Serotonin Type 2A Research Articles

Nondepolarizing neuromuscular blockers inhibit the serotonin-type 3A receptor expressed in Xenopus oocytes.

Molecular cloning and sequence comparison indicates a high degree of structural homology between muscle nicotinic acetylcholine (nACh) and serotonin-type 3 (5-HT(3A)) receptors, both members of the direct ligand-gated family of ion channels. Because of the structural similarities and common evolutionary origin of these receptors, neuromuscular blockers (competitive nACh antagonists) may demonstrate pharmacologic cross talk and exhibit attributes of 5-HT(3A) receptor antagonists. We examined six clinically-used neuromuscular blockers for their ability to antagonize currents flowing through the 5-HT(3A) receptors in voltage clamped Xenopus oocytes. The neuromuscular blockers reversibly inhibited the 5-HT(3A) receptor-gated current in the rank order potency of (IC50 mean +/- SEM): d-tubocurarine (0.046 +/- 0.003 microM), atracurium (0.40 +/- 0.03 microM), mivacurium (15.1 +/- 2.93 microM), vecuronium (16.3 +/- 2.24 microM), and rocuronium (19.5 +/- 2.31 microM). Gallamine was essentially inactive as a 5-HT(3A) receptor antagonist with an extrapolated IC50 of 1170 microM. We demonstrate that drugs classically known as competitive nACh receptor antagonists also block 5-HT(3A) receptors. It is likely that certain neuromuscular blockers share pharmacological properties with 5-HT(3A) receptor antagonists, such as a reduction in postoperative nausea and vomiting. With careful drug selection, pharmacological cross talk could potentially be used to minimize polypharmacy and optimize patient management. Muscle nicotinic acetylcholine and serotonin-type 3A (5-HT(3A)) receptors are similar. Therefore neuromuscular relaxants may block 5-HT(3A) receptors. Our pharmacological study demonstrates that neuromuscular relaxants, as with ondansetron, are 5-HT(3A) receptor antagonists. It is likely that certain neuromuscular relaxants exhibit ondansetron-like clinical properties, such as reduction in postoperative nausea and vomiting.

Reduced binding of [ [formula omitted]]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction

The serotonin (5-HT) neurotransmitter system, which has a widespread distribution in the central nervous system, has been implicated in regulating mood and many human behaviors. There is evidence from postmortem human studies and limited information from prior in vivo studies to support a decline in 5-HT2A receptor density with aging. We examined nine elderly (ages 61–76) and nine young (ages 18–29) healthy individuals with positron emission tomography (PET) and [ 18 F ]altanserin, a ligand with high affinity for the 5-HT2A binding site. The PET data were corrected for differences in brain tissue volume between the young and elderly subjects using a magnetic resonance (MR) imaging-based partial volume correction method. Highly significant and widespread cortical reductions in 5-HT2A specific binding were demonstrated in the elderly group relative to young controls. Regional losses averaged 61% before and 57% following correction for effects of cerebral atrophy. This finding, which is consistent with prior postmortem and in vivo studies, has both etiological and potential therapeutic implications for behavioral changes commonly observed in the elderly, including geriatric depression.

Effector Pathway-Dependent Relative Efficacy at Serotonin Type 2A and 2C Receptors: Evidence for Agonist-Directed Trafficking of Receptor Stimulus

There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin2A (5-HT2A) and 5-HT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed "agonist-directed trafficking of receptor stimulus" recently proposed by Kenakin [Trends Pharmacol Sci 16:232-238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.

Amperozide Influences Feeding Independently of 5-HT2A Receptor Antagonism

Amperozide has been biochemically classified as a selective 5-HT_2A (serotonin type 2A) receptor antagonist. However, research on the behavioral effects of amperozide suggests the possibility of other mechanisms. The present study in the male rat is an investigation of the effect of amperozide on feeding, a behavior which can be inhibited by 5-HT_2A agonists such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Experiments revealed that amperozide acted to inhibit feeding behavior both when administered alone and when administered in combination with DOI. These results are inconsistent with 5-HT_2A receptor antagonism by amperozide. Further experiments suggested that amperozide may be acting via α₂-adrenergic or 5-HT_1A receptors to inhibit feeding. These studies imply that amperozide’s selective 5-HT_2A antagonistic activity is behaviorally specific.

