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1.
  1. The effects induced by 5-hydroxytryptamine (5-HT) on gastrointestinal myoelectric activity in conscious sheep were recorded through electrodes chronically implanted and analysed by computer. The 5-HT receptors and the cholinergic neuronal pathways involved in these actions were investigated.
  2. The intravenous (i.v.) administration of 5-HT (2, 4 and 8 μg kg−1 min−1, 5 min) induced an antral inhibition concomitant with a duodenal activity front that migrated to the jejunum, followed by a period of intestinal inactivity. This myoelectric pattern closely resembled that observed in the phases III and I of the migrating myoelectric complex (MMC) in sheep. The 0.5 μg kg−1 min−1 dose evoked the same pattern in only two out of the six animals used. Likewise, the 1 μg kg−1 min−1 dose similarly affected four of the six animals. In addition, a transient stimulation was observed in the antrum and jejunum when the two highest doses were used.
  3. The 5-HT1 antagonist, methiothepin (0.1 mg kg−1), the 5-HT2 antagonists, ritanserin (0.1 mg  kg−1) and ketanserin (0.3 mg  kg−1), the 5-HT3 antagonists, granisetron (0.2 mg kg−1) and ondansetron (0.5 mg kg−1), as well as the 5-HT4 antagonist, GR113808 (0.2 mg kg−1), did not modify the spontaneous gastrointestinal myoelectric activity. However, the cholinoceptor antagonists, atropine (0.2 mg kg−1) and hexamethonium (2 mg kg−1), inhibited gastrointestinal activity.
  4. When these antagonists were injected i.v. 10 min before 5-HT (2 or 4 μg kg−1 min−1, 5 min), only GR113808, atropine and hexamethonium were able to modify the 5-HT-induced actions, all of them being completely blocked by the three antagonists.
  5. Our data show that 5-HT initiates a MMC-like pattern in the gastrointestinal area in sheep through 5-HT4 receptors. Furthermore, these actions are mediated by cholinergic neural pathways involving muscarinic and nicotinic receptors. However, our results do not indicate a role for either 5-HT1, 5-HT2 or 5-HT3 receptors in the 5-HT-induced effects.
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2.
  1. The receptors responsible for 5-hydroxytryptamine (5-HT)-mediated contraction of rabbit isolated epicardial coronary artery denuded of endothelium was examined by bioassay.
  2. A variety of 5-HT mimetics caused concentration-dependent contractions. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT)>5-HT>(±)-α-methyl-5-hydroxytryptamine ((±)-α-me-5-HT)=sumatriptan. This was not consistent with relative potencies at any single recognized 5-HT receptor, suggesting the presence of a mixed receptor population. In one subset of preparations precontracted with U46619 (10–30 nM) with the endothelium intact, none of the agonists caused a relaxation.
  3. Contractions to 5-HT were antagonized by ketanserin, a 5-HT2A-selective antagonist, but the displacement of concentration-response curves was inconsistent with an interaction between 5-HT and a single receptor population; the slope of regression between antagonist log M concentration and agonist log (concentration-ratio −1) was shallow (0.57). Responses to 5-HT were also antagonized by the 5-HT1B/1D-receptor antagonist GR127935 and, again, the slope of regression was shallow (0.68). These data suggest a possible involvement of 5-HT2A and 5-HT1B or 5-HT1D receptors in the response to 5-HT.
