RESUMO
Rapid adenosine transiently regulates dopamine and glutamate via A1 receptors, but other neurotransmitters, such as serotonin, have not been studied. In this study, we examined the rapid modulatory effect of adenosine on serotonin release in the dorsal raphe nuclei (DRN) of mouse brain slices by using fast-scan cyclic voltammetry. To mimic adenosine release during damage, a rapid microinjection of adenosine at 50 pmol was applied before electrical stimulation of serotonin release. Transient adenosine significantly reduced electrically evoked serotonin release in the first 20 s after application, but serotonin release recovered to baseline as adenosine was cleared from the slice. The continuous perfusion of adenosine did not change the evoked serotonin release. Surprisingly, the modulatory effects of adenosine were not regulated by A1 receptors as adenosine still inhibited serotonin release in A1KO mice and also after perfusion of an A1 antagonist (8-cyclopentyl-1,3-dipropyl xanthine). The inhibition was also not regulated by A3 receptors as perfusion of the A3 antagonist (MRS 1220) in A1KO brain slices did not eliminate the inhibitory effects of transient adenosine. In addition, adenosine also inhibited serotonin release in A2AKO mice, showing that A2A did not modulate serotonin. However, perfusion of a selective 5HT1A autoreceptor antagonist drug [(S)-WAY 100135 dihydrochloride] abolished the inhibitory effect of transient adenosine on serotonin release. Thus, the transient neuromodulatory effect of adenosine on DRN serotonin release is regulated by serotonin autoreceptors and not by adenosine receptors. Rapid, transient adenosine modulation of neurotransmitters such as serotonin may have important implications for diseases such as depression and brain injury.
Assuntos
Núcleo Dorsal da Rafe , Serotonina , Camundongos , Animais , Serotonina/farmacologia , Adenosina , Antagonistas da Serotonina/farmacologia , Receptores de Serotonina/fisiologiaRESUMO
Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.
Assuntos
Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Neurônios/efeitos dos fármacos , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Neurônios Dopaminérgicos/efeitos dos fármacos , Histamínicos/farmacologia , Histamínicos/uso terapêutico , Humanos , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Purinérgicos/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologiaRESUMO
Neurons synthesizing gonadotropin-inhibitory hormone (GnIH) have been implicated in the control of reproduction, food intake and stress. Serotonin (5-HT) receptors have been shown in GnIH neurons; however, their functional role in the regulation of GnIH neurons remains to be elucidated. In this study, we measured intracellular calcium ion levels following 5-HT treatment to hypothalamic primary cultures of enhanced fluorescent green protein-tagged GnIH (EGFP-GnIH) neurons from Wistar rat pups of mixed sex. Three days after initial seeding of the primary cultures, the test groups were pre-treated with lithium chloride to selectively inhibit glycogen synthase kinase 3 beta to promote intracellular calcium levels, whereas the control groups received culture medium with no lithium chloride treatment. 24 h later, the cultures were incubated with rhodamine-2AM (rhod-2AM) calcium indicator dye for one hour prior to imaging. 5-HT was added to the culture dishes 5 min after commencement of imaging. Analysis of intracellular calcium levels in EGFP-GnIH neurons showed that pre-treatment with lithium chloride before 5-HT treatment resulted in significant increase in intracellular calcium levels, two times higher than the baseline. This suggests that lithium chloride enhances the responsiveness of GnIH neurons to 5-HT.
