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)

Recent studies have provided evidence that activation of 5-HT1A receptors increases epileptic activity in the WAG/Rij rat model of absence epilepsy, and additional data have suggested the involvement of 5-HT7 receptors as well. Therefore, we have tested the effects of the selective 5-HT1A receptor antagonist WAY-100635 and the selective 5-HT7 receptor antagonist SB-258719 on spontaneous epileptic activity. In general, both compounds reduced epileptic activity compared to vehicle. Significant decreases were found in the number of paroxysms and the cumulative and average duration of spike-wave discharges (SWDs), although the time courses of these effects induced by the two compounds were clearly different. These results provide evidence that activation of 5-HT1A and 5-HT7 receptors plays a significant role in regulating SWD activity in this animal model of absence epilepsy.
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PMID:Selective 5-HT1A and 5-HT7 antagonists decrease epileptic activity in the WAG/Rij rat model of absence epilepsy. 1505 Jul 8

The developing prefrontal cortex receives a dense serotonergic innervation, yet little is known about the actions of serotonin [5-Hydroxytryptamine (5-HT)] in this region during development. Here, we examined the developmental regulation of 5-HT receptors controlling the excitability of pyramidal neurons of this region. Using whole-cell recordings in in vitro brain slices, we identified a dramatic shift in the effects of 5-HT on membrane potential during the postnatal developmental period. In slices derived from young animals [postnatal day (P) 6 to P19], administration of 5-HT elicits a robust depolarization of layer V pyramidal neurons, which gradually shifts to a hyperpolarization commencing during the third postnatal week. This progression is the result of coordinated changes in the function of 5-HT7 and 5-HT2A receptors, which mediate different aspects of the depolarization, and of 5-HT1A receptors, which signal the late developing hyperpolarization. The loss of the 5-HT7 receptor-mediated depolarization and the appearance of the 5-HT1A receptor-mediated hyperpolarization appears to reflect changes in receptor expression. In contrast, the decline in the 5-HT2A receptor depolarization with increasing age was associated with changes in the effectiveness with which these receptors could elicit a membrane depolarization, rather than loss of the receptors per se. Together, these results outline coordinated changes in the serotonergic regulation of cortical excitability at a time of extensive synaptic development and thus suggest a key role for these receptor subtypes in the postnatal development of the prefrontal cortex.
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PMID:Serotonergic regulation of membrane potential in developing rat prefrontal cortex: coordinated expression of 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 receptors. 1515 41

In chloralose-anaesthetised cats, we studied the effects of intravenous and intra-carotid injections of 5-HT on the middle meningeal artery and the way these were modified by 5-HT antagonists. Cats were prepared for blood pressure recording and intravenous injections and a catheter inserted into one carotid artery via a lingual artery. The middle meningeal arteries were exposed and blood flow recorded with laser Doppler probes. Intravenous injections of 5-HT, 2-50 microg kg(-1) (5.2-129 nmole kg(-1)), produced a dose-dependent fall in blood pressure, a rise in meningeal blood flow, and an associated fall in middle meningeal resistance. Resistance changes were the result of a local dilatation and not due to changes downstream of the recording probe. Intracarotid injections of 5-HT produced similar systemic and craniovascular responses, which were larger in the ipsilateral middle meningeal artery. Dose-response curves of vascular resistance changes to intravenous injection of 5-HT were not significantly affected by WAY100635 (5-HT1A antagonist), GR127935 (5-HT(1B/1D) antagonist), methiothepin (5-HT2C and 5-HT7 antagonist), ketanserin (5-HT2A antagonist), SB203186 (5-HT4 antagonist) or cervical sympathectomy, but were blocked by the 5-HT(3/4) antagonist tropisetron, the 5-HT3 antagonist ondansetron, the ganglion-blocking drug hexamethonium and by vagotomy. These drugs and procedures did not significantly antagonise the response to intra-arterially injected 5-HT. We conclude that intravenously-administered 5-HT is a vasodilator in vivo in the cat dural circulation, and that the dilation is not mediated by 5-HT1, 5-HT2, 5-HT4 or 5-HT7 receptors, but is primarily mediated by a vagal reflex, initiated via 5-HT3 receptor activation and brought about by an increase in parasympathetic tone to the middle meningeal artery as part of the von Bezold-Jarisch reflex. There also appears to be a direct vasodilator effect mediated by unknown receptor types, particularly after intra-arterial administration. Neither of these effects is, however, likely to be of importance in the pathophysiology of migraine or other vascular headaches.
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PMID:Dilatation induced by 5-HT in the middle meningeal artery of the anaesthetised cat. 1519 36

Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [3H]serotonin ([3H]5-HT), superfused, and the electrically induced efflux of radioactivity was determined. The nonselective 5-HT receptor agonist 5-carboxamido-tryptamine (5-CT; 0.001 to 1 microM) inhibited the electrically stimulated [3H]5-HT overflow from raphe nuclei slices (IC50 of 3.34 +/- 0.37 nM). This effect of 5-CT on [3H]5-HT overflow was antagonized by the 5-HT7 receptor antagonist SB-258719 (10 microM) and the 5-HT(1B/1D) antagonist SB-216641 (1 microM), the IC50 values for 5-CT in the presence of SB-258719 and SB-216641 were 94.23 +/- 4.84 and 47.81 +/- 4.66 nM. The apparent pA2 values for SB-258719 and SB-216641 against 5-CT were 6.43 and 7.12, respectively. The inhibitory effect of 5-CT on [3H]5-HT overflow was weakly antagonized by 10 microM of WAY-100635, a 5-HT1A receptor antagonist (IC50 6.65 +/- 0.56 nM, apparent pA2 4.99). The antagonist effect of SB-258719 (10 microM) on 5-CT-evoked [3H]5-HT overflow inhibition was also determined in the presence of 1 microM SB-216641 or 1 microM SB-216641 and 10 microM WAY-100635, and additive interactions were found between the antagonists of 5-HT7 and 5-HT1 receptor subtypes. Addition of the Na+ channel blocker tetrodotoxin (1 microM) in the presence of SB-216641 (1 microM) and WAY-100635 (10 microM) attenuated the inhibitory effect of 5-CT on KCl-induced [3H]5-HT overflow. These findings indicate that 5-CT inhibits [3H]5-HT overflow from raphe nuclei slices of the rat by stimulation of 5-HT7 and 5-HT(1B/1D receptors, whereas the role of 5-HT1A receptors in this inhibition is less pronounced. They also suggest that 5-HT7 receptors are probably not located on serotonergic neurons and thus may serve as heteroreceptors in regulation of 5-HT release in the raphe nuclei. 5-CT (0.1 microM) also inhibited [3H]glutamate release, and SB-258719 (10 microLM) suspended this effect. We therefore speculated that the axon terminals of the glutamatergic cortico-raphe neurons may possess 5-HT7 receptors that inhibit glutamate release, which consequently leads to decreased activity of serotonergic neurons. The postulated glutamatergic-serotonergic interaction in the raphe nuclei was further evidenced by the finding that N-methyl-D-aspartate and AMPA enhanced [3H]5-HT release.
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PMID:A 5-HT7 heteroreceptor-mediated inhibition of [3H]serotonin release in raphe nuclei slices of the rat: evidence for a serotonergic-glutamatergic interaction. 1526 Jan 25

Cardiac vagal preganglionic neurones (CVPNs) are located within the dorsal vagal nucleus (DVN) and the nucleus ambiguus (nA). In mammals, CVPNs within the nA have small myelinated axons and mediate major chronotropic effects, those in the DVN have non-myelinated axons and mediate smaller chronotropic, dromotropic and inotropic effects. Numerous studies demonstrate important influences of serotonin (5-HT) at multiple sites controlling autonomic outflows including the nucleus tractus solitarius (NTS) where cardiorespiratory afferent fibres terminate, and the CVPNs and rostral ventrolateral medulla (RVLM), the location of sympathetic premotor neurones. We have demonstrated roles for some of the numerous 5-HT receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7) in brainstem regions involved in cardiac control. Intracisternal application of selective ligands was used to study the effect of 5-HT receptors on heart rate and its reflex control. Further electrophysiological studies were also carried out to delineate their location and the mechanisms of action of these ligands. Blocking 5-HT1A receptors attenuated bradycardias evoked by stimulating baroreceptor and cardiopulmonary afferents but not arterial chemoreceptors, whereas antagonizing 5-HT7 receptors markedly attenuated all these reflex bradycardias. Within the DVN, nA and NTS, activation of 5-HT1A receptors could excite or inhibit neurones. In the NTS 5-HT2 receptors also had variable effects; 5-HT2B receptors excite and 5-HT2C receptors inhibit. Antagonism of 5-HT3 receptors attenuated upper airway and cardiopulmonary reflex bradycardias; this is compatible with data showing that 5-HT3 receptors excite DVN and NTS neurones by a glutamate-dependent mechanism. The origin of the glutamate (neuronal or glial) remains unresolved but glia are a possibility as baroreceptor-sensitive NTS neurones receive few direct 5-HT-containing synaptic contacts. Thus, 5-HT plays a critical role in the control of vagal outflow to the heart; however, why so many different receptors are involved, and their relative functional roles, remains unresolved.
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PMID:Vagal control of the heart: central serotonergic (5-HT) mechanisms. 1560 9

