BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diar...BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.展开更多
Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have re...Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have reported the association between the serotonin receptor family （5-HTR） gene polymorphisms and ADHD, but the results are still controversial. In this study, we conducted a meta-analysis of the association between 5-HTRIB, 5-HTR2A, and 5-HTR2C genetic variants and ADHD. The results showed that the 861G allele of 5-HTRIB SNP rs6296 could significantly increase the risk of ADHD （OR= 1.09, 95% CI： 1.01-1.18）; the 5-HTR2C gene rs518147 （OR=1.69, 95% CI： 1.38-2.07） and rs3813929 （OR = 1.57, 95% CI： 1.25-1.97） were all associated with the risk of ADHD. In addition, we also carried on a case- control study to explore the relevance between potential candidate genes 5-HTR1A, 5-HTRIE, 5-HTR3A and ADHD. The results indicated that 5-HTRIA rs6295 genotype （CC＋CG vs. GG OR=Z00, 95% CI： 1.23-3.27） and allele （OR=1.77, 95% CI： 1.16-2.72） models were statistically significantly different between case group and control group. This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD, and it also provides more evidence for the etiology of ADHD.展开更多
AIM:To determine the molecular mechanisms of Shugan decoction(SGD) in the regulation of colonic motility and visceral hyperalgesia(VHL) in irritable bowel syndrome(IBS).METHODS:The chemical compounds contained in SGD ...AIM:To determine the molecular mechanisms of Shugan decoction(SGD) in the regulation of colonic motility and visceral hyperalgesia(VHL) in irritable bowel syndrome(IBS).METHODS:The chemical compounds contained in SGD were measured by high-performance liquid chromatography.A rat model of IBS was induced by chronic water avoidance stress(WAS).The number of fecal pellets was counted after WAS and the pain pressure threshold was measured by colorectal distension.Morphological changes in colonic mucosa were detected by hematoxylin-eosin staining.The contents of tumor necrosis factor(TNF)-αin colonic tissue and calcitonin-gene-related peptide(CGRP)in serum were measured by ELISA.The protein expression of serotonin[5-hydroxytryptamide(5-HT)],serotonin transporter(SERT),chromogranin A(Cg A)and CGRP incolon tissue was measured by immunohistochemistry.RESULTS:SGD inhibited colonic motility dysfunction and VHL in rats with IBS.Blockers of transient receptor potential(TRP)vanilloid 1(TRPV1)(Ruthenium Red)and TRP ankyrin-1(TRPA1)(HC-030031)and activator of protease-activated receptor(PAR)4 increased the pain pressure threshold,whereas activators of PAR2and TRPV4 decreased the pain pressure threshold in rats with IBS.The effect of SGD on pain pressure threshold in these rats was abolished by activators of TRPV1(capsaicin),TRPV4(RN1747),TRPA1(Polygodial)and PAR2(AC55541).In addition,CGRP levels in serum and colonic tissue were both increased in these rats.TNF-αlevel in colonic tissue was also significantly upregulated.However,the levels of 5-HT,SERT and Cg A in colonic tissue were decreased.All these pathological changes in rats with IBS were attenuated by SGD.CONCLUSION:SGD alleviated VHL and attenuated colon motility in IBS,partly by regulating TRPV1,TRPV4,TRPA1,PAR2,5-HT,Cg A and SERT,and reducing CGRP and TNF-αlevel.展开更多
Abnormal serotonin 2C receptor (5HTR2C) alternative splicing and RNA editing are involved in the etiology of pain disorders. Functional 5HTR2C can only be generated when alternative exon Vb is included within the mRNA...Abnormal serotonin 2C receptor (5HTR2C) alternative splicing and RNA editing are involved in the etiology of pain disorders. Functional 5HTR2C can only be generated when alternative exon Vb is included within the mRNA;the small nucleolar RNA RBII-52 is complementary to exon Vb and promotes its inclusion. The expression of HBII-52 (the human equivalent of RBII-52) is reduced in Prader-Willi syndrome, patients of which have a high pain threshold. Here, we measured the pain threshold in a rat model of orofacial neuropathic pain and related it to the expression levels of wild-type and variant 5HTR2C and RBII-52. We generated an infraorbital nerve loose ligation model of neuropathic pain in rats and measured the pain threshold of the animals using mechanical stimulation with von Frey filaments. We then sacrificed the animals and examined the RNA levels of 5HTR2C and RBII-52 in the cervical spinal cord by real-time PCR. On post-injury day 28, pain threshold values in injured rats were significantly lower than in sham-operated or na?ve animals. The levels of total and exon Vb-skipped 5HTR2C mRNA were significantly lower in injured rats than in that sham-operated or na?ve rats, and the ratio of exon Vb-skipped 5HTR2C to total 5HTR2C was significantly higher. There were no significant differences in RBII-52 expression among the groups. Our data suggest that neuropathic pain induces serotonergic dysfunction mediated by 5HTR2C alternative splicing. 5HTR2C might be subject to complicated and fine regulation both by RNA editing and by alternative splicing.展开更多