Assuntos
Cálcio/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/fisiologia , Proteínas de Fluorescência Verde , Cloreto de Lítio/farmacologia , Neurônios/metabolismo , Serotonina/farmacologia , Animais , Células Cultivadas , Sinergismo Farmacológico , Feminino , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hipotálamo/citologia , Masculino , Ratos Wistar , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologia , Serotonina/metabolismoRESUMO
Recent studies have shown the 5-HT6 receptors are expressed in regions which are important in pain processing such as the cortex, amygdala, thalamus, PAG, spinal cord and dorsal root ganglia (DRG), suggesting a putative role of 5-HT6 receptors in pain modulation. The ventrolateral orbital cortex (VLO) is part of an endogenous analgesic system, consisting of the spinal cord - thalamic nucleus submedius (Sm) - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study assessed the possible role of 5-HT6 receptors in the VLO in formalin-induced inflammatory pain model. Firstly we found that microinjection of selective 5-HT6 receptor agonists EMD-386088 (5⯵g in 0.5⯵l) and WAY-208466 (8⯵g in 0.5⯵l) both augmented 5% formalin-induced nociceptive behavior. Microinjection of selective 5-HT6 receptor antagonist SB-258585 (1,2 and 4⯵g in 0.5⯵l) significantly reduced formalin-induced flinching. Besides, the pronociceptive effects of EMD-386088 and WAY-208466 were dramatically reduced by SB-258585, implicating 5-HT6 receptor mechanisms in mediating these responses. In addition, the pronociceptive effect of EMD-386088 was also prevented by the adenylate cyclase (AC) inhibitor SQ-22536 (2â¯nmol in 0.5⯵l) and the protein kinase A (PKA) inhibitor H89 (10â¯nmol in 0.5⯵l), respectively. We further confirmed the above results with quantification of spinal c-fos expression. Taken together, our results suggested that 5-HT6 receptors play a pronociceptive role in the VLO in the rat formalin test due to its activation of AC - PKA pathway. Therefore, cerebral cortical 5-HT6 receptors could be a new target to develop analgesic drugs.
Assuntos
Nociceptividade/fisiologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/psicologia , Córtex Pré-Frontal/fisiologia , Receptores de Serotonina/fisiologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Comportamento Animal , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/efeitos dos fármacos , Indóis/farmacologia , Isoquinolinas/farmacologia , Masculino , Metilaminas/farmacologia , Dor/metabolismo , Dor/psicologia , Piperazinas/farmacologia , Córtex Pré-Frontal/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/metabolismo , Sulfonamidas/farmacologiaRESUMO
The Chinese mitten crab (Eriocheir sinensis) is a commercially important crab in China and is usually managed at high stocking densities. Agonistic behavior directly impacts crab integrity, survival, and growth and results in economic losses. In the present study, we evaluated the modulatory effects of serotonin (5-HT) and dopamine (DA) though the 5-HT2 and DA2 receptor-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway on agonistic behavior. The results showed that injection of either 10-6 mol/crab 5-HT or DA reduced the agonistic behavior of E. sinensis (P < 0.05), as did 10-10 mol/crab DA and 10-8 mol/crab 5-HT and DA (P < 0.05); however, a dose of 10-10 mol/crab 5-HT promoted agonistic behavior. 5-HT significantly increased the mRNA expression level of 5-HT7 receptor and reduced that of the DA2 receptor in the cerebral ganglion (P < 0.05). In contrast to 5-HT, DA significantly decreased 5-HT2B mRNA levels and increased 5-HT7 and DA2 receptor levels in the thoracic ganglia (P < 0.05). In addition, injections of either 5-HT or DA increased the cAMP and PKA levels in hemolymph (P < 0.05). By using in vitro culture of the thoracic ganglia, the current study showed that ketanserin (5-HT2 antagonist) and [R(-)-TNPA] (DA2 agonist) had obvious effects on the expression levels of the two receptors (P < 0.05). In vivo experiments further demonstrated that ketanserin and [R(-)-TNPA] could both significantly reduce the agonistic behavior of the crabs (P < 0.05). Furthermore, both ketanserin and [R(-)-TNPA] promoted the cAMP and PKA levels (P < 0.05). The injection of CPT-cAMP (cAMP analogue) elevated the PKA levels and inhibited agonistic behavior. In summary, this study showed that 5HT-2B and DA2 receptors were involved in the agonistic behavior that 5-HT/DA induced through the cAMP-PKA pathway in E. sinensis.