  4. Contractions to (±)-α-me-5-HT, which is selective for 5-HT2A over 5-HT1B and 5-HT1D receptors, were competitively antagonized by low concentrations of ketanserin. The regression between antagonist log M concentration and agonist log (concentration-ratio −1) fitted the Schild equation with a slope that was not significantly different from unity (0.95), giving a pA2 value of 9.0. GR127935 (3–30 nM), had no effect on the contractile response to (±)-α-me-5-HT. These data establish, unequivocally, the presence of 5-HT2A receptors in the tissue.
  5. Sumatriptan, a relatively selective 5-HT1B/1D-receptor agonist, induced contractions that were antagonized competitively by GR127935 (3–30 nM), although there was a reduction in the maximum response when concentrations of GR127935 exceeded 3 nM. The apparent pA2 (estimated by imposing a unit slope on the log agonist (concentration-ratio −1) value in the presence of 3 nM GR127935) was 8.92. Contractions to sumatriptan were not affected by low (5-HT2A receptor-selective) concentrations of ketanserin, but were antagonized in a competitive manner at higher concentrations (pA2 6.5). These data appear to confirm the presence of 5-HT1B and/or 5-HT1D receptors in the tissue.
  6. Antagonism of 5-HT responses by GR127935 was reassessed after blockade of 5-HT2A receptors with 1 μM ketanserin. Under these conditions, GR127935 was able to antagonize 5-HT-induced contractions fully. The slope of regression between log M antagonist concentration and log agonist (concentration-ratio −1) fitted the Schild equation with a slope not significantly different from unity (1.1) (albeit there was still a reduction in maximum response when GR127935 concentration exceeded 3 nM). The apparent pA2 value was 8.8. This reinforces the evidence that 5-HT1B and/or 5-HT1D receptors contribute to the effects of 5-HT in the tissue.
  7. In conclusion, in endothelium denuded rabbit epicardial coronary arteries, 5-HT activates 5-HT2A and 5-HT1D and/or 5-HT1B receptors to cause contraction. This appears to be similar to the situation in man.
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3.
The dentate gyrus of the hippocampus has been implicated in mechanisms of action of selective serotonin reuptake inhibitors (SSRIs). We have recently demonstrated that the SSRI fluoxetine can reverse the state of maturation of the adult dentate granule cells and enhances serotonin 5-HT4 receptor-mediated synaptic potentiation at the synapses formed by their mossy fiber axons. Here, we show that fluoxetine can induce long-lasting enhancement of dopaminergic modulation at the mossy fiber synapse. Synaptic responses arising from the mossy fiber-CA3 pyramidal cell synapse were recorded using acute mouse hippocampal slices. Dopamine potentiates mossy fiber synaptic transmission by activating D1-like receptors. Chronic fluoxetine treatment induced a prominent increase in the magnitude of dopamine-induced synaptic potentiation, and this effect was maintained at least up to 1 month after withdrawal of fluoxetine. Quantitative autoradiography revealed that binding of the D1-like receptor ligand [3H]SCH23390 was selectively increased in the dentate gyrus and along the mossy fiber in fluoxetine-treated mice. However, binding of the 5-HT4 receptor ligand [3H]GR113808 was not significantly changed. These results suggest that chronic fluoxetine enhanced the dopaminergic modulation at least in part by upregulating expression of D1-like receptors, while the enhanced serotonergic modulation may be mediated by modifications of downstream signaling pathways. These enhanced monoaminergic modulations would greatly increase excitatory drive to the hippocampal circuit through the dentate gyrus. The highly localized upregulation of D1-like receptors further supports the importance of the dentate gyrus in the mechanism of action of SSRIs.  相似文献   