Nausea and Vomiting: Underlying Mechanisms and Upcoming Treatments.

Nausea and vomiting (emesis) occur under a variety of conditions in response to activation of one or more emetic triggers, such as abdominal visceral, cardiac and vestibular nerve afferents, the area postrema chemoreceptor trigger zone in the caudal brainstem, and higher brain centers. The act of vomiting is coordinated by neuronal circuitry located in the brainstem and extending from the nucleus of the solitary tract through the lateral tegmental field of the reticular formation to the ventrolateral medulla. The sensation of nausea is thought to involve the cerebral cortex. The motor act of vomiting is produced primarily by complicated changes in the activity of the respiratory muscles. There are also complex changes in the activity of the gastrointestinal tract, which are mediated by the vagus nerve but are not essential for vomiting. The recently introduced serotonin type 3 receptor antagonists are very effective in combating nausea and vomiting induced by cancer chemotherapy and radiation therapy. More broad based anti-emetic action has been achieved in animal models by using serotonin type 1A receptor agonists and neurokinin type 1 receptor antagonists. Stimulation of the P6 acupuncture point is reported to be effective against motion and pregnancy sickness, and postoperative and cancer chemotherapy-induced nausea and vomiting. Greater understanding of the mechanisms underlying nausea and vomiting and more effective treatments are still required, especially in conditions such as pregnancy sickness, postoperative nausea and vomiting, the delayed phase of vomiting following cisplatin therapy, and cyclical vomiting.

Genetic variation of the 5-HT2A receptor gene and bipolar affective disorder.

Abnormalities of the serotonergic system have classically been associated with the origin of affective disorders through the biochemical action of therapeutic agents and their role in affective and perceptual states. In the present study, we hypothesized that genetic variation in the 5-hydroxytryptamine (serotonin) type 2A (5-HT2A) receptor gene (HTR2A) might have an effect on the aetiology of bipolar affective disorder. Four different polymorphisms in the HTR2A gene were studied in 88 patients with bipolar affective disorder and 113 healthy controls, all of Spanish origin. No significant association was observed between any of the four polymorphisms at the HTR2A locus, whether tested individually or as haplotypes, and bipolar affective disorder. The lack of association suggests that HTR2A is not a major risk factor for bipolar affective disorder.

Chimeric Mutagenesis of Putative G-protein Coupling Domains of the α2A-Adrenergic Receptor: LOCALIZATION OF TWO REDUNDANT AND FULLY COMPETENT G1 COUPLING DOMAINS

We have investigated potential Gi and Gs coupling domains within the intracellular regions of the alpha2AAR subtype using a series of nine chimeric mutations. The second intracellular loop (ICL2, amino acids 133-149) and the amino- and carboxyl-terminal regions of the third intracellular loop (ICL3, amino acids 218-235 and 355-371, respectively) of the cloned human alpha2AAR were substituted with the analogous sequence from either the Gs-coupled beta2AR or the Gi-coupled serotonin type 1A receptor (5-HT1AR). Mutant and wild type alpha2AAR were stably expressed in Chinese hamster ovary cells and functional coupling of each receptor to Gi and Gs was assessed in membrane adenylyl cyclase assays. Substitution of 5-HT1AR sequence into ICL2 ablated coupling to Gs but not to Gi, whereas substitution of beta2AR sequence significantly depressed coupling to Gi but not to Gs. Thus, the ICL2 of the alpha2AAR contains elements essential for both signaling pathways. Substitution of either the amino- or carboxyl-terminal segments of ICL3 with 5-HT1AR sequence ablated agonist stimulation of adenylyl cyclase activity (without affecting inhibition), suggesting that both domains are necessary for alpha2AAR coupling to Gs. In contrast, individual substitution of beta2AR sequence into ICL3 amino or carboxyl termini had no appreciable effect on Gi coupling. Concomitant substitution of beta2AR sequence into both regions substantially impaired Gi coupling, implying that each is capable of independently supporting functional coupling. Substitution of 5-HT1AR at either locus had no effect on Gi coupling. Thus, for Gs coupling, these two domains within ICL3 are both required for functional coupling. However, for Gi coupling, the alpha2AAR appears to have two distinct regions within ICL3 that are capable of supporting Gi coupling independently. There has been no previous elucidation of a receptor having redundant, fully competent domains for coupling to a single class of G-protein. Such duplicity of functional domains within alpha2AR may suggest strong evolutionary pressure to maintain Gi coupling.

