RESUMEN

This mini-review presents our current understanding of serotonin type 7 receptor research focusing on the possible network mechanisms underlying the behavioral action of receptor antagonists. The serotonin type 7 receptor is expressed widely throughout the nervous system and known to be involved in various cognitive and physiological mechanisms. It became a clinically significant target after the discovery that its selective antagonist SB 269970 can exert rapid-onset antidepressant effects either alone or in combination with lower doses of conventional antidepressant drugs. Further research has shown that administration of SB 269970 can effectively counteract negative neurobiological outcomes in various chronic stress paradigms. The authors hope they can introduce a wider scientific audience to this promising pharmacological target which, if successful, could in time lead to more discoveries and a better understanding of the underlying serotonin receptor biology as well as its clinical potential. HIGHLIGHTS.

Asunto(s)

Antagonistas de la Serotonina , Estrés Psicológico , Animales , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Antagonistas de la Serotonina/uso terapéutico , Antagonistas de la Serotonina/farmacología , Humanos , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Enfermedad Crónica , Sulfonamidas/uso terapéutico , Sulfonamidas/farmacología , Modelos Animales de Enfermedad

RESUMEN

Exogenous corticosterone administration reduces GABAergic transmission and impairs its 5-HT7 receptor-dependent modulation in the rat dorsal raphe nucleus (DRN), but it is largely unknown how neuronal functions of the DRN are affected by repeated physical and psychological stress. This study compared the effects of repeated restraint stress and corticosterone injections on DRN neuronal excitability, spontaneous synaptic transmission, and its 5-HT7 receptor-dependent modulation. Male Wistar rats received corticosterone injections for 7 or 14 days or were restrained for 10 min twice daily for 3 days. Repeated restraint stress and repeated corticosterone administration evoked similar changes in performance in the forced swim test. They increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from DRN neurons. In contrast to the treatment with corticosterone, restraint stress-induced changes in sEPSC kinetics and decreased intrinsic excitability of DRN neurons did not modify inhibitory transmission. Repeated injections of the 5-HT7 receptor antagonist SB 269970 ameliorated the effects of restraint on excitability and sEPSC frequency but did not restore the altered kinetics of sEPSCs. Thus, repeated restraint stress and repeated corticosterone administration differ in consequences for the intrinsic excitability of DRN projection neurons and their excitatory and inhibitory synaptic inputs. Effects of repeated restraint stress on DRN neurons can be partially abrogated by blocking the 5-HT7 receptor.

Asunto(s)

Corticosterona , Núcleo Dorsal del Rafe , Ratas , Masculino , Animales , Núcleo Dorsal del Rafe/fisiología , Corticosterona/farmacología , Serotonina/farmacología , Potenciales Postsinápticos Inhibidores , Ratas Wistar , Transmisión Sináptica , Neuronas

RESUMEN

OBJECTIVES: Recently, studies have demonstrated that serotonin type 7 receptors (5-HT7) have conflincting effects on neuronal excitability in different brain regions. However, the effect of 5-HT7 on seizures has not been exactly elucidated yet. Therefore, our aim in this study was to investigate the effects of 5-HT7 antagonist SB-269970 on pentylenetetrazole (PTZ) induced fully kindled rats. METHODS: In the study, 32 adult male Wistar Albino rats (weighing 220-260 g) were used. Rats were injected with PTZ (35 mg/kg) intraperitoneally every other day to generate kindling model. 5-CT (0.1 mg/kg) and SB-269970 (1 mg/kg) were administered 30 min before acute seizure induction with PTZ (35 mg/kg). Seizure stages were determined according to the Racine scale. After electrocorticography (ECoG) recordings of seizure-induced rats were obtained, the animals were sacrificed by decapitation. The hippocampal GABA levels were determined by ELISA kit and the number of c-Fos positive neurons in the hippocampal dentate gyrus (DG), CA1 and CA3 areas were measured by immunohistochemical method. RESULTS: The results showed that SB-269970 reduced the number of spikes, percent seizure duration and duration of generalized tonic-clonic seizures (dGTCS), while increasing the onset time of generalized tonic-clonic seizures (oGTCS). The hippocampal GABA levels were significantly increased in the SB-269970 group compared with the PTZ group. In addition, SB-269970 reduced the number of c-Fos positive cells in hippocampal CA1 area. DISCUSSION: 5-HT7 antagonist SB-269970 displays anticonvulsant effects on PTZ-induced seizures in fully kindled rats and these effects may be related to GABAergic activity in the hippocampus.