4.
  1. It was previously shown that porcine cranial arteriovenous anastomoses (AVAs) constrict to 5-hydroxytryptamine (5-HT), ergotamine, dihydroergotamine, as well as sumatriptan and that sumatriptan acts exclusively via 5-HT1B/1D receptors. The present study was devoted to establish the contribution of 5-HT1B/1D receptors in the constriction of AVAs elicited by 5-HT (in presence of 0.5 mg kg−1 ketanserin), ergotamine and dihydroergotamine in anaesthetized pigs.
  2. Intracarotid infusion of 5-HT (2 μg kg−1 min−1) and intravenous doses of ergotamine (2.5–20 μg kg−1) and dihydroergotamine (3–100 μg kg−1) reduced AVA and increased nutrient blood flows and vascular conductances. The vasodilator response to 5-HT, observed mainly in the skin and ear, was much more prominent than that of the ergot alkaloids.
  3. Treatment with the 5-HT1B/1D receptor antagonist GR127935 (0.5 mg kg−1, i.v.) significantly attenuated both ergot-induced AVA constriction and arteriolar dilatation, whereas GR127935 only slightly affected the carotid vascular effects of 5-HT.
  4. The results suggest that 5-HT constricts carotid AVAs primarily via receptors, which seem to differ from those (5-HT1B/1D) stimulated by sumatriptan. The ergot alkaloids produce AVA constriction for a substantial part via 5-HT1B/1D receptors, but also stimulate unidentified receptors. Both these non-5-HT1B/1D receptors may be targets for the development of novel antimigraine drugs.
  5. The moderate vasodilator response to the ergot derivatives seems to be mediated, at least in part, by 5-HT1B/1D receptors, whereas the arteriolar dilatation caused by 5-HT may be mediated by other, possibly 5-HT7 receptors.
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5.
  1. The mechanism of action of sumatriptan on coronary flow was examined before and after two different forms of endothelial ablation in guinea-pig isolated hearts. The mechanism was assessed in terms of the influence of the integrity of the coronary endothelium, the role of release of nitric oxide (NO) from the endothelium, and the receptor subtypes mediating the effects.
  2. Continuous perfusion with sumatriptan reduced coronary flow, but the concentration-response curve was v-shaped. Sumatriptan (0.001–0.1 μM) caused a concentration-dependent decrease in coronary flow with the maximum effect achieved at 0.23±0.04 μM. The pEC50 was 8.49±0.07. At higher concentrations (0.1–10 μM) there was a concentration-dependent diminution of the vasoconstrictor effect. Endothelial ablation by saponin removed the diminution in the vasoconstrictor effect. In contrast, pretreatment with NG-nitro L-arginine methyl ester (L-NAME) (100 μM, 45 min perfusion) did not affect it. This was despite both saponin and L-NAME being effective in reducing basal release of NO into the coronary effluent (measured by chemiluminescence) to the same extent (71±3 and 73±2%, respectively).
  3. GR127935, a selective 5-hydroxytryptamine1D (5-HT1D) receptor antagonist (3 and 10 nM), which by itself had no effect on coronary flow or NO release, antagonized the vasoconstrictor response to sumatriptan and unmasked a sumatriptan-induced concentration-dependent increase in coronary flow and NO release. These increases in coronary flow and NO release were abolished by pretreatment with either saponin or L-NAME.
  4. Mesulergine, a 5-HT2 receptor antagonist which had no effect by itself on basal coronary flow or NO release, inhibited the vasodilator response to sumatriptan that occurred in the presence of GR127935, and actually enhanced the vasoconstrictor response, increasing the maximum fall in coronary flow from −3.9±0.4 to −5.2±0.4 ml min−1 g−1 (P<0.05). The diminution of vasoconstrictor effect of sumatriptan was abolished by mesulergine and by pretreatment with saponin, but not by L-NAME.
  5. In conclusion, guinea-pig coronary arteries constrict to low concentrations of sumatriptan, causing a reduction in coronary flow. This effect appears to be caused by 5-HT1D agonism with the receptors located on the coronary vascular smooth muscle. With higher concentrations of sumatriptan this is partially offset by a weaker vasodilator effect, which is caused by low affinity 5-HT2 agonism. Although this effect is endothelium-dependent, it is not caused by the release of NO. Interestingly, when the vasoconstrictor effect of sumatriptan was inhibited by the 5-HT1D antagonist GR127935, a high affinity vasodilator effect of sumatriptan was unmasked. This is 5-HT2 receptor mediated and is caused by release of NO from the coronary endothelium.
  6. In man, sumatriptan and 5-HT may both be capable of causing pathogenic coronary vasoconstriction. The implications of the present data are that the scope for this may depend greatly on (i) the extent of underlying endothelial dysfunction, (ii) the extent of endothelial 5-HT2 receptor-mediated release of vasodilator autacoids (which include NO) and (iii) the extent of smooth muscle 5-HT1D receptor-mediated vasoconstriction.
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6.
  1. The effects of GR205171, a selective tachykinin NK1 receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet.
  2. Animals receiving cisplatin (5.5 mg kg−1, i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0−15 min), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg−1), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg−1) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n=8), 0.3 (n=16) or 1.0 (n=13) mg kg−1. In eight additional piglets, GR205171 (1 mg kg−1) was administered 15 min before the onset of the delayed phase (T16−15 min). A further five piglets received GR205171 (1 mg kg−1) every 6 h throughout the experiment.
  3. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0−15 min, and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0−15 min with GR205171 1 mg kg−1, eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg−1) at T16−15 min exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171.
  4. These results demonstrate the long-lasting anti-emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.
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7.
Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT4 receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety- and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT4 receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT4 receptor activation is necessary for these effects of SSRIs. 5-HT4 receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.  相似文献   