Assuntos
Comportamento Agonístico/fisiologia , Dopamina/farmacologia , Receptor 5-HT1B de Serotonina/fisiologia , Receptores de Dopamina D2/fisiologia , Receptores de Serotonina/fisiologia , Serotonina/farmacologia , Comportamento Agonístico/efeitos dos fármacos , Animais , Braquiúros , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Receptores de Dopamina D2/agonistas , Antagonistas da Serotonina/farmacologiaRESUMO
AIM: This study aimed to investigate the role of the 5-HT7 receptor in fever mechanisms and its possible effect on the antipyretic mechanism of paracetamol. MATERIALS AND METHODS: The study consisted of eight experimental groups and one control group. Group I: healthy, II: LPS, III: LPS + PARA, IV: LPS + AGO, V: LPS + ANTA, VI: LPS + AGO + ANTA, VII: LPS + AGO + PARA, VIII: LPS + ANTA + PARA, and IX: LPS + AGO + ANTA + PARA. Rectal temperatures were measured with a rectal thermometer. At the end of the experiment, tissues were examined molecularly. Real-time PCR mRNA expression analyses were performed for the 5-HT7 receptor, IL-6, and TNF-α in hypothalamus tissue. RESULTS: The mean differences in rectal temperature increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group and decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the healthy group. The IL-6 and TNF-α mRNA expression increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group in the 2nd and 4th hours. The IL-6 and TNF-α expression decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the LPS group in the 2nd and 4th hours. The 5-HT7 receptor mRNA expression increased in the LPS group when compared to the healthy group in the 2nd hour. The 5-HT7 receptor mRNA expression decreased in the LPS + AGO and LPS + AGO + PARA groups when compared to the LPS group in the 2nd hour. The 5-HT7 receptor mRNA expression increased the in LPS + ANTA and LPS + ANTA + PARA groups when compared to the LPS group in the 2nd hour. CONCLUSION: The 5-HT7 receptor is a potential defense mechanism in stopping fever and the antipyretic property of paracetamol is not due to the 5-HT7 receptor.
Assuntos
Acetaminofen/farmacologia , Antipiréticos/farmacologia , Febre/tratamento farmacológico , Receptores de Serotonina/fisiologia , Animais , Temperatura Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/análise , Receptores de Serotonina/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
KEY POINTS: Concurrent 5-HT2A (Q pathway) and 5-HT7 (S pathway) serotonin receptor activation cancels phrenic motor facilitation due to mutual cross-talk inhibition. Spinal protein kinase Cδ (PKCδ) or protein kinase A inhibition restores phrenic motor facilitation with concurrent Q and S pathway activation, demonstrating a key role for these kinases in cross-talk inhibition. Spinal PKCδ inhibition enhances adenosine-dependent severe acute intermittent hypoxia-induced phrenic long-term facilitation (S pathway), consistent with relief of cross-talk inhibition. ABSTRACT: Intermittent spinal serotonin receptor activation elicits long-lasting phrenic motor facilitation (pMF), a form of respiratory motor plasticity. When activated alone, spinal Gq protein-coupled serotonin 2A receptors (5-HT2A ) initiate pMF by a mechanism that requires ERK-MAP kinase signalling and new BDNF protein synthesis (Q pathway). Spinal Gs protein-coupled serotonin 7 (5-HT7 ) and adenosine 2A (A2A ) receptor activation also elicits pMF, but via distinct mechanisms (S pathway) that require Akt signalling and new TrkB protein synthesis. Although studies have shown inhibitory cross-talk interactions between these competing pathways, the underlying cellular mechanisms are unknown. We propose the following hypotheses: (1) concurrent 5-HT2A and 5-HT7 activation undermines pMF; (2) protein kinase A (PKA) and (3) NADPH oxidase mediate inhibitory interactions between Q (5-HT2A ) and S (5-HT7 ) pathways. Selective 5-HT2A (DOI hydrochloride) and 5HT7 (AS-19) agonists were administered intrathecally at C4 (three injections, 5-min intervals) in anaesthetized, vagotomized and ventilated male rats. With either spinal 5-HT2A or 5-HT7 activation alone, phrenic amplitude progressively increased (pMF). In contrast, concurrent 5-HT2A and 5-HT7 activation failed to elicit pMF. The 5-HT2A -induced Q pathway was restored by inhibiting PKA activity (Rp-8-Br-cAMPS). NADPH oxidase inhibition did not prevent cross-talk inhibition. Therefore, we investigated alternative mechanisms to explain Q to S pathway inhibition. Spinal protein kinase C (PKC) inhibition with Gö6983 or PKCδ peptide inhibitor restored the 5-HT7 -induced S pathway to pMF, revealing PKCδ as the relevant isoform. Spinal PKCδ inhibition enhanced the S pathway-dependent form of pMF elicited by severe acute intermittent hypoxia. We suggest that powerful constraints between 5-HT2A and 5-HT7 or A2A receptor-induced pMF are mediated by PKCδ and PKA, respectively.