The present study examines the effects of serotonin (5-HT) 1A receptor ligands on humoral im-mune response in two rat lines selected for over 75 generations for the enhancement or elimination of aggression. Activation...The present study examines the effects of serotonin (5-HT) 1A receptor ligands on humoral im-mune response in two rat lines selected for over 75 generations for the enhancement or elimination of aggression. Activation of presynaptic 5-HT1A receptors with a low dose of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) or the blockade of postsynaptic 5-HT1A receptors with the antagonist WAY-100635 (1.0 mg/kg) did not affect the numbers of IgM-antibody forming cells (IgM-AFC) in the spleen of highly aggressive rats, which were characterized by higher immune responsiveness compared to nonaggressive line. On the other hand, the same doses of 8-OH-DPAT and WAY-100635, as well as a higher dose of 8-OH-DPAT (1.0 mg/kg), which is known to activate postsynaptic 5-HT1A receptors, produce immunostimulation in nonaggressive rats. However, only the highest dose of 8-OH-DPAT (5.0 mg/kg) was able to cause immunosuppression in nonaggressive rats that was mainly dependent on stimulation of postsynaptic 5-HT1A receptors. In contrast to nonaggressive rats, the dose of 1.0 mg/kg 8-OH-DPAT was sufficient to produce a decrease in the numbers of IgM-AFC in highly aggressive rats. Thus, pharmacological activation of pre- and postsynaptic 5-HT1A receptors, as well as the blockade of postsynaptic 5-HT1A receptors, produced different effects on the immune response in two lines of rats selected for high level of aggression or its absence. These data may have implications for more efficient treatments of a number of mental disorders associated with abnormal aggression.展开更多
Previously, we reported that changes induced in autonomic neurotransmission in rats by Lactobacillus brevis SBC8803 may be mediated by serotonin 3 (5-HT3) receptors. In this study, we evaluated the effects of heat-kil...Previously, we reported that changes induced in autonomic neurotransmission in rats by Lactobacillus brevis SBC8803 may be mediated by serotonin 3 (5-HT3) receptors. In this study, we evaluated the effects of heat-killed L. brevis SBC8803 on serotonin (5-HT) releasing from intestinal cells. In the in vitro study, L. brevis SBC8803 stimulated 5-HT release from cultured rat endocrine RIN-14B cells (SBC8803 vs. sterile water;P in vivo study, 2 mg of heat-killed L. brevis SBC8803 was administered using a stomach sonde (feeding needle) to C57BL/6J mice. Analysis of plasma by ELISA showed gradually increase in 5-HT concentrations (0 min vs. 60 min;P ex vivo cultured intestinal loops composed of duodenum and part of the jejunum, from C3H/HeN and C57BL/6J male mice indicated that L. brevis SBC8803 effectively induced 5-HT release (SBC8803 vs. sterile water;P L. brevis SBC8803 may stimulate 5-HT release from mouse intestinal cells such as enterochromaffin cells.展开更多
Serotonin 5-HT2A receptors are playing an important role in the pathophysiology of aggressive behaviors and in the control of immune function. In the present study, we analyzed the effects of activation and blockade o...Serotonin 5-HT2A receptors are playing an important role in the pathophysiology of aggressive behaviors and in the control of immune function. In the present study, we analyzed the effects of activation and blockade of 5-HT2A receptors with selective ligands on the immune response formation in animals with aggressive behaviors induced by genetic factors (rats selected for the increased aggressiveness toward human) or by chronic social stress (mice of the CBA/Lac strain engaged in 10 days of social confrontations). Activation of 5-HT2A receptors with DOI at 1.0 mg/kg reduced the immune response level both in aggressive rats and mice compared to the corresponding vehicle-treated groups, while DOI administration did not alter the immune reaction in nonaggressive animals. The blockade of 5-HT2A receptors with ketanserin at 1.0 mg/kg resulted in immunostimulation both in mice of the CBA strain not subjected to social stress (the controls) and in nonaggressive rats selected for elimination of aggressiveness. On the other hand, its administration to CBA mice demonstrating offensive aggression enhanced the immune reaction, while the same dose of ketanserin did not modify the immune response level in rats with genetic predisposition to the increased defensive aggression. Thus, our data suggest that the role of 5-HT2A receptors in immunomodulation depends on the specific type of aggression that may be taking into account in the treatment of some neuropsychiatric disorders with the antipsychotic drugs and antidepressants targeting 5-HT2A receptors.展开更多
基金The Health Commission of Jinshan District,Shanghai,China,No.JSKJ-KTMS-2019-01The Youth Research Foundation of Jinshan Hospital of Fudan University,No.JYQN-JC-202101 and No.JYQN-JC-202216The Reserve Discipline Construction of Jinshan Hospital of Fudan University,No.HBXK-2021-2.