Asunto(s)

Excitación Neurológica , Pentilenotetrazol , Animales , Hipocampo , Masculino , Pentilenotetrazol/toxicidad , Fenoles , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Receptores de Serotonina , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Sulfonamidas , Ácido gamma-Aminobutírico/metabolismo

RESUMEN

General anesthesia is widely utilized in the clinic for surgical and diagnostic procedures. However, growing evidence suggests that anesthetic exposure may affect cognitive function negatively. Unfortunately, little is known about the underlying mechanisms and efficient prevention and therapeutic strategies for the anesthesia-induced cognitive dysfunction. 5-HT7R, a serotonin receptor family member, is functionally associated with learning and memory. It has recently become a potential therapeutic target in various neurological diseases as its ligands have a wide range of neuropharmacological effects. However, it remains unknown the role of 5-HT7R in the long-term isoflurane anesthesia-induced memory impairment and whether prior activation or blockade of 5-HT7R before anesthesia has modulating effects on this memory impairment. In this study, 5-HT7R selective agonist LP-211 and 5-HT7R selective antagonist SB-269970 were pretreated intraperitoneally to mice before anesthesia; their effects on the cognitive performance of mice were assessed using fear conditioning test and novel object recognition test. Furthermore, the transcriptional level of 5-HT7R in the hippocampus was detected using qRT-PCR, and proteomics was conducted to probe the underlying mechanisms. As a result, long-term exposure to isoflurane anesthesia caused memory impairment and an increase in hippocampal 5-HT7R mRNA expression, which could be attenuated by SB-269970 pretreatment but not LP-211pretreatment. According to the proteomics results, the antiamnestic effect of SB-269970 pretreatment was probably attributed to its action on the gene expression of Slc6a11, Itpka, Arf3, Srcin1, and Epb41l2, and synapse organization in the hippocampus. In conclusion, 5-HT7R is involved in the memory impairment induced by long-term isoflurane anesthesia, and the prior blockade of 5-HT7R with SB-269970 protects the memory impairment. This finding may help to improve the understanding of the long-term isoflurane anesthesia-induced memory impairment and to construct potential preventive and therapeutic strategies for the adverse effects after long-term isoflurane exposure.

Asunto(s)

Anestésicos por Inhalación/administración & dosificación , Disfunción Cognitiva/inducido químicamente , Isoflurano/administración & dosificación , Memoria/efectos de los fármacos , Animales , Hipocampo/metabolismo , Aprendizaje , Masculino , Ratones , Ratones Endogámicos C57BL , Fenoles/farmacología , Piperazinas/farmacología , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Sulfonamidas/farmacología

RESUMEN

Prostate cancer (PCa) is one of the most common types of cancer seen among men worldwide. Previous studies have demonstrated that serotonin regulates cell proliferation, migration, and invasion in vitro; the presence of 5-HT receptors in cancer cells; and the role of serotonin in tumor development. The most recently discovered of these receptors is 5-HT7 but also least characterized receptors of serotonin. The aim of this study is to investigate the existence and possible role of 5-HT7 receptors in healthy and cancerous prostate tissues and also investigate effects of receptor agonists and antagonists on PC-3 cells to evaluate potential therapeutic effects. PC-3 cells were cultured and effects of 5-HT7 receptor agonist (LP-44) and antagonist (SB-269970) were evaluated on these cells. After proliferation analyses, relative expression of apoptotic markers and 5-HT7 receptor mRNA expression levels were determined through real-time PCR. Annexin V-FITC/PI double staining and Hoechst 33258 staining assay methods were applied to determine apoptosis. Additional PCR studies were performed on healthy and cancerous prostate tissue to see existence of receptors in human samples. The viability of PC-3 cells was decreased by SB-269970 after 48 and 72 h of incubation. However, LP-44 increased PC-3 cell proliferation at all time points. In 10-6 M SB-269970 treated PC-3 cells, there was significant increase in the expression of CAS-3 (4-fold), CAS-9 (2.5-fold), BAX (1.9-fold), and Tp-53 (4.8-fold) gene mRNA levels when compared to non-treated control group. Conversely, there was a significant decrease in NF-κB (2.9-fold) and 5-HT7 receptor (3.6-fold) mRNA expression in cells treated with SB-269970 when compared to control. SB-269970 that antagonized 5-HT7 receptors also induced apoptosis in Annexin V-FITC/PI double staining assay and Hoechst 33258 staining assays when compared with other groups. In human samples, 5-HT7 receptor mRNA expression was approximately 200-fold higher than that of heathy ones. In this study, for the first time, the 5-HT7 receptor antagonist SB-269970 has been shown to inhibit proliferation in PC-3 cells and to be associated with an apoptosis-inducing effect. These results suggest blocking 5-HT7 receptors can be a novel therapeutic target for the treatment of prostate cancer.