Assuntos
Hipóxia/fisiopatologia , Nervo Frênico/fisiologia , Proteína Quinase C-delta/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Serotonina/fisiologia , Medula Espinal/fisiologia , Anfetaminas/farmacologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Masculino , Proteína Quinase C-delta/antagonistas & inibidores , Pirazóis/farmacologia , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/farmacologia , Tetra-Hidronaftalenos/farmacologiaRESUMO
OBJECTIVES: To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT7 receptor (5-HT7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). MATERIALS AND METHODS: In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT7 R-selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot. RESULTS: LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1-30 µg/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non-voiding contractions. The 5-HT7 R antagonist, SB-269970 (10 µg/kg), partially reversed LP44-induced changes. Using PRV retrograde tracing and immunofluorescence, 5-HT7 Rs were found in the L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5-HT7 Rs in the ventral L6-S1 spinal cord in SCI rats. CONCLUSION: A 5-HT7 R agonist, given i.t., improved voiding efficiency in urethane-anesthetised SCI rats, and the 5-HT7 R was significantly up-regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5-HT7 R could be a target for therapeutic interventions.
Assuntos
Receptores de Serotonina/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Micção/efeitos dos fármacos , Animais , Western Blotting , Doença Crônica , Modelos Animais de Doenças , Feminino , Injeções Espinhais , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/fisiologia , Traumatismos da Medula Espinal/patologia , Micção/fisiologiaRESUMO
RATIONALE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment, neuronal death, and synaptic loss in the hippocampus. Long-term potentiation (LTP), a type of synaptic plasticity, occurs during learning and memory. Serotonin receptor type 7 (5-HTR7) activation is suggested as a possible therapeutic target for AD. OBJECTIVE: The aim of the present study was to examine the effects of chronic treatment with the 5-HTR7 agonist, AS19, on cognitive function, memory, hippocampal plasticity, amyloid beta (Aß) plaque accumulation, and apoptosis in an adult rat model of AD. METHODS: AD was induced in rats using Aß (single 1 µg/µL intracerebroventricular (icv) injection during surgery). The following experimental groups were included: control, sham-operated, Aß + saline (1 µL icv for 30 days), and Aß + AS19 (1 µg/µL icv for 30 days) groups. The animals were tested for cognition and memory performance using the novel object recognition and passive avoidance tests, respectively. Next, anesthetized rats were placed in a stereotaxic apparatus for electrode implantation, and field potentials were recorded in the hippocampal dentate gyrus. Lastly, brains were removed and Aß plaques and neuronal apoptosis were evaluated using Congo red staining and TUNEL assay, respectively. RESULTS: Administration of AS19 in the Aß rats increased the discrimination index of the novel object recognition test. Furthermore, AS19 treatment decreased time spent in the dark compartment during the passive avoidance test. AS19 also enhanced both the population spike (PS) amplitude and the field excitatory postsynaptic potential (fEPSP) slope evoked potentials of the LTP components. Aß plaques and neuronal apoptosis were decreased in the AS19-treated Aß rats. CONCLUSIONS: These results indicate that chronic treatment with a 5-HTR7 agonist can prevent Aß-related impairments in cognition and memory performance by alleviating Aß plaque accumulation and neuronal apoptosis, hence improving neuronal plasticity. AS19 may be useful as a therapeutic agent for AD.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Apoptose/fisiologia , Aprendizagem da Esquiva/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Fragmentos de Peptídeos/toxicidade , Receptores de Serotonina/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Apoptose/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Neurônios/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos , Resultado do TratamentoRESUMO