8.

Background and purpose:

Activation of post-synaptic 5-HT1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A receptor agonist.

Experimental approach:

F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo.

Key results:

F15599 was highly selective for 5-HT1A receptors in binding experiments and in [35S]-GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT1A receptors. In cell lines expressing h5-HT1A receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT1A receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [35S]-GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gαi than Gαo activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A receptors in vivo almost as potently as F13714.

Conclusions and implications:

F15599 showed a distinctive activation profiles for 5-HT1A receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.  相似文献   

9.
  1. G-protein activation by the 5-ht1F receptor agonist 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate (LY334370) was investigated by use of autoradiography of receptor-activated G-proteins in guinea-pig brain sections and [35S]-GTPγS binding responses in cell lines stably expressing human 5-HT1A (h 5-HT1A) receptors.
  2. LY334370 (10 μM) caused little or no stimulation of [35S]-GTPγS binding in guinea-pig brain regions enriched in 5-ht1F binding sites (e.g., claustrum, caudate/putamen and thalamic nuclei), as identified by labelling with 10 nM [3H]-sumatriptan plus 10 nM 5-carboxamidotryptamine (5-CT).
  3. Application of LY334370 (10 μM) to guinea-pig brain sections resulted in an increase of [35S]-GTPγS binding in hippocampus (123±17%), lateral septum (58±14%), dorsal raphe (57±10%), entorhinal (37±11%) and cingulate cortex (28±10%). This distribution fits with the G-protein activation mediated by 5-HT1A receptors as found with lisuride (10 μM), and labelling of 5-HT1A receptors by 140 pM [125I]-4-(2′-methoxy-phenyl)-1-[2′-(n-2′′-pyridinyl)-p-iodobenzamido]-ethyl-piperazine (p-MPPI).
  4. The LY334370-mediated [35S]-GTPγS response was antagonized by the selective, silent 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635, 1 μM) in each of the brain structures investigated. The distribution pattern of the [35S]-GTPγS binding response and the antagonist profile suggest that the LY334370-induced response in guinea-pig brain is mediated by 5-HT1A receptors.
  5. The maximal LY334370-induced [35S]-GTPγS binding response (83 to 94%) in membranes of recombinant C6-glial/h 5-HT1A and HeLa/h 5-HT1A cells was close to that of 5-HT, suggesting LY334370 to exert high intrinsic activity at h 5-HT1A receptors.
  6. In conclusion, in guinea-pig brain sections and recombinant cell lines the 5-ht1F receptor agonist LY334370 causes G-protein activation that is mediated by 5-HT1A receptors. Caution should be taken when employing this ligand as a putative selective 5-ht1F agonist.
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10.
  1. Bradykinin has multiple effects on differentiated NG108-15 neuroblastoma×glioma cells: it increases Ins(1,4,5)P3 production and intracellular Ca2+ concentration [Ca2+]i, evokes a Ca2+ activated K+ current (IK(Ca)) and inhibits M current (IM). We studied the effect of the aminosteroid U73122 and the antibiotic neomycin, both putative blockers of phospholipase C (PLC), on these four bradykinin effects.
  2. Preincubation with 1 or 5 μM U73122 for 15 min partly suppressed Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by 1 μM bradykinin. U73122 10 μM caused total and irreversible inhibition. The inactive analogue U73343 was without effect.
  3. Resting levels of Ins(1,4,5)P3 were not affected. However, resting [Ca2+]i was increased by 10 μM U73122, but not by U73343. Individual cells responded to 10 μM U73122 with a small increase in [Ca2+]i, followed in some cells by a large further rise.
  4. Pretreatment of whole-cell clamped cells with 1 μM U73122 for 30 min reduced the bradykinin-induced IK(Ca) to a fifth of its normal size. To suppress it totally, a 7–12 min pretreatment with 5 μM U73122 was required. Again, U73343 was without effect.
  5. U73122 and U73343 at concentrations of 5–10 μM irreversibly decreased the holding current (Ih) which at a holding potential of −30 or −20 mV mainly flows through open M channels. The decrease was often preceded by a transient increase.
  6. M current (IM) measured with 1 s pulses, was also decreased by 5–10 μM U73122 and U73343, but short applications of U73122 could cause a small increase. The bradykinin-induced inhibition of IM was not affected by U73122.
  7. Preincubation with 1 or 3 mM neomycin for 15 min did not affect Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by bradykinin. Pretreatment with 3 mM neomycin for about 20 min diminished the bradykinin-induced IK(Ca) to a fifth of its normal size.
  8. The four main conclusions drawn from the results are: (a) U73122 suppresses bradykinin-induced PLC activation and IK(Ca), but not IM inhibition. (b) This indicates that the transient outward current IK(Ca), but not the decrease of IM in response to bradykinin, is mediated by PLC. (c) U73122 itself inhibits IM and mobilizes Ca2+ from intracellular stores. (d) Externally applied neomycin is not an effective inhibitor of PLC-mediated signalling pathways in NG108-15 cells.
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11.