Asunto(s)

Fenoles/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Sulfonamidas/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Células PC-3 , Piperazinas/farmacología , Piperazinas/uso terapéutico , Neoplasias de la Próstata/patología , ARN Mensajero/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/uso terapéutico , Tetrahidronaftalenos/farmacología , Tetrahidronaftalenos/uso terapéutico , Factores de Tiempo

RESUMEN

5-HT7 receptor antagonism has been shown to ameliorate ketamine-induced schizophrenia-like deficits in extradimensional set-shifting using the attentional set-shifting task (ASST). However, this rodent paradigm distinguishes between several types of cognitive rigidity associated with neuropsychiatric conditions. The goal of this study was to test 5-HT7 receptor involvement in the reversal learning component of the ASST because this ability depends primarily on the orbito-frontal cortex, which shows strong 5-HT7 receptor expression. We found that impaired performance on the ASST induced by NMDA receptor blockade (MK-801, 0.2 mg/kg) in 14 rats was reversed by coadministration of the 5-HT7 receptor antagonist SB-269970. The strongest effect was found on the reversal phases of ASST, whereas injection of SB-269970 alone had no effect. These results indicate that 5-HT7 receptor mechanisms may have a specific contribution to the complex cognitive deficits, increasing perseverative responding, in psychiatric diseases, including schizophrenia, depression, and anorexia nervosa, which express different forms of cognitive inflexibility.

Asunto(s)

Receptores de Serotonina , Aprendizaje Inverso , Animales , Atención , Ratas , Ratas Sprague-Dawley

RESUMEN

The presence of 5-HT7r's in both human and rat cardiovascular and immune tissues and their contribution to inflammatory conditions prompted us to hypothesize that these receptors contribute in acute myocardial infarction (MI) with underlying chronic endothelial dysfunction. We investigated the role of 5-HT7 receptors on heart tissue that damaged by isoproterenol (ISO)-induced MI in rats with high-fat diet (HFD). In vitro and in vivo effects of 5-HT7r agonist (LP44) and antagonist (SB269970) have been investigated on the H9C2 cell line and rats, respectively. For in vivo analyses, rats were fed with HFD for 8 weeks and after this period ISO-induced MI model has been applied to rat. To investigate the role of 5-HT7r's, two different doses of LP44 and SB269970 were evaluated and compared with standard hypolipidemic agent, atorvastatin. In vitro studies showed that LP44 has protective and proliferative effects on rat cardiomyocytes. Also in in vivo studies stimulating 5-HT7r's by LP44 improved blood lipid profile (decreased total cholesterol, low-density lipoprotein-C, and triglyceride, increased high-density lipoprotein), decreased cardiac damage markers (creatine kinase and troponin-I), and corrected inflammatory status (tumor necrosis factor-α, interleukin-6). Our results showed significant improvement in LP44 administered rats in terms of histopathologic analyses. In damaged tissues, 5-HT7 mRNA expression increased and agonist administration decreased this elevation significantly. We determined for the first time that 5-HT7r's are overexpressed in ISO-induced MI of rats with underlying HFD-induced endothelial dysfunction. Restoration of this overexpression by LP44, a 5-HT7r agonist, ameliorated heart tissue in physiopathologic, enzymatic, and molecular level, showing the cardiac role of these receptors and suggesting them as future potential therapeutic targets.

Asunto(s)

Dieta Alta en Grasa , Isoproterenol , Infarto del Miocardio , Receptores de Serotonina/genética , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Corazón/efectos de los fármacos , Masculino , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Fenoles/farmacología , Ratas Wistar , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Sulfonamidas/farmacología