Serotonin (5-hydroxytryptamine, 5-HT) plays a key role in modulating diverse physiological processes and behaviors in both protostomes and deuterostomes. These functions are mediated through the binding of serotonin to its receptors, which are recognized as potential insecticide targets. We investigated the sequence, pharmacology and tissue distribution of three 5-HT receptors (Piera5-HT1A, Piera5-HT1B, Piera5-HT7) from the small white butterfly Pieris rapae, an important pest of cultivated cabbages and other mustard family crops. Activation of Piera5-HT1A or Piera5-HT1B by 5-HT inhibited the production of cAMP in a dose-dependent manner. Stimulation of Piera5-HT7 with 5-HT increased cAMP level significantly. Surprisingly, with the exception of 5-methoxytryptamine, agonists including α-methylserotonin, 8-Hydroxy-DPAT and 5-carboxamidotryptamine activated these receptors poorly. The results are consistent with previous findings in Manduca sexta. All three receptors were blocked by methiothepin, but ketanserin and yohimbine were not effective. The selective mammalian 5-HT receptor antagonists SB 216641 and SB 269970 displayed potent inhibition effects on Piera5-HT1B and Piera5-HT7 respectively. The results we achieved here indicate that the pharmacological properties of Lepidoptera 5-HT receptors are quite different from those in other insects and vertebrates and may contribute to development of new selective pesticides. This study offers important information on three 5-HT receptors from P. rapae that will facilitate further analysis of the functions of 5-HT receptors in insects.
Assuntos
Borboletas/metabolismo , Proteínas de Insetos/fisiologia , Receptores de Serotonina/fisiologia , Animais , Borboletas/efeitos dos fármacos , AMP Cíclico/biossíntese , Especificidade de Órgãos , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Beta-amyloid peptide (Aß) induced neurotoxicity is considered as a hallmark of the pathogenesis of Alzheimer's disease (AD). The present study demonstrated the neuroprotective role of 5-HT6 receptors against Aß-induced neurotoxicity in PC-12 cells. The 5-HT6 receptor agonist EMD-386088 and antagonist SB-399885 were used as pharmacological tools. The NMDA receptor antagonist, memantine, was used as reference standard. The Aß25-35 (50 µM) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 µM EMD-386088 and SB-399885 had significantly protected neuronal cell death by maintaining higher cell viability through attenuation of intracellular ROS. Further, both compounds significantly prevented Aß25-35-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented Aß25-35-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from Aß25-35 induced toxicity by reducing ROS and through prevention of impairment in neurite outgrowth. Therefore, 5-HT6 receptor could be an important disease-modifying therapeutic target for AD.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Fragmentos de Peptídeos/toxicidade , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Indóis/farmacologia , Células PC12 , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Sulfonamidas/farmacologiaRESUMO
Sperm hyperactivation is regulated by hormones present in the oviduct. In hamsters, 5-hydroxytryptamine (5HT) enhances hyperactivation associated with the 5HT2 receptor and 5HT4 receptor, while 17ß-estradiol (E2) and γ-aminobutyric acid (GABA) suppress the association of the estrogen receptor and GABAA receptor, respectively. In the present study, we examined the regulatory interactions among 5HT, GABA, and E2 in the regulation of hamster sperm hyperactivation. When sperm were exposed to E2 prior to 5HT exposure, E2 did not affect 5HT-enhanced hyperactivation. In contrast, GABA partially suppressed 5HT-enhanced hyperactivation when sperm were exposed to GABA prior to 5HT. GABA suppressed 5HT-enhanced hyperactivation associated with the 5HT2 receptor although it did not suppress 5HT-enhanced hyperactivation associated with the 5HT4 receptor. These results demonstrate that hamster sperm hyperactivation is regulated by an interaction between the 5HT2 receptor-mediated action of 5HT and GABA.
