal and the reserpine-treated rat

In normal rats, the dopamine D₃ receptor-selective ligand, 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT), produced biphasic effects on spontaneous locomotor activity, i.e. suppression at low doses (0.06–0.25 μmol kg⁻¹ s.c.), followed by a gradual increase in motor activity (1.0–4.0 μmol kg⁻¹). The core temperature was decreased at these latter high doses only. The reserpine-induced (8.2 μmol kg⁻¹ s.c.) increase in neostriatal 3,4-dihydroxyphenylalanine (DOPA) accumulation, following treatment with m-hydroxybenzylhydrazine-(NSD-1015) (475 μmol kg⁻¹ i.p.), was dose dependently antagonized by 7-OH-DPAT in the dose range 0.02–4.0 μmol kg⁻¹. The reserpine-induced suppression of spontaneous locomotor activity, however, was antagonized at higher doses only (1.0–4.0 μmol kg⁻¹). Finally, there were no region-selective effects of 7-OH-DPAT on DOPA accumulation in the neustriatum. Thus, it appears that the dopamine D₃ receptor-preferring ligand, 7-OH-DPAT, displays the profile of a dopamine D₂ receptor agonist, pre- and postsynaptically.     

Long-term effects of postnatal amphetamine treatment on striatal protein kinase A activity, dopamine D1-like and D2-like binding sites, and dopamine content

The purpose of the present study was to determine whether exposure to amphetamine during the preweanling period would alter dopaminergic functioning in the dorsal striatum of adult rats. In three experiments, we assessed the effects of repeated amphetamine treatment on striatal protein kinase A (PKA) activity, dopamine (DA) D₁-like and D₂-like binding sites, and DA content. Rats were pretreated with saline or amphetamine (2.5 mg/kg, ip) for 7 consecutive days starting on postnatal day (PD) 11. At PD 90, rats were killed and their dorsal striata (i.e., caudate–putamen) were removed and frozen until time of assay. Amphetamine pretreatment produced long-term reductions in both striatal PKA activity and DA content. Early amphetamine exposure also resulted in an upregulation of D₂-like binding sites, while leaving D₁-like binding sites unaffected. It is likely that the upregulation of D₂-like binding sites was stimulated by the persistent decline in striatal DA levels. Although speculative, it is possible that excess striatal D₂-like receptors were responsible for inhibiting PKA activity through actions on the cAMP signal transduction pathway. The behavioral relevance of these amphetamine-induced neurochemical changes has not yet be determined.     

Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors

In the introductory section an overview is given of the strategies which have been proposed in the search for side-effect free antipsychotics. Special attention is paid to the role of predominant 5HT₂ receptor blockade over D₂ blockade. Whereas D₂ receptor blockade seems to be essential for the treatment of positive symptoms of schizophrenia, it also underlies the induction of extrapyramidal side effects (EPS). Predominant 5HT₂ receptor blockade may reduce the EPS liability and can ameliorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eight new antipsychotics that recently entered clinical trial, 5HT₂ and D₂ receptor binding affinity (K_i values) and the rank order in affinity for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the complete receptor binding profile (including 33 radioligand receptor binding and neurotransmitter uptake models) is reported. Furthermore, for a series of 120 compounds the relative affinity for D₂ receptors and D₃ receptors (a recently cloned new dopamine receptor subtype) is compared. Finally, original findings are reported for the new antipsychotic risperidone and for haloperidol and clozapine on the in vivo occupation of neurotransmitter receptors in various brain areas after systemic treatment of rats or guinea pigs. The receptor occupation by the drugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the test compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT₂ and D₂ receptor mediated effects. With risperidone a high degree of central 5HT₂ receptor occupation was achieved before other neurotransmitter receptors became occupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D₂ receptor-mediated effects was achieved at widely varying degrees of D₂ receptor occupancy, from just about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic effects may be achieved at a relatively low degree of D₂ receptor occupancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiation between the various D₂ receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patients.     

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist

(S)1- {;2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl };-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK₁ receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK₁ receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK₁ receptors such as [Sar⁹,Met(O₂)¹¹]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 μM, it had no effect in bioassays for NK₂ ([βAla⁸]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK₃ ([MePhe⁷]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK₁ receptors was apparently non-competitive, with pD'₂ values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar⁹,Met(O₂)¹¹]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar⁹,Met(O₂¹¹]substance P-induced hypotension in dogs (ED₅₀ = 3 μg/kg i.v., bronchoconstriction in guinea-pig (ED₅₀ = 42 μg/kg i.v.) and plasma extravasation in rats (ED₅₀ = 7 μg/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED = 0.2 μg/kg i.v.).     

Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors

Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT_2A receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD and related drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT_2C receptor and an agonist at the 5HT_2A receptor. LSD exhibited agonist activity at both receptors. These data were interpreted as indicating that the 5HT_2C receptor might be the initiating site of action for hallucinogens. To test this hypothesis, recombinant cells expressing 5HT_2A and 5HT_2C receptors were used to determine the actions of LSD and lisuride. LSD and lisuride were potent partial agonists at 5HT_2A receptors with EC₅₀ values of 7.2 nM and 17 nM, respectively. Also, LSD and lisuride were partial agonists at 5HT_2C receptors with EC₅₀ values of 27 nM and 94 nM, respectively. We conclude that lisuride and LSD have similar actions at 5HT_2A and 5HT_2C receptors in recombinant cells. As agonist activity at brain 5HT_2A receptors has been associated with hallucinogenic acitivity, these results indicate that lisuride may possess hallucinogenic activity, although the psychopharmacological effects of lisuride appear to be different from the hallucinogenic effects of LSD. Received: 19 September 1997/Final version: 31 October 1997     

