Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study utilised the selective 5-ht(5A) receptor antagonist, SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), to investigate 5-ht5A receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [35S]GTPgammaS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht5A receptor (pA2 8.1+/-0.1) and displayed 100-fold selectivity versus the serotonin transporter and those 5-HT receptor subtypes (5-HT(1A/B/D), 5-HT2A/C and 5-HT7) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1 microM) did not alter neuronal firing per se but attenuated the 5-CT-induced depression in serotonergic neuronal firing in a subpopulation of cells insensitive to the 5-HT1A receptor-selective antagonist WAY-100635 (100 nM). In contrast, SB-699551-A (100 or 300 nM) failed to affect both electrically-evoked 5-HT release and 5-CT-induced inhibition of evoked release measured using fast cyclic voltammetry in vitro. SB-699551-A (0.3, 1 and 3 mg/kg s.c.) did not modulate extracellular levels of 5-HT in the guinea pig frontal cortex in vivo. However, when administered in combination with WAY-100635 (0.3 mg/kg s.c.), SB-699551-A (0.3, 1 or 3 mg/kg s.c.) produced a significant increase in extracellular 5-HT levels. These studies provide evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain.
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PMID:SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain. 1684 20

An overview of pharmacophore models, developed for different subtypes of serotonin receptors belonging to the GPCR family, is presented. Starting with early models for 5-HT1A and 5-HT2 receptor ligands, and ending with the latest ones for 5-HT6- and 5-HT7 receptors, as many as fifty others are briefly summarized. No models have been developed for 5-HT1F-, 5-HT2B- and 5-HT5B receptor ligands, and in the case of 5-HT1E- and 5-HT5A Rs only single pilot studies with non-selective tryptamine derivatives are reported. For all the other subtypes of 5-HTRs, various pharmacophore hypotheses--either qualitative and/or quantitative--are characterized by sets of ligands used for their generation, a templates for alignment, the computational methods applied and, eventually, interfeature distances and/or statistical results--if available.
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PMID:Pharmacophore models for metabotropic 5-HT receptor ligands. 1701 71

Serotonin (5-HT)-containing neurons in the dorsal raphe project to the external and internal segments of the pallidum, which express several 5-HT receptors. Although the involvement of 5-HT in basal ganglia movement control has been suggested, little is known about the physiological action of 5-HT in the pallidum. Previous anatomical studies and in vitro physiological studies in other brain areas have suggested the following possibilities: (1) 5-HT suppresses GABAergic inhibition through presynaptic 5-HT1B receptors; (2) 5-HT decreases the firing of pallidal neurons through postsynaptic 5-HT1A receptors; and (3) 5-HT postsynaptically excites pallidal neurons through activation of 5-HT2C, 5-HT4, or 5-HT7 receptors. To test these possibilities, we examined the effects of locally applied agonists and antagonists of 5-HT on spontaneous neuronal firing and on excitatory and inhibitory responses of pallidal neurons to electrical stimulation of the motor cortex in awake monkeys. Although in vivo experiments could not conclusively determine the receptor types or the active sites involved in the observed effects, the results suggested the following possibilities: (1) 5-HT strongly suppresses GABAergic inhibition probably through 5-HT1B receptors; (2) in the external pallidal segment, the suppression may involve additional receptors or mechanisms; and (3) 5-HT suppresses glutamatergic excitation probably through 5-HT1A (and not 5-HT1B) receptors. The present study did not isolate or identify the existence of strong, direct postsynaptic inhibitory or excitatory effects of 5-HT. Thus, present results imply that 5-HT modulates synaptic inputs of both pallidal segments and exerts a significant role in movement control.
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PMID:Serotonin modulates pallidal neuronal activity in the awake monkey. 1720 74