Assuntos
Serotonina/farmacologia , Espermatozoides/fisiologia , Ácido gama-Aminobutírico/farmacologia , Animais , Estradiol/metabolismo , Estrogênios/metabolismo , Feminino , Masculino , Mesocricetus , Oócitos/metabolismo , Oviductos/metabolismo , Progesterona/metabolismo , Receptores de GABA-A/fisiologia , Receptores de Serotonina/fisiologia , Capacitação Espermática , Motilidade dos Espermatozoides , Espermatozoides/metabolismo , Fatores de TempoRESUMO
Whole genome sequencing of a severely affected dizygotic twin with an autism spectrum disorder and intellectual disability revealed a compound heterozygous mutation in the HTR7 gene as the only variation not detected in control databases. Each parent carries one allele of the mutation, which is not present in an unaffected stepsister. The HTR7 gene encodes the 5-HT7 serotonin receptor that is involved in brain development, synaptic transmission, and plasticity. The paternally inherited p.W60C variant is situated at an evolutionary conserved nucleotide and predicted damaging by Polyphen2. A mutation akin to the maternally inherited pV286I mutation has been reported to significantly affect the binding characteristics of the receptor. Therefore, the observed sequence alterations provide a first suggestive link between a genetic abnormality in the HTR7 gene and a neurodevelopmental disorder. © 2016 Wiley Periodicals, Inc.
Assuntos
Transtorno do Espectro Autista/genética , Receptores de Serotonina/genética , Alelos , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/genética , Criança , Predisposição Genética para Doença/genética , Humanos , Masculino , Mutação , Receptores de Serotonina/fisiologia , Análise de Sequência de DNA , Serotonina/genética , Serotonina/metabolismo , Gêmeos Dizigóticos/genética , Gêmeos Dizigóticos/psicologiaRESUMO
Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.
Assuntos
Neurônios Dopaminérgicos/transplante , Discinesia Induzida por Medicamentos/fisiopatologia , Transplante de Tecido Fetal/efeitos adversos , Transtornos Parkinsonianos/metabolismo , Receptores de Serotonina/fisiologia , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , AMP Cíclico/metabolismo , Diterpenos/farmacologia , Diterpenos Clerodânicos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Etilaminas/farmacologia , Feminino , Técnicas de Introdução de Genes , Humanos , Indóis/farmacologia , Oxidopamina , Transtornos Parkinsonianos/cirurgia , Complicações Pós-Operatórias , Ratos , Receptores de Serotonina/biossíntese , Receptores de Serotonina/efeitos dos fármacosRESUMO
BACKGROUND: Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways. METHODS: Normal primary human esophageal epithelial cells were cultured with use of an air-liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT7) was assessed by Western blotting. The involvement of 5-HT7 was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers. RESULTS: Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT7 antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT7 agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT7 antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK. CONCLUSIONS: Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease.
Assuntos
Mucosa Esofágica/efeitos dos fármacos , Serotonina/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Impedância Elétrica , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Esofágica/citologia , Mucosa Esofágica/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologia , Serotonina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease.