5-HT1A和5-HT2A/2C受体在粉防己碱增强戊巴比妥钠睡眠中的介导作用

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。     

BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex

In the search for antidepressant agents with a rapid onset of action, we have found that compound BIMT 17 (1-[2-[4-(3-trifluoromethylphenyl)piperazin1-yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity for cerebral cortical 5-HT_1A (pK _i = 7.72) and 5-HT_2A (pK _i = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT_2C. BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC₅₀ = 6.09) and in the hippocampus (pEC₅₀ = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pK _i = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT_1A receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 {1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphtyl)]piperazine, claimed to be 5-HT_1A receptor agonists, did not reduce forskolin-stimulated cAMP formation in the cerebral cortex.On the basis of these data, it was concluded that BIMT 17 was the only compound that behaved as a full agonist with respect to the CAMP response in the cortex, while exerting concurrent agonism at 5-HT_1A receptors and antagonism at 5-HT_2A receptors. These characteristics might explain the peculiar behaviour of BIMT 17 in mimicking the inhibitory action of 5-HT on the basal firing rate of the cortical neurons (see accompanying paper).     

Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT2A receptor binding in the rat

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-HT_1A and 5-HT_2A 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-HT_1A binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT_1A binding (frontal cortex, remaining cortex and hippocampus) or 5-HT_2A binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT_2A binding or postsynaptic 5-HT_1A binding. Furthermore, 3-week CTD did not significantly alter 5-HT_1A binding but significantly increased cortical 5-HT_2A 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-HT_2A-receptor binding. Conclusion ATD-induced reduction in somatodendritic 5-HT_1A autoreceptor binding may represent an intrinsic ‘homeostatic response’ reducing serotonergic feedback in dorsal raphe projection areas. In contrast, the increase in 5-HT_2A receptor after CTD may be a compensatory response to a long-term reduction in 5-HT.     

The pharmacology of the hypothermic response in mice to 8-hydroxy-2-(DI-n-propylamino)tetralin (8-OH-DPAT) : A model of presynaptic 5-HT1 function

In the mouse, injection (subcutaneously) of the putative 5-HT₁ agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), produced a dose-related hypothermia (ED₅₀:0.36mg/kg). A maximum response was elicited by intracerebroventricular (i.c.v.) injection of 8-OH-DPAT (3 μg) and almost abolished by lesion of 5-HT-containing terminals in the brain with 5,7-dihydroxytryptamine (5,7-DHT; i.c.v.) or long-term treatment with p-chlorophenylalanine. The response was unaltered by a range of neurotransmitter antagonists: prazosin (α₁-adrenoceptor), idazoxan (α₂-adrenoceptor), metoprolol (β₁-adrenoceptor), erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol (β₂-adrenoceptor), (?)propranolol or (±)pindolol (β-adrenoceptor), flupenthixol (dopamine) or Ro 15–1788 (benzodiazepine binding site). Classical 5-HT antagonists (methysergide, metergoline, cinanserin and methiothepin) were either without effect or facilitated the response and the 5-HT₂ antagonist, ritanserin was also without effect. In contrast, quipazine and haloperidol produced a dose-related antagonism of the response.Since the response was almost abolished by a lesion induced by 5,7-DHT and was antagonised by quipazine, which is known to antagonise presynaptic 5-HT function in vitro, it is suggested that the hypothermie response is due to 8-OH-DPAT acting as an agonist at a presynaptic 5-HT receptor, which also appears to be sensitive to butyrophenones (the antagonism elicited by haloperidol but not by flupenthixol). The hypothermie response of mice to 8-OH-DPAT, therefore, may provide a simple and convenient in vivo model in which to measure the function of the presynaptic 5-HT receptor.     

A Search for New 5-HT1A/5-HT2A Receptor Ligands. In Vitro and in vivo Studies of 1-[ω-(4-Aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones

A series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5-HT_1A/5-HT_2A activity. The majority of those compounds ( 2–5, 7, 10–13 ) exhibited a high 5-HT_1A (K_i = 2 – 44 nM) and/or 5-HT_2A affinity (K_i = 51 and 39 for 5 and 7 , respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT_1A receptors. The 5-HT_2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-6-fluoroindolin-2(1H)-one ( 5 ) and 1-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}indolin-2(1H)-one ( 7 ), demonstrated a high 5-HT_1A/5-HT_2A affinity and an in vivo antagonistic activity towards both receptor subtypes.     

白香丹含药血清对大鼠海马神经元中5-羟色胺2C受体的表达及其下游信号通路中IP_3的影响

目的观察白香丹胶囊含药血清对原代海马神经元中5-羟色胺2C受体(5-HTR2C)蛋白表达水平及下游信号通路中IP3含量的影响,探讨其可能的中枢作用机制。方法采用情志刺激为主多因素造模法制备经前期综合征(PMS)肝气逆证大鼠模型,给予白香丹干预,制备大鼠含药血清,结合中药血清药理学,对体外培养的新生大鼠原代海马神经元进行不同血清干预,运用Western blot方法检测海马神经元中5-HTR2C蛋白表达水平,运用ELISA法检测各组海马神经细胞内IP3的含量。结果与正常血清组相比,PMS肝气逆模型血清组海马神经元的5-HTR2C蛋白表达水平和下游信号通路中IP3含量均明显升高(P<0.01,P<0.01),白香丹含药血清能够明显降低5-HTR2C蛋白表达水平和IP3的含量(P<0.01,P<0.01)。结论 PMS肝气逆证模型大鼠血清使海马神经元中5-HTR2C蛋白表达异常升高,同时,可引起第二信使IP3含量升高;白香丹胶囊可能通过降低5-HTR2C蛋白表达水平,改变其下游信号通路中IP3的含量而发挥疗效。