Platelet serotonin 5-HT2A receptor binding in patients with carcinoid tumor

BACKGROUND: As carcinoid tumors produce and secrete serotonin, various serotonin markers in blood, plasma and urine have been used as diagnostic tools, and quantification of the urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) is the method most frequently used. METHODS: [3H]lysergic acid diethylamide ([3H]LSD) binding to the platelet serotonin 5-HT2A receptor was investigated in nine patients with carcinoid tumors. The possible effect of serotonin-rich food on the receptor binding was also investigated. RESULTS: B(max) for [3H]LSD binding was significantly lower in the carcinoid group than in the control group (mean +/- SD: 17.6 +/- 1.3 vs. 23.9 +/- 5.2 fmol/mg protein; p = 0.007). Kd for [3H]LSD binding was significantly higher in the carcinoid group than in the control group (median: 1.14 vs. 0.71 nmol/L; p = 0.03). B(max) was inversely related to the urinary 5-HIAA excretion, but the correlation did not reach statistical significance (r(s) = -0.57; p = 0.14). Intake of five bananas per day for one week had no effect on B(max) or Kd in healthy volunteers. CONCLUSIONS: The results are consistent with a down-regulation of the 5-HT2A receptor as a response to the high serotonin levels found in patients with carcinoid tumors. Intake of serotonin-rich food does not affect the receptor characteristics. Further studies are needed to determine whether the platelet 5-HT2A receptor status can be used as a supplement to urinary 5-HIAA and other biochemical variables in carcinoid tumors.     

Functions of 5-HT2A receptor and its antagonists in the cardiovascular system

The serotonin (5-hydroxytryptamine, 5-HT) receptors have conventionally been divided into seven subfamilies, most of which have several subtypes. Among them, 5-HT(2A) receptor is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Accordingly, selective 5-HT(2A) antagonists may have potential in the treatment of cardiovascular diseases. Sarpogrelate, a selective 5-HT(2A) antagonist, has been introduced clinically as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis. Molecular modeling studies also suggest that sarpogrelate is a 5-HT(2A) selective antagonist and is likely to have pharmacological effects beneficial in the treatment of cardiovascular diseases. This review describes the above findings as well as the signaling linkages of the 5-HT(2A) receptors and the mode of agonist binding to 5-HT(2A) receptor using data derived from molecular modeling and site-directed mutagenesis.     

5-HT2 receptor blockade by ICI 169,369 and other 5-HT2 antagonists modulates the effects of D-2 dopamine receptor blockade

The effects of D-2 dopamine (DA) receptor blockade were modulated by ICI 169,369, a selective 5-hydroxytryptamine (5-HT)2 receptor antagonist, and by other 5-HT2 antagonists. Specifically, it appears that blockade of 5-HT2 receptors can attenuate the effects of D-2 receptor blockade on rat striatal dopaminergic transmission. Thus, the blockade of D-2 receptors by haloperidol results in a compensatory increase in rat striatal DA metabolism, which is enhanced by ICI 169,369. By itself, ICI 169,369 did not significantly alter DA metabolism. Conversely, several compounds which possess appreciable activity at 5-HT2 sites in ex vivo binding assays, but possess little activity at D-2 sites (i.e., pirenperone, setoperone, fluperlapine and clozapine), all produced large increases in striatal DA metabolism. Therefore, these data suggest that the 5-HT2 component of these compounds, by enhancing DA metabolism, may act to attenuate the blockade of striatal D-2 receptors by these compounds. Consistent with this hypothesis, the chronic blockade of D-2 receptors by haloperidol increases the number of striatal D-2 DA receptors, and these increases are attenuated by the coadministration of ICI 169,369. Likewise, pirenperone and clozapine, at doses which acutely produced elevations in DA metabolism which were similar to those produced by haloperidol, failed to increase the number of D-2 receptors in striatum. Interestingly, 5-HT2 receptor blockade did not appear to potently modulate the effects of D-2 receptor blockade in the olfactory tubercle, a brain region which is innervated by mesolimbic DA-containing neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Desensitization of 5-HT1A receptors by 5-HT2A receptors in neuroendocrine neurons in vivo