RESUMEN

5-HT7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT7 receptors in the brain in vivo. 5-HT produced hypothermia in wildtype mice by either i.p. or i.c.v. routes but did not in 5-HT7 receptor knockout mice. 5-HT-induced hypothermia was not attenuated by drugs selectively blocking alpha1 or 5-HT1A receptors. Doses of DR-4004 and SB-269970 that blocked 5-HT-induced hypothermia, did not display significant anxiolytic-like (elevated plus maze; vogel conflict) or antidepressant-like efficacy (tail-suspension test) in mouse models. These compounds did demonstrate some antipsychotic-like properties in the PCP-induced hyperactivity assay and anxiolytic/anti-stress effects in the stress-induced cGMP assay. Negative findings were substantiated by positive control drugs that were active in each assay system. We conclude that 5-HT-induced hypothermia can be used to estimate blockade of central 5-HT7 receptors. Effects of DR-4004 and SB-269970 in animal models are generally consistent with the experimental literature that the evidence is mixed or not robust regarding the potential efficacy of 5-HT7 receptor antagonism in the treatment of anxiety, depression, or schizophrenia.

Asunto(s)

Indoles/farmacología , Fenoles/farmacología , Psicotrópicos/farmacología , Piridinas/farmacología , Receptores de Serotonina , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Animales , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/metabolismo , Temperatura Corporal/efectos de los fármacos , GMP Cíclico/metabolismo , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Hipotermia/inducido químicamente , Indoles/química , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fenoles/química , Psicotrópicos/química , Piridinas/química , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Antagonistas de la Serotonina/química , Sulfonamidas/química

RESUMEN

So far, no suitable 5-HT7 R radioligand exists for clinical positron emission tomography (PET) imaging. [18 F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non-human primates (NHPs). Furthermore, we investigate species differences in 5-HT7 R binding with [3 H]SB-269970 autoradiography in post-mortem pig, NHP, and human brain tissue. Specific binding of [18 F]2FP3 was investigated by intravenous administration of the 5-HT7 R specific antagonist SB-269970. [3 H]SB-269970 autoradiography was performed as previously described. [18 F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB-269970 only resulted in decreased binding of 20% in the thalamus, a 5-HT7 R-rich region. Autoradiography on post-mortem pig, NHP, and human tissues revealed that specific binding of [3 H]SB-269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [18 F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5-HT7 R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5-HT7 Rs in vivo and that part of the PET signal arises from targets other than the 5-HT7 R.

Asunto(s)

Encéfalo/diagnóstico por imagen , Radioisótopos de Flúor/química , Radiofármacos/farmacocinética , Antagonistas de la Serotonina/química , Animales , Femenino , Macaca mulatta , Masculino , Fenoles/farmacocinética , Tomografía de Emisión de Positrones/métodos , Radiofármacos/síntesis química , Receptores de Serotonina/metabolismo , Sulfonamidas/farmacocinética , Porcinos

RESUMEN

RATIONALE: Chronic stress and corticosterone have been shown to affect serotonin (5-HT) neurotransmission; however, the influence of stress on the activity of the dorsal raphe nucleus (DRN), the main source of 5-HT in the forebrain, is not well understood. In particular, it is unknown if and how stress modifies DRN 5-HT7 receptors, which are involved in the modulation of the firing of local inhibitory interneurons responsible for regulating the activity of DRN projection cells. OBJECTIVES: Our study aimed to investigate the effect of repeated corticosterone injections on the modulation of the inhibitory transmission within the DRN by 5-HT7 receptors and whether it could be reversed by treatment with a 5-HT7 receptor antagonist. METHODS: Male Wistar rats received corticosterone injections repeated twice daily for 14 days. Spontaneous inhibitory postsynaptic currents (sIPSCs) were then recorded from DRN projection cells in ex vivo slice preparations obtained 24 h after the last injection. RESULTS: Repeated corticosterone administration resulted in decreased frequency, but not amplitude, of sIPSCs in DRN projection cells. There were no changes in the excitability of these cells; however, corticosterone treatment suppressed the 5-HT7 receptor-mediated increase in sIPSC frequency. Administration of the 5-HT7 receptor antagonist SB 269970 for 7 days beginning on the eighth day of corticosterone treatment reversed the detrimental effects of corticosterone on 5-HT7 receptor reactivity and GABAergic transmission in the DRN. CONCLUSIONS: Elevated corticosterone level reduces DRN 5HT7 receptor reactivity and decreases GABAergic transmission within the DRN, which can be reversed by the 5-HT7 receptor antagonist SB 269970.