Background and Purpose

Pattern separation, that is, the formation of distinct representations from similar inputs, is an important hippocampal process implicated in cognitive domains like episodic memory. A deficit in pattern separation could lead to memory impairments in several psychiatric and neurological disorders. Hence, mechanisms by which pattern separation can be increased are of potential therapeutic interest.

Experimental approach

5-HT1A receptors are involved in spatial memory. Herein we tested the ‘biased’ 5-HT1A receptor agonists F15599, which preferentially activates post-synaptic heteroreceptors, and F13714, which preferentially activates raphe-located autoreceptors, in rats in a novel spatial task assessing pattern separation, the object pattern separation (OPS) task.

Key Results

The acetylcholinesterase inhibitor donepezil, which served as a positive control, significantly improved spatial pattern separation at a dose of 1 mg·kg−1, p.o. F15599 increased pattern separation at 0.04 mg·kg−1, i.p., while F13714 decreased pattern separation at 0.0025 mg·kg−1, i.p. The selective 5-HT1A receptor antagonist WAY-100635 (0.63 mg·kg−1, s.c.) counteracted the effects of both agonists. These data suggest that acute preferential activation of post-synaptic 5-HT1A heteroreceptors improves spatial pattern separation, whereas acute preferential activation of raphe-located 5-HT1A autoreceptors impairs performance.

Conclusions and Implications

We successfully established and validated a novel, simple and robust OPS task and observed a diverging profile of response with ‘biased’ 5-HT1A receptor agonists based on their targeting of receptors in distinct brain regions. Our data suggest that the post-synaptic 5-HT1A receptor consists of a potential novel molecular target to improve pattern separation performance.  相似文献   

12.

Background and purpose:

F15599, a novel 5-hydroxytryptamine (5-HT)1A receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT1A heteroreceptors.

Experimental approach:

In vivo single unit and local field potential recordings and microdialysis in the rat.

Key results:

F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 µg·kg−1 i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 µg·kg−1 i.v.). Both effects were reversed by the 5-HT1A antagonist (±)WAY100635. F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 µg·kg−1 i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 µg·kg−1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (±)WAY100635.

Conclusions and implications:

These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT1A receptors in PFC rather than somatodendritic 5-HT1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT1A receptor agonists, which preferentially activate somatodendritic 5-HT1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.  相似文献   

13.
  1. The observation that 5-hydroxytryptamine (5-HT) is effective in treating acute attacks of migraine when administered intravenously resulted in a research effort that led to the discovery of the 5-HT1B/1D receptor agonist sumatriptan.
  2. Clinical experience has shown sumatriptan to be an effective treatment with some limitations, such as relatively poor bioavailability, which naratriptan was developed to address. Increasing bioavailability has been achieved with greater lipophilicity and thus the potential for greater activity in the central nervous system.
  3. In this study the increased access to central sites has been exploited in an attempt to characterize the pharmacology of those central receptors with the newer tools available. Trigeminovascular activation was examined in the model of superior sagittal sinus stimulation.
  4. Cats were anaesthetized with α-chloralose (60 mg kg−1, intraperitoneal), paralyzed (gallamine 6 mg kg−1, intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation (250 μs pulses, 0.3 Hz, 100 V) by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation.
  5. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.69±0.1 at a latency of 9.2±0.2 ms. Intravenous (i.v.) administration of naratriptan at clinically relevant doses (30 and 100 μg kg−1), inhibited neuronal activity in trigeminal neurones of the C2 dorsal horn, reducing probability of firing without affecting latency.
  6. The effect of naratriptan could be reversed by administration of the selective 5-HT1B/1D receptor antagonist GR127935 (100 μg kg−1, i.v.).
  7. These data establish that naratriptan acts on central trigeminal neurones since sagittal sinus stimulation activates axons within the tentorial nerve and there are no inhibitory effects mediated within the trigeminal ganglion. Furthermore, given that this inhibition could be reversed by the relatively selective 5-HT1B/1D receptor antagonist GR127935, it is highly likely that the anti-migraine effects of drugs of this class with central nervous system access are mediated, at least in part, by 5-HT1B/1D receptors within the trigeminal nucleus.
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14.
Monitoring changes in opioid receptor binding with positron emission tomography (PET) could lead to a better understanding of tolerance and addiction because altered opioid receptor dynamics following agonist exposure has been linked to tolerance mechanisms. We have studied changes in kappa opioid receptor (KOR) binding availability in vivo with PET following kappa opioid agonist administration. Male Sprague–Dawley rats (n=31) were anesthetized and treated with the (KOR) agonist salvinorin A (0.01–1.8 mg/kg, i.v.) before administration of the KOR selective radiotracer [11C]GR103545. When salvinorin A was administered 1 min prior to injection of the radiotracer, [11C]GR103545 binding potential (BPND) was decreased in a dose-dependent manner, indicating receptor binding competition. In addition, the unique pharmacokinetics of salvinorin A (half-life ~8 min in non-human primates) allowed us to study the residual impact on KOR after the drug had eliminated from the brain. Salvinorin A was administered up to 5 h prior to [11C]GR103545, and the changes in BPND were compared with baseline, 2.5 h, 1 h, and 1 min pretreatment times. At lower doses (0.18 mg/kg and 0.32 mg/kg) we observed no prolonged effect on KOR binding but at 0.60 mg/kg salvinorin A induced a sustained decrease in KOR binding (BPND decreased by 40–49%) which persisted up to 2.5 h post administration, long after salvinorin A had been eliminated from the brain. These data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET.  相似文献   