An imbalance between serotonin-2A (5-HT2A) and 5-HT1A receptors may underlie several mood disorders. The present studies determined whether 5-HT2A receptors interact with 5-HT1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 microg/kg s.c.). The 5-HT(2A/2C) receptor agonist (-)DOI [(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl] (1 mg/kg s.c.) injected 2 h prior to (+)8-OH-DPAT significantly reduced the oxytocin and ACTH responses to (+)8-OH-DPAT, producing a heterologous desensitization of the 5-HT1A receptors. Microinjection of the 5-HT2A receptor antagonist MDL100,907 [(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; 0, 10, or 20 nmol, 15 min prior to (-)DOI] into the PVN dose-dependently prevented the desensitization of 5-HT1A receptors induced by the 5-HT2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT1A and 5-HT2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT1A receptor signaling after changes in function of 5-HT2A receptors; for example, during pharmacotherapy of mood disorders.     

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5-HT(2B) receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT(2B) receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT(2B) receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose-dependently prevented mechanical allodynia and significantly reduced cold allodynia 17 days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT(2B) receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages.     

An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning

Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.     

Therapeutics of 5-HT3 receptor antagonists: current uses and future directions

The 5-Hydroxytryptamine3 (5-HT3) receptor is a member of the cys-loop family of ligand gated ion channels, of which the nicotinic acetylcholine receptor is the prototype. All other 5-HT receptors identified to date are metabotropic receptors. The 5-HT3 receptor is present in the central and peripheral nervous systems, as well as a number of non-nervous tissues. As an ion channel that is permeable to the cations, Na(+), K(+), and Ca(2+), the 5-HT3 receptor mediates fast depolarizing responses in pre- and post-synaptic neurons. As such, 5-HT3 receptor antagonists that are used clinically block afferent and efferent synaptic transmission. The most well established physiological roles of the 5-HT3 receptor are to coordinate emesis and regulate gastrointestinal motility. Currently marketed 5-HT3 receptor antagonists are indicated for the treatment of chemotherapy, radiation, and anesthesia-induced nausea and vomiting, as well as irritable bowel syndrome. Other therapeutic uses that have been explored include pain and drug addiction. The 5-HT3 receptor is one of a number of receptors that play a role in mediating nausea and vomiting, and as such, 5-HT3 receptor antagonists demonstrate the greatest anti-emetic efficacy when administered in combination with other drug classes.     

Plasticity of 5-HT serotonin receptor in patients with analgesic-induced transformed migraine

Chronic drug exposure can induce a significant change in neurotransmitter receptor systems and is possibly involved in the pathogenesis of drug-induced neurological disorders. Abuse of analgesics is known to induce deterioration in headache status in patients with primary headaches, especially migraine. To assess the possibility of 5-HT2A serotonin receptor plasticity in this condition, we investigated receptor binding on the platelet membrane in patients with analgesic-induced transformed migraine, patients with migraine, and nonheadache controls. Various concentrations of [3H]-spiperone (0.4 to 12 nmol) was used as a radioligand, and ketanserin was used to determine nonspecific binding. A lower maximal number of receptors (Bmax) was observed in patients with migraine as compared to patients with transformed migraine, and controls (467 +/- 58, 708 +/- 36, and 786 +/- 64 fmol/mg protein, respectively, P<0.01); whereas the value of the dissociation equilibrium constant (Kd) remained unchanged (1.72 +/- 0.16, 1.41 +/- 0.13, and 1.25 +/- 0.21 nmol for patients with migraine, patients with transformed migraine, and nonheadache controls, respectively). A significant decrease in Bmax value was observed in patients with transformed migraine after 4 weeks of analgesic withdrawal (770 +/- 25 and 345 +/- 31 fmol/mg protein, P<0.001), whilst no significant change in Kd value was observed (1.95 +/- 0.12 and 2.47 +/- 0.30 nmol, respectively). These findings indicate that 5-HT2A serotonin receptor system is altered in patients with transformed migraine with analgesic overuse. Such receptor plasticity may be an important step in the pathogenic mechanism of transformed migraine.     