Assocation between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2A receptor gene

Assocation between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2A receptor gene

Regulation of synapse density by 5-HT2A receptor agonist and antagonist in the spinal cord of chicken embryo

Identification of mechanisms that regulate the number of synapses in the brain has been a key issue for understanding the mechanism of plasticity. Here, we report that the density of synapses can be changed using an antagonist and/or an agonist of serotonin (5-HT) type 2A receptors in the chicken spinal cord. Because of the widespread distribution pattern of 5-HT fibers and 5-HT2A receptors in the central nervous system, 5-HT is thought to play a role in the formation and maintenance of synapses that are involved in normal brain function and mechanism of plasticity.

Evaluation of nefazodone as a serotonin uptake inhibitor and a serotonin antagonist in vivo

Nefazodone (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3 H-1,2,4-triazol-3-one) has been reported to be effective in the treatment of depression. Antagonism of serotonin type 2A (5HT 2A) receptors, as well as inhibition of the serotonin (5HT) uptake carrier, has been suggested to contribute to the antidepressant action of nefazodone in vivo (Eison et al., 1990). Nefazodone weakly antagonized the quipazine-induced rise in rat serum corticosterone levels and the quipazine-induced increase in rat hypothalamic 3-methoxy-4-hydroxy-phenylglycol sulfate, suggesting blockade of 5HT 2A receptors in vivo. Nefazodone, however, failed to antagonize the p-chloroamphetamine-induced depletion of mouse or rat brain 5HT, displaying a lack of effect on the 5HT uptake carrier. These data extend previous in vitro and in vivo data (Eison, et al. 1990) reporting nefazodone to be an antagonist at 5HT 2A receptors, but fail to show inhibition of the 5HT uptake carrier in the same dose range.

Synthesis and biological activity of the putative metabolites of the atypical antipsychotic agent tiospirone

Putative oxidative metabolites of the lead antipsychotic agent tiospirone (1) were synthesized to assist in the identification of the authentic metabolic products found in human urine samples. Thus far, six authentic metabolites have been correlated to the synthetic species. The putative metabolites were further examined in vitro to assess their central nervous system therapeutic potential. SAR analysis of these derivatives indicates that hydroxyl substitution, particularly in the azaspirodecanedione region of the molecule, diminishes the dopamine D-2 affinity of the species without significantly altering the serotonin type-1A and type-2 interactions. In addition, an increase in alpha 1-adrenergic affinity appears to be linked to the attenuation of effects at the dopamine receptors. The biological profile of the 6-hydroxytiospirone metabolite 42 was exemplary in these respects and the in vivo actions of this compound suggest potent antipsychotic potential with a minimal liability for extrapyramidal side effects (EPS). While compound 42 has been unambiguously characterized as an actual human metabolite of tiospirone, the role of 42 in the observed antipsychotic activity of the parent drug, if any, has not yet been determined.

Gepirone in the Treatment of Major Depression

Gepirone is a serotonin (5-hydroxytryptamine, 5-HT) type1A receptor agonist and a pharmacologic analogue of buspirone. Two double-blind, placebo-controlled studies show the efficacy of gepirone in the treatment of major depression. Study 1 demonstrates gepirone's superiority over placebo in an 8-week acute treatment of patients with major depression, including the melancholic subtype. Gepirone's antidepressant dose range is tentatively established at 5-30 mg/day. Study 2 reveals the benefit of gepirone compared with placebo in 4-week continuation therapy of patients with major depression who initially responded to 6 weeks of open therapy with gepirone. Analysis of Hamilton Rating Scale for Depression item scores show gepirone especially improves scores on items of core depression.