15.

Background and purpose:

5-Hydroxytryptamine (5-HT) is a key regulator of the gastrointestinal system and we have shown that submucosal neuronal 5-HT3 receptors exerted a novel inhibitory effect on colonic ion transport. The aim of the present study was to investigate the precise mechanism(s) underlying this inhibitory effect.

Experimental approach:

Mucosa/submucosa or mucosa-only preparations from rat distal colon were mounted in Ussing chambers for measurement of short-circuit current (Isc) as an indicator of ion secretion. Somatostatin release was determined with radioimmunoassay. Intracellular cAMP content was measured with enzyme-linked immunoadsorbent assay (elisa). Immunohistochemical techniques were used to study the expression of 5-HT3 receptors, somatostatin and somatostatin receptors in colonic tissue.

Key results:

In rat distal colonic mucosa/submucosa preparations, pretreatment with 5-HT3 receptor antagonists enhanced 5-HT-induced increases in Isc. However, in mucosa-only preparations without retained neural elements, pretreatment with 5-HT3 receptor antagonists inhibited 5-HT-induced ΔIsc. Pretreatment with a somatostatin-2 (sst2) receptor antagonist in mucosa/submucosa preparations augmented 5-HT-induced ΔIsc. Combination of sst2 and 5-HT3 receptor antagonists did not cause further enhancement of 5-HT-induced ΔIsc. Moreover, both sst2 and 5-HT3 receptor antagonists enhanced 5-HT-induced increase in intracellular cAMP concentration in the mucosa/submucosa preparations. 5-HT released somatostatin from rat colonic mucosa/submucosa preparations, an effect prevented by pretreatment with 5-HT3 receptor antagonists. Immunohistochemical staining demonstrated the presence of 5-HT3 receptors on submucosal somatostatin neurons and of sst2 receptors on colonic mucosa.

Conclusion and implications:

Activation of neuronal 5-HT3 receptors in the submucosal plexus of rat colon suppressed 5-HT-induced ion secretion by releasing somatostatin from submucosal neurons.  相似文献   

16.

Background and purpose:

Many cystic fibrosis (CF)-associated mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels affect CFTR-activated HCO3− transport more than Cl− transport. Targeting the CFTR HCO3− conductance, if possible, may therefore be of major therapeutic benefit. In the present study, we examined the effects of genistein and forskolin on duodenal mucosal HCO3− and Cl− secretion.

Experimental approach:

Murine duodenal mucosal HCO3− and Cl− secretions were examined in vitro in Ussing chambers by the pH stat and short circuit current (Isc) techniques.