These studies investigated the role of serotonin-1A (5-HT1A) and 5-HT2A receptors in the behavioral effects of dipropyltryptamine (DPT). Eight rats discriminated 0.56 mg/kg 2,5-dimethoxy-4-methylamphetamine (DOM) from saline and responded under a fixed ratio 5 schedule of food presentation; 12 other rats were used for observational studies. DOM and DPT increased responding on the DOM lever with 3.2 mg/kg DPT producing greater than 95% responding on the DOM lever; this effect of DPT was antagonized by the 5-HT2A receptor antagonist MDL100907. In another study, the 5-HT1A and 5-HT7 receptor agonist 8-OH-DPAT produced lower-lip retraction and, at larger doses, flat body posture; DPT alone produced flat body posture and not lower-lip retraction; MDL100907 alone did not produce either effect. Pretreatment with DPT blocked 8-OH-DPAT-elicited lower-lip retraction, suggesting antagonist activity of DPT at 5-HT1A receptors; however, in the presence of MDL100907 DPT produced not only flat body posture but also lower-lip retraction, suggesting that agonist activity of DPT at 5-HT2A receptors masked agonist activity at 5-HT1A receptors. Lower-lip retraction and flat body posture by DPT in the presence of MDL100907 were attenuated by the 5-HT1A receptor antagonist WAY100635. These findings suggest that DPT has agonist activity at 5-HT1A and 5-HT2A receptors and that effects at 5-HT2A receptors mask effects at 5-HT1A receptors.
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PMID:Behavioral effects of dipropyltryptamine in rats: evidence for 5-HT1A and 5-HT2A agonist activity. 1755 20

Here we report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides 16-29 that were designed to elucidate both structure-affinity and -activity relationships for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compounds were determined. A series of substituents covering a wide range of electronic, steric, and polar properties was evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CH(CH3)2, N(CH3)2, CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (22) were identified as potent 5-HT7 receptor agonists (Ki = 0.13-1.1 nM, EC50 = 0.90-1.77 microM), showing selectivity over 5-HT1A, 5-HT2A, and D2 receptors.
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PMID:Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2. 1764 88

Lurasidone (SM-13496) is a novel atypical antipsychotic with high affinities to dopamine D2, serotonin 5-HT7, 5-HT2A, 5-HT1A receptors and alpha2C adrenoceptor. In this study, the effects of lurasidone on the rat passive-avoidance response and its impairment by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) were evaluated and compared with those of other antipsychotics. The passive-avoidance response was examined by measuring the step-through latency, 1 day after the animals received foot-shock training. When given before the training session, lurasidone did not affect the passive-avoidance response at any dose tested (1-30 mg/kg, p.o.). All the other atypical antipsychotics examined (i.e., risperidone, olanzapine, quetiapine, clozapine and aripiprazole), however, significantly reduced the step-through latency at relatively high doses. A pre-training administration of lurasidone significantly and dose-dependently reversed the MK-801-induced impairment of the passive-avoidance response. At doses lower than those that affected the passive-avoidance response, risperidone, quetiapine, and clozapine partially reduced the MK-801-induced impairment, whereas haloperidol, olanzapine, and aripiprazole were inactive. In addition, the post-training administration of lurasidone was as effective in countering the MK-801 effect as the pre-training administration, suggesting that lurasidone worked, at least in part, by restoring the memory consolidation process disrupted by MK-801. These results suggest that lurasidone is superior to other antipsychotics in improving the MK-801-induced memory impairment and may be clinically useful for treating cognitive impairments in schizophrenia.
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PMID:Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. 1766 68

The present study was designed to investigate the role of the 5-HT7 receptors in lordosis and compare the lordotic responses with 5-HT1A agent under the influence of different steroid-priming regimens in ovariectomized, non-receptive and receptive rats. 8-OH DPAT, a 5-HT1A agonist and 5-CT, a 5-HT7 agonist inhibited the lordosis differently in non-receptive and receptive rats, however, the response was attenuated in a dose-dependent manner following 5-CT treatment in the first two tests. Treatment with 5-HT1A antagonist, WAY 100 135 caused a protective effect which was evident in the second test only. Priming with 25 microg OB attenuated in the first test in non-receptive rats whereas the same dose repeated a similar pattern in receptive rats. The attenuation of LQ was evident in rats treated with 5-HT7 antagonist, SB 269970-A. This finding shows that WAY 100 135, a 5-HT1A antagonist has potency to attenuate inhibitory influence of 8-OH DPAT by enhancing lordosis behavior acutely in female rats with a low estrous state. Treatment with 5-CT and SB 269970-A as 5-HT7, agonist and antagonist, respectively, have mimicked 5-HT-mediated lordotic response as moderate affinity towards 5-HT1A receptors has been reported. This offers a comparable effect on lordosis as a result of the two 5-HT agents used.
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PMID:Attenuating effects of prior oestradiol benzoate priming on 5-HT-mediated lordosis behavior in rats are dose-dependent. 1785 73