文摘BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.
文摘Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have reported the association between the serotonin receptor family （5-HTR） gene polymorphisms and ADHD, but the results are still controversial. In this study, we conducted a meta-analysis of the association between 5-HTRIB, 5-HTR2A, and 5-HTR2C genetic variants and ADHD. The results showed that the 861G allele of 5-HTRIB SNP rs6296 could significantly increase the risk of ADHD （OR= 1.09, 95% CI： 1.01-1.18）; the 5-HTR2C gene rs518147 （OR=1.69, 95% CI： 1.38-2.07） and rs3813929 （OR = 1.57, 95% CI： 1.25-1.97） were all associated with the risk of ADHD. In addition, we also carried on a case- control study to explore the relevance between potential candidate genes 5-HTR1A, 5-HTRIE, 5-HTR3A and ADHD. The results indicated that 5-HTRIA rs6295 genotype （CC＋CG vs. GG OR=Z00, 95% CI： 1.23-3.27） and allele （OR=1.77, 95% CI： 1.16-2.72） models were statistically significantly different between case group and control group. This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD, and it also provides more evidence for the etiology of ADHD.
基金Supported by Innovation Program of the Shanghai Municipal Education Commission,No.12YZ065National Natural Science Foundation of China,No.81072786,No.81473630 and No.81202665+2 种基金Longhua Medical Project,No.D-09High level Project of the University of Educational Commission of Shanghai,China,No.2008GSP19Shanghai Leading Academic Discipline Project,No.J50305
文摘AIM:To determine the molecular mechanisms of Shugan decoction(SGD) in the regulation of colonic motility and visceral hyperalgesia(VHL) in irritable bowel syndrome(IBS).METHODS:The chemical compounds contained in SGD were measured by high-performance liquid chromatography.A rat model of IBS was induced by chronic water avoidance stress(WAS).The number of fecal pellets was counted after WAS and the pain pressure threshold was measured by colorectal distension.Morphological changes in colonic mucosa were detected by hematoxylin-eosin staining.The contents of tumor necrosis factor(TNF)-αin colonic tissue and calcitonin-gene-related peptide(CGRP)in serum were measured by ELISA.The protein expression of serotonin[5-hydroxytryptamide(5-HT)],serotonin transporter(SERT),chromogranin A(Cg A)and CGRP incolon tissue was measured by immunohistochemistry.RESULTS:SGD inhibited colonic motility dysfunction and VHL in rats with IBS.Blockers of transient receptor potential(TRP)vanilloid 1(TRPV1)(Ruthenium Red)and TRP ankyrin-1(TRPA1)(HC-030031)and activator of protease-activated receptor(PAR)4 increased the pain pressure threshold,whereas activators of PAR2and TRPV4 decreased the pain pressure threshold in rats with IBS.The effect of SGD on pain pressure threshold in these rats was abolished by activators of TRPV1(capsaicin),TRPV4(RN1747),TRPA1(Polygodial)and PAR2(AC55541).In addition,CGRP levels in serum and colonic tissue were both increased in these rats.TNF-αlevel in colonic tissue was also significantly upregulated.However,the levels of 5-HT,SERT and Cg A in colonic tissue were decreased.All these pathological changes in rats with IBS were attenuated by SGD.CONCLUSION:SGD alleviated VHL and attenuated colon motility in IBS,partly by regulating TRPV1,TRPV4,TRPA1,PAR2,5-HT,Cg A and SERT,and reducing CGRP and TNF-αlevel.