Asunto(s)

Corticosterona/toxicidad , Núcleo Dorsal del Rafe/fisiología , Neuronas GABAérgicas/fisiología , Fenoles/farmacología , Receptores de Serotonina/fisiología , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Animales , Núcleo Dorsal del Rafe/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas Wistar , Serotonina/farmacología

RESUMEN

RATIONALE: The effect of atypical antipsychotic drugs (AAPDs), e.g., lurasidone, to improve cognitive impairment associated with schizophrenia (CIAS), has been suggested to be due, in part, to enhancing release of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in cortex and hippocampus. RESULTS: The present study found acute lurasidone reversed the cognitive deficit in novel object recognition (NOR) in subchronic (sc) phencyclidine (PCP)-treated mice, an animal model for CIAS. This effect of lurasidone was blocked by pretreatment with the 5-HT1AR antagonist, WAY-100635, or the 5-HT7R agonist, AS 19. Lurasidone significantly increased medial prefrontal cortex (mPFC) ACh, DA, and Glu efflux, all of which were blocked by WAY-100635, with similar effects in the dorsal striatum (dSTR), except for the absence of an effect on Glu increase. AS 19 inhibited Glu, but not DA efflux, in the dSTR. The selective 5-HT7R antagonist, SB-26970, increased mPFC DA, 5-HT, Glu, and, importantly, also GABA efflux and striatal DA, NE, 5-HT, and Glu efflux, indicating tonic inhibition of the release of these neurotransmitters by 5-HT7R stimulation. These results provide new evidence that GABA release in the mPFC is tonically inhibited by 5-HT7R stimulation and suggest that a selective 5-HT7R antagonist might be clinically useful to enhance cortical GABAergic release. All SB-269970 effects were blocked by AS 19 or WAY-100635, suggesting 5-HT1AR agonism is necessary for the release of these neurotransmitters by SB-269970. Lurasidone increased ACh, DA, and NE but not Glu efflux in mPFC and dSTR DA and Glu efflux in 5-HT7 KO mice. CONCLUSION: We conclude that lurasidone-induced Glu efflux in mPFC requires 5-HT7R antagonism while its effects on cortical ACh and DA efflux are mainly due to 5-HT1AR stimulation.

Asunto(s)

Acetilcolina/fisiología , Dopamina/fisiología , Ácido Glutámico/fisiología , Memoria Episódica , Receptores de Serotonina/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Ácido gamma-Aminobutírico/fisiología , Animales , Antipsicóticos/farmacología , Agonismo Parcial de Drogas , Clorhidrato de Lurasidona/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenciclidina/toxicidad , Antagonistas de la Serotonina/farmacología

RESUMEN

BACKGROUND: In liver fibrosis, a major morbid and mortal disease, oxidative stress motivation of hepatic stellate cells (HSCs)-into myofibroblasts terminated in collagen deposition remain the key pathophysiological deal. Serotonin (5-HT) through its HSCs-expressed receptors, especially 5-HT2A and 7, shows crucial events in fibrogenesis of chronic liver diseases. Molecular hepatic oxidative stress-fibrotic roles of 5-HT2A and 7 receptors antagonists (ketanserin and SB-269970 respectively) are still a challenging issue. METHODS: Seven groups of adult male Wistar rats (n=10) were used. A carbon tetrachloride (CCl4) solution was injected intraperitoneally twice weekly for 6 weeks. On the 7th week, rats developed liver fibrosis were treated either by ketanserin (1mg/kg/day, ip) or SB-269970 (2mg/kg/day, ip) for 14days. Survival rates, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in addition to hepatic malondialdehyde (MDA) and reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and transforming growth factor-beta1 (TGF-ß1) and procollagen type I N-terminal propeptide (PINP) levels, beside the hepatic histopathological fibrotic changes, were evaluated. RESULTS: In CCl4-challenged rats, each therapeutic approach showed significant reductions in elevated serum ALT, and AST levels, hepatic MDA, TGF-ß1, and PINP levels, and histopathological hepatic fibrotic scores as well as significant elevations in survival rates, reduced hepatic GSH levels, and SOD, and CAT activities. Remarkably, significant ameliorative measurements were observed in SB-269970 treated group. CONCLUSION: Blockade of 5-HT2A and 7 receptors each alone could be a future reliable therapeutic approach in liver fibrosis through a reduction in oxidative stress/TGF-ß1-induced HSCs activation pathway.