Using Long-Evans rats tested in a water maze, this study assessed the role of 5-HT1A/5-HT7 receptors of the medial septum in encoding, consolidation, and retrieval of spatial information. The testing protocol (acquisition: daily four-trial sessions over three consecutive days; retention: probe trial on day 4) was first validated by showing that intraseptal infusions of lidocaine (LIDO; 40 microg/0.5 microL) disrupted acquisition and retrieval of the task. 8-OH-DPAT (4 microg/0.5 microL) infused before each acquisition session prevented learning/retention of the platform location, an effect attenuated by pretreatment with the 5-HT1A receptor antagonist WAY 100635. With the 5-HT7 antagonist SB 269970, the 8-OH-DPAT-induced acquisition deficit seemed attenuated, but there was no subsequent retention. When infused immediately, 1, 4, or 6 h after each acquisition session, 8-OH-DPAT did not hinder consolidation. When the infusions were performed 2 h postacquisition, however, consolidation was disrupted. Finally, when infused before a probe trial after drug-free acquisition, 8-OH-DPAT had no effect, suggesting no interference with retrieval processes. We also established that 8-OH-DPAT had no effects when the platform was visible, and altered neither home-cage activity nor anxiety-related behavior (elevated plus-maze). Altogether, these results show that 5-HT1A receptors in the septal region contribute both to declarative-like information encoding and subsequently, within a given postacquisition time window, to its consolidation. They do not participate in the retrieval of recently learned declarative-like information. These observations suggest that 5-HT1A receptors of the medial septum contribute to a serotonin-mediated mechanism involved in the encoding and consolidation, not the retrieval of spatial hippocampal-dependent knowledge. These results might have some relevance to approaches aimed at modifying serotonergic functions in the brain for the treatment of disorders such as depression, anxiety, post-traumatic stress, and amnesia.
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PMID:Activation of septal 5-HT1A receptors alters spatial memory encoding, interferes with consolidation, but does not affect retrieval in rats subjected to a water-maze task. 1792 24

In urethane-chloralose anesthetized, neuromuscularly blocked, ventilated rats, microinjection of NMDA (12 pmol) into the right fourth thoracic segment (T4) spinal intermediolateral nucleus (IML) immediately increased ipsilateral brown adipose tissue (BAT) sympathetic nerve activity (SNA; peak +492% of control), expired CO2 (+0.1%) heart rate (+48 beats min(-1)) and arterial pressure (+8 mmHg). The increase in BAT SNA evoked by T4 IML microinjection of NMDA was potentiated when it was administered immediately following a T4 IML microinjection of 5-hydroxytryptamine (5-HT, 100 pmol) or the 5-HT1A/5-HT7 receptor agonist, 8-OH-DPAT (600 pmol), (area under the curve: 184%, and 259% of the NMDA-only response, respectively). In contrast, T4 IML microinjection of the 5-HT2 receptor agonist, DOI (28 pmol) did not potentiate the NMDA-evoked increase in BAT SNA (101% of NMDA-only response). Microinjection into the T4 IML of the selective 5-HT1A antagonist, WAY-100635 (500 pmol), plus the 5-HT7 antagonist, SB-269970 (500 pmol), prevented the 5-HT-induced potentiation of the NMDA-evoked increase in BAT SNA. When administered separately, WAY-100635 (800 pmol) and SB-269970 (800 pmol) attenuated the 8-OH-DPAT-induced potentiation of the NMDA-evoked increase in BAT SNA through effects on the amplitude and duration of the response, respectively. The selective 5-HT2 receptor antagonist, ketanserin (100 pmol), did not attenuate the potentiations of the NMDA-evoked increase in BAT SNA induced by either 5-HT or 8-OH-DPAT. These results demonstrate that activation of 5-HT1A/5-HT7 receptors can act synergistically with NMDA receptor activation within the IML to markedly increase BAT SNA.
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PMID:Brown adipose tissue sympathetic nerve activity is potentiated by activation of 5-hydroxytryptamine (5-HT)1A/5-HT7 receptors in the rat spinal cord. 1808 30