文摘Abnormal serotonin 2C receptor (5HTR2C) alternative splicing and RNA editing are involved in the etiology of pain disorders. Functional 5HTR2C can only be generated when alternative exon Vb is included within the mRNA;the small nucleolar RNA RBII-52 is complementary to exon Vb and promotes its inclusion. The expression of HBII-52 (the human equivalent of RBII-52) is reduced in Prader-Willi syndrome, patients of which have a high pain threshold. Here, we measured the pain threshold in a rat model of orofacial neuropathic pain and related it to the expression levels of wild-type and variant 5HTR2C and RBII-52. We generated an infraorbital nerve loose ligation model of neuropathic pain in rats and measured the pain threshold of the animals using mechanical stimulation with von Frey filaments. We then sacrificed the animals and examined the RNA levels of 5HTR2C and RBII-52 in the cervical spinal cord by real-time PCR. On post-injury day 28, pain threshold values in injured rats were significantly lower than in sham-operated or na?ve animals. The levels of total and exon Vb-skipped 5HTR2C mRNA were significantly lower in injured rats than in that sham-operated or na?ve rats, and the ratio of exon Vb-skipped 5HTR2C to total 5HTR2C was significantly higher. There were no significant differences in RBII-52 expression among the groups. Our data suggest that neuropathic pain induces serotonergic dysfunction mediated by 5HTR2C alternative splicing. 5HTR2C might be subject to complicated and fine regulation both by RNA editing and by alternative splicing.
文摘The present study examines the effects of serotonin (5-HT) 1A receptor ligands on humoral im-mune response in two rat lines selected for over 75 generations for the enhancement or elimination of aggression. Activation of presynaptic 5-HT1A receptors with a low dose of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) or the blockade of postsynaptic 5-HT1A receptors with the antagonist WAY-100635 (1.0 mg/kg) did not affect the numbers of IgM-antibody forming cells (IgM-AFC) in the spleen of highly aggressive rats, which were characterized by higher immune responsiveness compared to nonaggressive line. On the other hand, the same doses of 8-OH-DPAT and WAY-100635, as well as a higher dose of 8-OH-DPAT (1.0 mg/kg), which is known to activate postsynaptic 5-HT1A receptors, produce immunostimulation in nonaggressive rats. However, only the highest dose of 8-OH-DPAT (5.0 mg/kg) was able to cause immunosuppression in nonaggressive rats that was mainly dependent on stimulation of postsynaptic 5-HT1A receptors. In contrast to nonaggressive rats, the dose of 1.0 mg/kg 8-OH-DPAT was sufficient to produce a decrease in the numbers of IgM-AFC in highly aggressive rats. Thus, pharmacological activation of pre- and postsynaptic 5-HT1A receptors, as well as the blockade of postsynaptic 5-HT1A receptors, produced different effects on the immune response in two lines of rats selected for high level of aggression or its absence. These data may have implications for more efficient treatments of a number of mental disorders associated with abnormal aggression.
文摘Previously, we reported that changes induced in autonomic neurotransmission in rats by Lactobacillus brevis SBC8803 may be mediated by serotonin 3 (5-HT3) receptors. In this study, we evaluated the effects of heat-killed L. brevis SBC8803 on serotonin (5-HT) releasing from intestinal cells. In the in vitro study, L. brevis SBC8803 stimulated 5-HT release from cultured rat endocrine RIN-14B cells (SBC8803 vs. sterile water;P in vivo study, 2 mg of heat-killed L. brevis SBC8803 was administered using a stomach sonde (feeding needle) to C57BL/6J mice. Analysis of plasma by ELISA showed gradually increase in 5-HT concentrations (0 min vs. 60 min;P ex vivo cultured intestinal loops composed of duodenum and part of the jejunum, from C3H/HeN and C57BL/6J male mice indicated that L. brevis SBC8803 effectively induced 5-HT release (SBC8803 vs. sterile water;P L. brevis SBC8803 may stimulate 5-HT release from mouse intestinal cells such as enterochromaffin cells.
文摘Serotonin 5-HT2A receptors are playing an important role in the pathophysiology of aggressive behaviors and in the control of immune function. In the present study, we analyzed the effects of activation and blockade of 5-HT2A receptors with selective ligands on the immune response formation in animals with aggressive behaviors induced by genetic factors (rats selected for the increased aggressiveness toward human) or by chronic social stress (mice of the CBA/Lac strain engaged in 10 days of social confrontations). Activation of 5-HT2A receptors with DOI at 1.0 mg/kg reduced the immune response level both in aggressive rats and mice compared to the corresponding vehicle-treated groups, while DOI administration did not alter the immune reaction in nonaggressive animals. The blockade of 5-HT2A receptors with ketanserin at 1.0 mg/kg resulted in immunostimulation both in mice of the CBA strain not subjected to social stress (the controls) and in nonaggressive rats selected for elimination of aggressiveness. On the other hand, its administration to CBA mice demonstrating offensive aggression enhanced the immune reaction, while the same dose of ketanserin did not modify the immune response level in rats with genetic predisposition to the increased defensive aggression. Thus, our data suggest that the role of 5-HT2A receptors in immunomodulation depends on the specific type of aggression that may be taking into account in the treatment of some neuropsychiatric disorders with the antipsychotic drugs and antidepressants targeting 5-HT2A receptors.