Contribution of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine: acute and chronic pharmacological analyses

The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in acute cocaine-evoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine (10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2CR antagonist SDZ SER-082 [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate]. The 5-HT2AR antagonist SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene] and the preferential 5-HT2CR agonist MK 212 [6-chloro-2-(1-piperazinyl)pyrazine HCl] (2 mg/kg) significantly attenuated acute cocaine-evoked hyperactivity; however, a lower dose of MK 212 (0.3 mg/kg) enhanced cocaine-evoked hyperactivity. The 5-HT2BR agonist BW 723C86 (1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl) and the 5-HT2BR antagonist SB 204741 [N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea] had no effect on cocaine-evoked hyperactivity. Repeated treatment with cocaine alone resulted in a 2-fold increase in hyperactivity upon challenge with cocaine 5 days after termination of the cocaine regimen (sensitization). The 5-HT2AR antagonist SR 46349B also blocked cocaine-evoked hyperactivity following repeated cocaine treatment, whereas the other 5-HT2R ligands were ineffective. When any of the 5-HT2R ligands was coadministered with cocaine during the treatment regimen (10 mg/kg/day for 5 days), the development of sensitization was unchanged as measured by the level of cocaine-evoked hyperactivity upon challenge 5 days after termination of the treatment. The present study implies that 5-HT2AR and 5-HT2CR exert oppositional influence upon hyperactivity evoked by acute administration of cocaine; this balance is altered following repeated cocaine administration.     

Effects of serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibition plus 5-HT(2A) receptor antagonism on the firing activity of norepinephrine neurons

YM992 [(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride] is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and a potent 5-HT(2A) antagonist. The aim of the present study was to assess, using in vivo extracellular unitary recordings, the effect of acute and sustained administration of YM992 (40 mg kg(-1) day(-1) s.c., using osmotic minipumps) on the spontaneous firing activity of locus coeruleus (LC) norepinephrine (NE) neurons. Acute intravenous injection of YM992 (4 mg kg(-1)) significantly decreased NE neuron firing activity by 29% and blocked the inhibitory effect of a subsequent injection of the 5-HT(2) agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride]. A 2-day treatment with YM992 decreased the firing rate of NE neurons by 66%, whereas a partial recovery was observed after a 7-day treatment and a complete one after a 21-day treatment. Following the injection of the alpha(2)-adrenoceptor antagonist idazoxan (1 mg kg(-1) i.v.), NE neuron firing was equalized in controls and 2-day YM992-treated rats. This put into evidence an increased degree of activation of alpha(2)-adrenergic autoreceptors in the treated rats. The suppressant effect of the alpha(2)-adrenoceptor agonist clonidine was significantly decreased in long-term YM992-treated rats. The recovery of LC firing activity after long-term YM992 administration could thus be explained by a decreased sensitivity of alpha(2)-adrenergic autoreceptors. Sustained SSRI administration leads to a gradual reduction of the firing activity of NE neurons during long-term administration, whereas YM992 produced opposite effects. The exact basis for the increased synaptic availability of NE by YM992 remains to be elucidated. This NE activity, resulting from 5-HT reuptake inhibition plus 5-HT(2A) receptor antagonism, might confer additional benefits in affective and anxiety disorders.     

Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors

2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)(2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A(2) (PLA(2))] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA(2) and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT(2A) or 5-HT(2C) receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT(2C) receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT(2A) receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT(2C) receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT(2C) receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA(2)-specific at the 5-HT(2A) receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT(2A) receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.     

Antagonists of the type 3 serotonin receptor (5 -HT3) in IBS

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.     

Mechanism of action of 5-HT3 receptor antagonists: clinical overview and nursing implications

Research has shown that the emetic response is linked to serotonin and the stimulation of the 5-HT3 receptors located in several areas of the body. Consequently, 5-HT3 receptor antagonists have been developed, and many studies have demonstrated their efficacy in controlling chemotherapy-induced nausea and vomiting. Oral formulations of 5-HT3 receptor antagonists are often equally or more effective than i.v. antiemetic regimens and are well tolerated and convenient. Adverse effects associated with the 5-HT3 receptor antagonists are generally mild to moderate in severity and transient in nature. A thorough patient assessment combined with a multidisciplinary approach that involves patients, nurses, physicians, and pharmacists optimizes antiemetic therapy.     