Key results:

Genistein markedly stimulated duodenal HCO3− secretion and Isc in a dose-dependent manner in CFTR wild-type mice, but not in CFTR null mice. CFTRinh-172, a highly specific CFTR inhibitor, inhibited genistein-stimulated duodenal HCO3− secretion and Isc in wild-type mice. Genistein induced 59% net HCO3− increase and 123% net Isc increase over basal value, whereas forskolin, an activator of adenylate cyclase, induced 94% net HCO3− increase and 507% net Isc increase, indicating that, compared with forskolin, genistein induced a relatively high HCO3−/Isc ratio. Further data showed that CFTR HCO3−/Cl− conductance ratio was 1.05 after genistein stimulation, whereas after forskolin stimulation, the CFTR HCO3−/Cl− conductance ratio was 0.27.

Conclusions and implications:

Genistein stimulates duodenal HCO3− and Cl− secretion through CFTR, and has a relatively high selectivity for the CFTR HCO3− conductance, compared with forskolin. This may indicate the feasibility of selective targeting of the HCO3− conductance of the CFTR channels.  相似文献   

17.
  1. 5-Hydroxytryptamine (5-HT; 1 nM–100 μM) concentration-dependently inhibited the amplitude and frequency of spontaneous contractions in longitudinal and circular muscles of the porcine myometrium. The circular muscle (EC50; 68–84 nM) was more sensitive than the longitudinal muscle (EC50; 1.3–1.44 μM) to 5-HT. To characterize the 5-HT receptor subtype responsible for inhibition of myometrial contractility, the effects of 5-HT receptor agonists on spontaneous contractions and of 5-HT receptor antagonists on inhibition by 5-HT were examined in circular muscle preparations.
  2. Pretreatment with tetrodotoxin (1 μM), propranolol (1 μM), atropine (1 μM), guanethidine (10 μM) or L-NAME (100 μM) failed to change the inhibition by 5-HT, indicating that the inhibition was due to a direct action of 5-HT on the smooth muscle cells.
  3. 5-CT, 5-MeOT and 8-OH-DPAT mimicked the inhibitory response of 5-HT, and the rank order of the potency was 5-CT>5-HT>5-MeOT>8-OH-DPAT. On the other hand, oxymethazoline, α-methyl-5-HT, 2-methyl-5-HT, cisapride, BIMU-1, BIMU-8, ergotamine and dihydroergotamine had almost no effect on spontaneous contractions, even at 10–100 μM.
  4. Inhibition by 5-HT was not decreased by either pindolol (1 μM), ketanserin (1 μM), tropisetron (10 μM), MDL72222 (1 μM) or GR113808 (10 μM), but was antagonized by the following compounds in a competitive manner (with pA2 values in parentheses): methiothepin (8.05), methysergide (7.92), metergoline (7.4), mianserin (7.08), clozapine (7.06) and spiperone (6.86).
  5. Ro 20-1724 (20 μM) and rolipram (10 μM) significantly enhanced the inhibitory response of 5-HT, but neither zaprinast (10 μM) nor dipyridamole (10 μM) altered the response of 5-HT.
  6. 5-HT (1 nM–1 μM) caused a concentration-dependent accumulation of intracellular cyclic AMP in the circular muscle.
  7. From the present results, the 5-HT receptor, which is functionally correlated with the 5-HT7 receptor, mediates the inhibitory effect of 5-HT on porcine myometrial contractility. This inhibitory response is probably due to an increase in intracellular cyclic AMP through the activation of adenylate cyclase that is positively coupled to 5-HT7 receptors.
  相似文献   

18.

Background and purpose:

Kv1.5 channels conduct the ultra-rapid delayed rectifier potassium current (IKur), and in humans, Kv1.5 channels are highly expressed in cardiac atria but are scarce in ventricles. Pharmacological blockade of human Kv1.5 (hKv1.5) has been regarded as effective for prevention and treatment of re-entry-based atrial tachyarrhythmias. Here we examined blockade of hKv1.5 channels by LY294002, a well-known inhibitor of phosphatidylinositol 3-kinase (PI3K).

Experimental approach:

hKv1.5 channels were heterologously expressed in Chinese hamster ovary cells. Effects of LY294002 on wild-type and mutant (T462C, H463C, T480A, R487V, A501V, I502A, I508A, L510A and V516A) hKv1.5 channels were examined by using the whole-cell patch-clamp method.

Key results:

LY294002 rapidly and reversibly inhibited hKv1.5 current in a concentration-dependent manner (IC50 of 7.9 µmol·L−1). In contrast, wortmannin, a structurally distinct inhibitor of PI3K, had little inhibitory effect on hKv1.5 current. LY294002 block of hKv1.5 current developed with time during depolarizing voltage-clamp steps, and this blockade was also voltage-dependent with a steep increase over the voltage range for channel openings. The apparent binding (k+1) and unbinding (k−1) rate constants were calculated to be 1.6 µmol·L−1−1·s−1 and 5.7 s−1 respectively. Inhibition by LY294002 was significantly reduced in several hKv1.5 mutant channels: T480A, R487V, I502A, I508A, L510A and V516A.