The aim of the thesis was to investigate in male Wistar rats, the involvement of serotonin (5-HT) and 5-HT receptors in the regulation of the gene expression of hypothalamic hormones and in the secretion of the pituitary gland hormones prolactin (PRL), adrenocorticotropic hormone (ACTH), vasopressin (AVP) and oxytocin in basal and stress conditions. Furthermore, to study the significance of some distinctive central nuclei in these processes, and the metabolism of 5-HT in the hypothalamus and the dorsal raphe nucleus (DRN). The experiments were focused on (1) determination of involved neurons and nuclei (2) the hypothalamic level and (3) the pituitary gland level of regulation. The studies were typically performed in vivo but some studies were performed in vitro. Stereotactically neurotoxic lesion with 5,7-dihydroxy-5-HT in the dorsal raphe nucleus (DRN) or the hypothalamic paraventricular nucleus (PVN) reduced the ACTH and AVP response to stress, indicating an importance of these structures for this response. In situ hybridization on rat brain slices with oligopeptides showed an increase of corticotropin releasing hormone (CRH) mRNA in the PVN and proopiomelanocortin in the anterior pituitary lobe upon stimulation of the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors. Stimulation of 5-HT2A+2C receptors increased AVP mRNA in the PVN but not in the supraoptic nucleus (SON), whereas the level of oxytocin (OT) mRNA was increased both in the SON and the PVN and this effect was in addition mediated via 5-HT1A+1B receptors. Serotonin infused directly into the PVN by microdialysis stimulated local release of AVP. CRH was found to have a major role but not a complete responsibility in the 5-HT-induced release of ACTH, since immunoneutralisation of CRH inhibited the POMC gene expression and the ACTH response and since 5-HT and 5-HT antagonists were able to modulate the ACTH release from anterior pituitary gland cells in vitro. Through the years of investigation, the classification of the 7 main groups of 5-HT receptors (5-HT1 - 5-HT7) has changed due to molecular biological characterisation of the receptors and new receptors have been identified. With a battery of 5-HT agonists and antagonists several pharmacological experiments were performed with systemically or central administration of compounds and radioimmuno assay of plasma for pituitary gland hormone levels. Specific substances were not available for all 5-HT receptors and subreceptors thus some conclusions are a based on combination of experiments. The 5-HT induced PRL response is mediated via 5-HT1A, 5-HT2A, 5-HT2C and 5-HT3 receptors. In addition an involvement of 5-HT1B, 5-HT5 or 5-HT7 receptors seem possible. The ACTH response to 5-HT is mediated via 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors and an involvement of the 5-HT4, 5-HT5 and 5-HT7 receptors is proposed. Peripheral secretion of AVP upon stimulation with 5-HT is mediated via 5-HT2C, 5-HT4 and 5-HT7 receptors but not 5-HT1A receptors. The secretion of OT is primarily mediated via 5-HT1A, 5-HT2C and 5-HT4 receptors and probably also 5-HT1B, 5-HT2A, 5-HT5A and 5-HT7 receptors. Physical and psychological stress activates hippocampal and hypothalamic 5-HT neurons. In contrast to other stress factors, restraint stress increases the content of 5-HT in the DRN but do not increase the metabolism of 5-HT and does not induce changes in hypothalamic levels of 5-HT. Large variations are found in the literature with different kinds of stress, different measurements and different time schedules. Restraint or ether stress induced secretion of PRL involves 5-HT2 and 5-HT3 receptors, whereas the ACTH secretion is mediated via 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present study restraint stress increased AVP secretion, but opposite findings has reported possibly due to differences in the stress procedure. The 5-HT2, 5-HT3 and 5-HT4 receptor is involved in the AVP response to restraint whereas the OT response involves the 5-HT1A and the 5-HT2 receptor. The 5-HT2 receptor is involved in the OT response to dehydration or haemorrhage, whereas the AVP responses to these stressors probably do not involve 5-HT. It can be concluded that 5-HT is involved in basal and stress-induced regulation of PRL, ACTH, AVP and oxytocin mainly via the 5-HT2A+2C receptors but other receptors are also important but differs from hormone to hormone. Serotonin affect the secretion of CRH and ACTH both at the hypothalamic, pituitary portal and pituitary gland level, and possibly also at the adrenal level.
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PMID:Studies on the neuroendocrine role of serotonin. 1820 78


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