Involvement of peripheral 5-HT2A receptor activation in inflammatory pain

Serotoninergic neuron is concerned as an one of the pivotal factor of the tissue inflammation which lead to pain behavior. Sarpogrelate HCl is a novel compound which may modulate inflammatory reaction through 5-HT2A receptor antagonist. We show the involvement of the 5-HT2A receptor activity in the inflammatory and neuropathic pain. Systemic or local sarpogrelate administration provokes antinociceptive effect on 5-HT- or formalin-produced inflammatory pain behaviour in relation to spinal glutamate. Local sarpogrelate inhibits apoptosis and neuronal degeneration after chronic construction injury(CCI). These effects are reversed by 5-HT2A receptor agonist. These results suggests sarpogrelate has a beneficial effect on hyperalgesia and neuropathic pain via inhibiting 5-HT2A receptor.     

5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction

This study was designed to analyse possible associations between DNA polymorphisms in the 5-hydroxytryptamine (5-HT; serotonin) 5-HT(2A) receptor and the 5-HT transporter (5-HTT) genes, and myocardial infarction (MI). 5-HT has been shown to be involved in cardiovascular pathophysiology. In addition to platelet aggregation and vascular contraction, 5-HT induces hyperplasia of artery smooth muscle cells. Recently, a 5-HT transporter gene polymorphism has been associated with MI. To determine the influence of genetic variation at the 5-HT(2A) receptor (T102C polymorphism) and the 5-HTT (insertion/deletion polymorphism) on the risk of developing early MI, we genotyped 210 MI patients of < 55 years old and 238 healthy control subjects for DNA polymorphisms in these genes. In addition, we genotyped 95 patients with late-onset MI (> 60 years old) to analyse the effects of these polymorphisms on the age at which the first MI episode occurred. The 5-HT(2A) receptor polymorphism was not associated with MI in our population. In addition, since the 5-HT(2A) receptor gene and genotype frequencies did not differ between patients with early and late onset of MI, this polymorphism does not appear to have an effect on age at the first MI episode. Gene and genotype frequencies for the 5-HTT promoter did not differ between patients < 55 years old and healthy controls (independent of smoking status). However, homozygotes for the deletion (the ss genotype, where s denotes the short allele) were present at a significantly higher frequency in patients >60 years old compared with patients < 55 years old (P = 0.009; P = 0.004 when only smokers were compared). According to our data, the ss genotype would seem to have a protective role against MI, delaying the age of onset of the first episode, especially among smokers. This could be a consequence of the lower 5-HTT levels linked to the s allele, so that individuals homozygous for the ss genotype may have lower 5-HT re-uptake by platelets.     

The role of 5-HT3 receptor antagonists in preventing postoperative nausea and vomiting

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POSTOPERATIVE NAUSEA AND VOMITING (PONV) is a frequent complication of surgery. Guidelines recommend using a 5-HT₃ receptor antagonist (eg, ondansetron, dolasetron, granisetron) combined with a second agent (eg, dexamethasone) for patients at moderate to high risk for PONV.

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ALTHOUGH ALL 5-HT₃ ANTAGONISTS are effective, ondansetron and granisetron have been found to be effective at substantially lower doses than those approved by the US Food and Drug Administration. Metabolism of granisetron differs from metabolism of other 5-HT₃ antagonists, so it is less likely to adversely interact with other medications.

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THIS ARTICLE EXPLAINS the clinical pharmacology of 5-HT₃ antagonists and provides recommendations for nursing management of PONV. AORN J 83 (January 2006) 209-220.

     

Selective 5-HT2 receptor blockade in exercise-induced asthma

Seven young extrinsic asthmatics participated in an open, pilot study to determine the protective effect of a selective 5-hydroxytryptamine (5-HT) blocking agent, ketanserin, on exercise induced asthma. Ketanserin in a dose of 10 mg given intravenously 20 min before exercise altered the basal bronchomotor tone in only 1 of 6 subjects and offered partial protection against exercise-induced bronchoconstriction in 1 of 5 asthmatics with no overall effect in the group. All patients experienced sleepiness after administration of ketanserin and one had bradycardia with hypotension. The ineffectiveness of ketanserin suggests indirectly that serotonin has a limited role in the pathogenesis of exercise-induced asthma.