Conclusions and implications:

LY294002 acts directly on hKv1.5 currents as an open channel blocker, independently of its effects on PI3K activity. Amino acid residues located in the pore region (Thr480, Arg487) and the S6 segment (Ile502, Ile508, Leu510, Val516) appear to constitute potential binding sites for LY294002.  相似文献   

19.

BACKGROUND AND PURPOSE

5-HT receptor agonists have variable nociceptive effects within the spinal cord. While there is some evidence for 5-HT1A spinally-mediated analgesia, the role of other 5-HT1 receptor subtypes remains unclear. In the present study, we examined the spinal actions of a range of 5-HT1 agonists, including sumatriptan, on acute pain, plus their effect on afferent-evoked synaptic transmission onto superficial dorsal horn neurons.

EXPERIMENTAL APPROACH

For in vivo experiments, 5-HT agonists were injected via chronically implanted spinal catheters to examine their effects in acute mechanical and thermal pain assays using a paw pressure analgesymeter and a Hargreave''s device. For in vitro experiments, whole-cell patch-clamp recordings of primary afferent-evoked glutamatergic EPSC were made from lamina II neurons in rat lumbar spinal slices.

KEY RESULTS

Intrathecal (i.t.) delivery of the 5-HT1A agonist R ± 8-OH-DPAT (30–300 nmol) produced a dose-dependent thermal, but not mechanical, analgesia. Sumatriptan and the 5-HT1B, 5-HT1D, 5-HT1F agonists CP93129, PNU109291 and LY344864 (100 nmol) had no effect on either acute pain assay. R ± 8-OH-DPAT (1 µM) and sumatriptan (3 µM) both reduced the amplitude of the evoked EPSC. In contrast, CP93129, PNU109291 and LY344864 (0.3–3 µM) had no effect on the evoked EPSC. The actions of both R ± 8-OH-DPAT and sumatriptan were abolished by the 5-HT1A antagonist WAY100635 (3 µM).

CONCLUSIONS AND IMPLICATIONS

These findings indicate that the 5-HT1A receptor subtype predominantly mediates the acute antinociceptive and cellular actions of 5-HT1 ligands within the rat superficial dorsal horn.  相似文献   

20.
  1. The nonpeptide bradykinin B2 receptor antagonist, FR173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-(2, 4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylaminocarbonylmethyl] acrylamide), was tested in models involving bradykinin-induced activation of primary afferent neurones in vitro and in vivo.
  2. Bradykinin-induced contractions of the rabbit isolated iris sphincter muscle mediated by tachykinin release from trigeminal afferent neurones were inhibited in a non-competitive manner by FR173657. A pKB value of 7.9 was calculated. Effects of substance P were unaffected by FR173657.
  3. Nociceptive behavioural responses following intraplantar injection of bradykinin in unanaesthetized rats were reduced by 0.3 μmol kg−1 FR173657 s.c. (P<0.05), and completely abolished by 3 μmol kg−1 (P<0.05). Peroral administration of 5 μmol kg−1 FR173657 abolished the bradykinin effects (P<0.05); lower doses had no significant effect.
  4. Shortening by intraplantar injection of bradykinin of the paw withdrawal latency in response to radiant heat was abolished by 3 μmol kg−1 FR173657 s.c. (P<0.05), while 300 nmol kg−1 had an intermediate effect. Hyperalgesia induced by prostaglandin E2 remained unaffected by FR173657.
  5. Blood pressure reflexes following i.p. instillation of bradykinin in anaesthetized rats were inhibited by FR173657 s.c. with an ID50 of 1.1 μmol kg−1, while the peptidic B2 antagonist icatibant (Hoe-140; D-Arg0-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) caused inhibition at significantly lower doses (ID50 8.5 nmol kg−1 P<0.001). Responses to hydrochloric acid i.p. remained unaffected by FR173657.
  6. FR173657 or similar nonpeptide compounds may be useful for the development of drugs for diseases involving pain induced by the release of endogenous kinins, i.e. especially in acute inflammatory conditions.
  相似文献   

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