Asunto(s)

Tetracloruro de Carbono/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Ketanserina/farmacología , Cirrosis Hepática/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Fenoles/farmacología , Sulfonamidas/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Células Estrelladas Hepáticas/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Masculino , Malondialdehído/metabolismo , Fitoterapia/métodos , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Tasa de Supervivencia

RESUMEN

The neurotransmitter 5-hydroxytryptamine (5-HT) is involved in regulation of local tissue inflammation and repair through a set of receptors (5-HT1-7 receptors), which are expressed in the lung. Considering the protective importance of 5-HT receptor antagonists against development of pulmonary fibrosis, we evaluated whether 5-HT7 receptor antagonist (SB-269970) modulates lung inflammatory and fibrogenic processes in comparison with 5-HT2A/B receptor antagonist (terguride), in bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) model. IPF model induced by a single dose of intra-tracheal BLM instillation (5mg/kg), and rats were treated with intraperitoneal injection of SB-269970 (1mg/kg day) or terguride (1.2mg/kg/d). The experiment was carried out on two separate sets of rats that were killed at day 7th and day 21st to evaluate the endpoint of the IPF inflammatory and fibrogenic phases, respectively. During the inflammatory phase 5-HT2A/B and 5-HT7 receptor antagonists attenuated the BLM-induced increase in the lung fluid content, the inflammatory cytokines levels and oxidative stress burden. In the fibrogenic phase, both SB-269970 and terguride reduced the serotonin concentrations in lung homogenates and significantly protected against IPF fibrogenic phase by attenuating collagen deposition and mRNA expression of both transforming growth factor-ß1 (TGF- ß1), and procollagen type Ӏ (PINP). 5-hydroxytryptamine 5-HT7 receptor antagonist showed more benefits than 5-HT2A/B receptor antagonist on the deleterious effects accompanied BLM instillation. The present study showed involvement of 5-HT7 receptor in the pathophysiology of BLM-induced IPF in rats and identified it as a potential therapeutic target in lung fibrotic disorders.

Asunto(s)

Bleomicina/efectos adversos , Regulación hacia Abajo/efectos de los fármacos , Lisurida/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Fenoles/farmacología , Fibrosis Pulmonar/tratamiento farmacológico , Receptores de Serotonina/metabolismo , Sulfonamidas/farmacología , Animales , Colágeno/metabolismo , Inflamación/metabolismo , Interleucina-6/metabolismo , Lisurida/farmacología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Fenoles/uso terapéutico , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Ratas , Sulfonamidas/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Agua/metabolismo

RESUMEN

Serotonin [5-hydroxytryptamine (5-HT)] causes relaxation of the isolated superior mesenteric vein, a splanchnic blood vessel, through activation of the 5-HT7 receptor. As part of studies designed to identify the mechanism(s) through which chronic (≥24 h) infusion of 5-HT lowers blood pressure, we tested the hypothesis that 5-HT causes in vitro and in vivo splanchnic venodilation that is 5-HT7 receptor dependent. In tissue baths for measurement of isometric contraction, the portal vein and abdominal inferior vena cava relaxed to 5-HT and the 5-HT1/7 receptor agonist 5-carboxamidotryptamine; relaxation was abolished by the 5-HT7 receptor antagonist SB-269970. Western blot analyses showed that the abdominal inferior vena cava and portal vein express 5-HT7 receptor protein. In contrast, the thoracic vena cava, outside the splanchnic circulation, did not relax to serotonergic agonists and exhibited minimal expression of the 5-HT7 receptor. Male Sprague-Dawley rats with chronically implanted radiotelemetry transmitters underwent repeated ultrasound imaging of abdominal vessels. After baseline imaging, minipumps containing vehicle (saline) or 5-HT (25 µg·kg-1·min-1) were implanted. Twenty-four hours later, venous diameters were increased in rats with 5-HT-infusion (percent increase from baseline: superior mesenteric vein, 17.5 ± 1.9; portal vein, 17.7 ± 1.8; and abdominal inferior vena cava, 46.9 ± 8.0) while arterial pressure was decreased (~13 mmHg). Measures returned to baseline after infusion termination. In a separate group of animals, treatment with SB-269970 (3 mg/kg iv) prevented the splanchnic venodilation and fall in blood pressure during 24 h of 5-HT infusion. Thus, 5-HT causes 5-HT7 receptor-dependent splanchnic venous dilation associated with a fall in blood pressure.NEW & NOTEWORTHY This research is noteworthy because it combines and links, through the 5-HT7 receptor, an in vitro observation (venorelaxation) with in vivo events (venodilation and fall in blood pressure). This supports the idea that splanchnic venodilation plays a role in blood pressure regulation.