The antinociceptive effects of the serotonin (5-HT)1A/7 receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) administered into the medial thalamus were evaluated. Pain behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization after discharges, VADs) levels of the neuraxis were elicited by tailshock. Administration of 8-OH-DPAT (5, 10, and 20 microg/side) into nucleus parafascicularis (nPf) produced dose-dependent increases in VDS and VAD thresholds, but failed to elevate SMR threshold. The increase in VAD threshold was significantly greater than that of VDS threshold. Similar effects were observed with administration of 8-OH-DPAT (20 microg/side) into the rostral portion of the central lateral thalamic nucleus. The bilateral or unilateral administration of 8-OH-DPAT (20 microg) into other thalamic nuclei, or into sites dorsal to nPf, did not elevate vocalization thresholds. Increases in vocalization thresholds produced by nPf-administered 8-OH-DPAT were mediated by both 5-HT1A and 5-HT7 receptors. Intra-nPf administration of the 5-HT1A receptor antagonist WAY-100635 (0.05 or 0.5 microg/side), or the 5-HT7 receptor antagonist SB-269970 (1 or 2 microg/side), but not the dopamine D2 receptor antagonist raclopride (10 microg/side), reversed 8-OH-DPAT induced elevations in vocalization thresholds. These results provide the first reported evidence of behavioral antinociception following the administration of a 5-HT agonist into the medial thalamus.
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PMID:Activation of 5-HT1A and 5-HT7 receptors in the parafascicular nucleus suppresses the affective reaction of rats to noxious stimulation. 1566 50

A solid-phase synthesis of the 64-member library of novel sulfonamide and carboxamide proline derivatives, focused on the 5-HT7 receptor antagonist SB-258741, was described. The final compounds were obtained in good yields and high purity upon cleavage from SynPhase Lanterns, functionalized by a BAL linker. The library representatives were screened for 5-HT7, 5-HT1A and D2 receptors to explore the impact of a tertiary amine moiety, the length of an alkylene spacer and the aryl fragment on the receptor affinity. The preliminary biological results provided data for further investigation aimed at a search for 5-HT7 receptor agents, and permitted the identification of several compounds with significant 5-HT1A receptor affinity.
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PMID:Parallel solid-phase synthesis and characterization of new sulfonamide and carboxamide proline derivatives as potential CNS agents. 1578 12

This work aimed to evaluate further the role of 5-HT7 receptors during memory formation in an autoshaping Pavlovian/instrumental learning task. Post-training administration of the potential 5-HT7 receptor agonist AS 19 or antagonist SB-269970 enhanced memory formation or had no effect, respectively. The AS 19 facilitatory effect was reversed by SB-269970, but not by the selective 5-HT1A antagonist WAY100635. Amnesia induced by scopolamine (cholinergic antagonist) or dizocilpine (NMDA antagonist) was also reversed by AS 19. Certainly, reservations regarding the selectivity of AS 19 for 5-HT7 and other 5-HT receptors in vivo are noteworthy and, therefore, its validity for use in animal models as a pharmacological tool. Having mentioned that, it should be noticed that together these data are providing further support to the notion of the 5-HT7 receptors role in memory formation. Importantly, this 5-HT7 receptor agonist AS 19 appears to represent a step forward respect to the notion that potent and selective 5-HT7 receptor agonists can be useful in the treatment of dysfunctional memory in aged-related decline and Alzheimer's disease.
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PMID:Effects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task. 1593 93

The present study discusses the well-known 5-HT7/5-HT1A selectivity issue through a new series of phenylpyrrole derivatives. The first hits emerged from a virtual screening performed on a chemolibrary. Further study led to an optimization of a preliminary 5-HT7 pharmacophore model. The importance of each pharmacophoric feature is confirmed, but these characteristics have to be coupled to geometric constraints in order to achieve a 5-HT7 selectivity. Indeed, 5-HT1A affinity probably arises from extended conformations, whereas a bent one appears to be best suited for 5-HT7 selectivity.
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PMID:Molecular modeling studies focused on 5-HT7 versus 5-HT1A selectivity. Discovery of novel phenylpyrrole derivatives with high affinity for 5-HT7 receptors. 1604 3

Antagonism of central 5-HT1A and 5-HT7 receptors inhibits reflex-evoked vagal bradycardias indicating that 5-HT is released during these reflexes. The present experiments examined the effect of 5-HT depletion with para-chlorophenylalanine (p-CPA) on the cardiac vagal baroreflex and cardiopulmonary reflex in awake and anesthetized rats. Immunocytochemistry and neurochemical detection showed that p-CPA depleted the brainstem of 5-HT, but not of norepinephrine or dopamine. Depletion of 5-HT was associated with an increase in mean arterial pressure (MAP) in awake rats. This difference was abolished by anesthesia, which reduced MAP in both groups of animals. The baroreflex gain, whether calculated from the rise in pressure induced by phenylephrine or the fall in pressure evoked by sodium nitroprusside, was significantly attenuated in depleted rats compared to controls. This attenuation of the baroreflex gain was unaffected by subsequent anesthesia. 5-HT depletion also attenuated the cardiopulmonary reflex vagal bradycardias but this only reached statistical significance when the rats were anesthetized. The data support the view that 5-HT is released in the reflex activation of the cardiac vagal pathway.
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PMID:Effect of 5-HT depletion on cardiovascular vagal reflex sensitivity in awake and anesthetized rats. 1605 1


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