Asunto(s)

Venas Mesentéricas/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Serotonina/farmacología , Circulación Esplácnica/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Presión Arterial/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Infusiones Intravenosas , Masculino , Venas Mesentéricas/diagnóstico por imagen , Venas Mesentéricas/metabolismo , Vena Porta/efectos de los fármacos , Vena Porta/metabolismo , Ratas Sprague-Dawley , Receptores de Serotonina/metabolismo , Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/administración & dosificación , Telemetría , Factores de Tiempo , Ultrasonografía , Vasodilatadores/administración & dosificación , Vena Cava Inferior/efectos de los fármacos , Vena Cava Inferior/metabolismo

RESUMEN

The medial vestibular nucleus (MVN) is a major output station for neurons that project to the vestibulo-spinal pathway. MVN neurons show capacity for long-term depression (LTD) during the juvenile period. We investigated LTD of MVN neurons using whole-cell patch-clamp recordings. High frequency stimulation (HFS) robustly induced LTD in 90% of type B neurons in the MVN, while only 10% of type A neurons were responsive, indicating that type B neurons are the major contributors to LTD in the MVN. The neuromodulator serotonin (5-HT) is known to modulate LTD in neural circuits of the cerebral cortex and the hippocampus. We therefore aim to determine the action of 5-HT on the LTD of type B MVN neurons and elucidate the relevant 5-HT receptor subtypes responsible for its action. Using specific agonists and antagonists of 5-HT receptors, we found that selective activation of 5-HT7 receptor in type B neurons in the MVN of juvenile (P13-16) rats completely abolished NMDA-receptor-mediated LTD in a protein kinase A (PKA)-dependent manner. Our finding that 5-HT restricts plasticity of type B MVN neurons via 5-HT7 receptors offers a mechanism whereby vestibular tuning contributes to the maturation of the vestibulo-spinal circuit and highlights the role of 5-HT in postural control.

Asunto(s)

Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Depresión Sináptica a Largo Plazo/fisiología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Serotonina/metabolismo , Núcleos Vestibulares/metabolismo , Animales , Femenino , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Neurotransmisores/farmacología , Técnicas de Placa-Clamp , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de Serotonina 5-HT1/metabolismo , Receptores de Serotonina 5-HT2/metabolismo , Técnicas de Cultivo de Tejidos , Núcleos Vestibulares/efectos de los fármacos

RESUMEN

This study aimed to investigate the effects of the 5-HT7 receptor agonist (LP44) and antagonist (SB269970) on LPS-induced in vivo tissue damage and cell culture by molecular methods. This study was conducted in two steps. For in vivo studies, 24 female rats were divided into four groups. Group I: healthy; II (2nd h): LPS 5 mg/kg administered intraperitoneally (i.p.); III (4th h): LPS 5 mg/kg administered i.p.; IV (8th h): LPS 5 mg/kg administered i.p. For in vitro studies, we used the A549 cell line. Groups: I control (healthy) (2-4 h); II LPS: 1 µg/ml E. Coli O55:B5 strain (2-4 h); III agonist (LP44) 10-9 M (2-4 h); IV antagonist (SB269970) 10-9 M (2-4 h); V LPS+agonist 10-9 M (LP44 1 µg/ml) (2-4 h); VI LPS+antagonist 10-9 M (2-4 h). In molecular analyses, we determined increased TNF-α, IL-1ß, NF-κB, and 5-HT7 mRNA expressions in rat lung tissues and increased TNF-α, iNOS, and 5-HT7 mRNA expressions in the A549 cell line. In in vitro parameters, LP44 agonist administration-related decrease was observed. Our study showed that lung 5-HT7 receptor expression is increased in LPS-induced endotoxemia. All this data suggest that 5-HT7 receptor overexpression is an important protective mechanism during LPS-induced sepsis-related cell damage.

Asunto(s)

Lesión Pulmonar , Receptores de Serotonina/metabolismo , Células A549 , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolisacáridos/toxicidad , Masculino , Transporte de Proteínas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa

RESUMEN

RATIONALE: Reversal learning (RL), a type of executive function, dependent on prefrontal cortical function, is impaired in rodents by subchronic (sc) treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), a widely studied model of cognitive impairment in schizophrenia (CIS). OBJECTIVE: The principal objective of this study was to determine the ability of serotonin (5-HT)1A partial agonism and 5-HT7 receptor antagonism to improve RL in scPCP-treated mice. METHODS: Male C57BL/6J mice were trained on an operant RL (ORL) task, then received PCP, 10 mg/kg, or saline, bid, for 7 days, followed by a 7-day washout period. RESULTS: scPCP significantly diminished the percent correct responding, increased total incorrect trials, and total incorrect responses, in the reversal phase performance of the ORL task. Pre-treatment with the selective 5-HT1A partial agonist, tandospirone, or the selective 5-HT7 antagonist, SB269970, but not the 5-HT7 agonist, AS 19, reversed the scPCP-induced deficit in RL. Pre-treatment with atypical antipsychotic drug lurasidone, which is a 5-HT1A partial agonist and 5-HT7 antagonist, as well as a 5-HT2A and dopamine (D)2 antagonist, also reversed RL deficit in the scPCP-treated mice. Furthermore, the selective 5-HT1A antagonist, WAY100635, blocked the ability of lurasidone to reverse the scPCP-induced RL deficit. CONCLUSIONS: These results indicate that 5-HT7 antagonism and 5-HT1A partial agonism contribute to restoration of RL in scPCP-treated mice. It is suggested that these two mechanisms are effective in restoring RL by decreasing excessive GABAergic inhibition of cortical pyramidal neurons following withdrawal of scPCP treatment.

Asunto(s)

Función Ejecutiva/efectos de los fármacos , Fenciclidina/toxicidad , Receptores de Serotonina , Aprendizaje Inverso/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/tratamiento farmacológico , Función Ejecutiva/fisiología , Isoindoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Fenciclidina/administración & dosificación , Fenoles/farmacología , Fenoles/uso terapéutico , Piperazinas/farmacología , Pirimidinas/farmacología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptor de Serotonina 5-HT1A/fisiología , Receptores de Serotonina/fisiología , Aprendizaje Inverso/fisiología , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Antagonistas de la Serotonina/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico

RESUMEN

A series of 39 arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines, was designed with the support of the Virtual Combinatorial Library-Virtual Screening protocol, and synthesized using solid-phase methodologies. Representative compounds were biologically evaluated for their affinity for 5-HT7Rs and for their selectivity over related 5-HTRs (5-HT1ARs, 5-HT2ARs, 5-HT6Rs), dopamine D2Rs and adrenergic α1Rs. The study identified the derivatives 27 (3-fluoro-N-{1-[2-(2-cyclopentylphenoxy)ethyl]piperidin-4-yl}-benzenesulfonamide; PZ-1417) and 35 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide; PZ-1150) as being potent 5-HT7R antagonists with antidepressant and anxiolytic properties in the forced swim test (0.625-5 mg/kg and 0.625 mg/kg, respectively), the tail suspension test (0.625 mg/kg and 0.625 mg/kg, respectively), and in four plate test (0.625 mg/kg and 1.25-2.5 mg/kg, respectively) in mice. It has to be stressed that new compounds displayed higher activity than that of SB-269970, a reference 5-HT7R antagonist. Finally, the study provided valuable insight into the development of potential therapeutic agents for the treatment of CNS disorders.

Asunto(s)

Aminas/farmacología , Ansiolíticos/farmacología , Antidepresivos/farmacología , Diseño de Fármacos , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Aminas/síntesis química , Aminas/química , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Antidepresivos/síntesis química , Antidepresivos/química , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Actividad Motora/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química

RESUMEN

The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl-D-aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail. The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed. MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5 mg/kg) and SB-269970 (1 mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801-induced working memory impairment in a T-maze. The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive-enhancing effects of pharmacological blockade of 5-HT7 receptors.

Asunto(s)

Conducta de Elección/fisiología , Conducta Impulsiva/fisiología , Tiempo de Reacción/efectos de los fármacos , Receptores de Serotonina/fisiología , Animales , Conducta de Elección/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Fluorobencenos/farmacología , Conducta Impulsiva/efectos de los fármacos , Masculino , Fenoles/farmacología , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología

RESUMEN

In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [(11)C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [(11)C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands.

Asunto(s)

Piperazinas/síntesis química , Tomografía de Emisión de Positrones , Propanoles/síntesis química , Pirazinas/síntesis química , Radiofármacos , Receptores de Serotonina/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Células CHO , Isótopos de Carbono , Cricetulus , Células HEK293 , Humanos , Cinética , Ligandos , Estructura Molecular , Fenoles/farmacología , Piperazinas/química , Propanoles/química , Pirazinas/química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Sulfonamidas/farmacología , Porcinos , Distribución Tisular