Assuntos
Antipsicóticos/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Receptores de Serotonina/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/uso terapêutico , Animais , Atenção/efeitos dos fármacos , Humanos , Memória Episódica , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Percepção SocialRESUMO
Calcific aortic valve disease (CAVD) is the most common heart valve disorder. There is no medical treatment to prevent and/or promote the regression of CAVD. Hence, it is of foremost importance to delineate and understand the key basic underlying mechanisms involved in CAVD. In the past decade our comprehension of the underpinning processes leading to CAVD has expanded at a fast pace. Hence, our understanding of the basic pathobiological processes implicated in CAVD might lead eventually to the development of novel pharmaceutical therapies for CAVD. In this review, we discuss molecular processes that are implicated in fibrosis and mineralization of the aortic valve. Specifically, we address the role of lipid retention, inflammation, phosphate signalling and osteogenic transition in the development of CAVD. Interplays between these different processes and the key regulation pathways are discussed along with their clinical relevance.
Assuntos
Estenose da Valva Aórtica/fisiopatologia , Valva Aórtica/patologia , Calcinose/fisiopatologia , Envelhecimento/fisiologia , Valva Aórtica/metabolismo , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Proteína Morfogenética Óssea 2/fisiologia , Calcinose/metabolismo , Calcinose/patologia , Endotélio/fisiologia , Humanos , Inflamação/fisiopatologia , Interleucina-6/fisiologia , Metabolismo dos Lipídeos , Lipoproteínas HDL/fisiologia , Lipoproteínas LDL/metabolismo , Nucleosídeos/metabolismo , Nucleotídeos/metabolismo , Fosfatos/fisiologia , Fosfolipases A2/fisiologia , RNA não Traduzido/fisiologia , Receptores de Serotonina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Sirtuínas/fisiologia , Estresse Mecânico , Fator de Crescimento Transformador beta1/fisiologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
BACKGROUND: Intestinal inflammation is often associated with an increased level of serotonin (5-HT), an important gastrointestinal signaling molecule involved in gut homeostasis through stimulation of specific receptors. In this study, we investigated the role of 5-HT7 receptor (5-HT7R) in the induction and development of intestinal inflammation using a mouse model of acute and chronic colitis and human patients with Crohn's disease (CD). METHODS: Acute colitis was induced through administration of dextran sodium sulfate to wild-type, 5-HT7R-deficient mice and hematopoietic bone marrow chimera. Chronic colitis was induced in interleukin 10-deficient mice. The role of 5-HT7R in gut inflammation was assessed using agonist/antagonist treatment. We investigated expression and distribution of 5-HT7R, extent of gut inflammation with magnetic resonance imaging and histological analysis, survival rate, and disease activity index. Finally, biopsies from the large intestine of patients with CD were analyzed. RESULTS: Under basal conditions, 5-HT7R is expressed both in enteric neurons and CD11c cells of the large intestine. Expression of 5-HT7R significantly increased after induction of colitis in mice and in inflamed intestinal regions of patients with CD in CD11c/CD86 double-positive cells. Pharmacological blockade or genetic ablation of 5-HT7R resulted in increased severity of both acute and chronic dextran sodium sulfate-induced colitis, whereas receptor stimulation showed an anti-inflammatory effect. Analysis of bone marrow chimera indicated importance of 5-HT7R expressed by hematopoietic cells in intestinal inflammation. CONCLUSIONS: The 5-HT7R expressed on CD11c/CD86-positive myeloid cells modulates the severity of intestinal inflammation in an acute and chronic colitis and thus represents a potential therapeutic target for the treatment of inflammatory disorders such as CD.
Assuntos
Colite/patologia , Doença de Crohn/patologia , Trato Gastrointestinal/patologia , Inflamação/patologia , Receptores de Serotonina/fisiologia , Doença Aguda , Adolescente , Adulto , Animais , Western Blotting , Doença Crônica , Colite/induzido quimicamente , Colite/metabolismo , Doença de Crohn/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Seguimentos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Humanos , Técnicas Imunoenzimáticas , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-10/fisiologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Serotonina/química , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/metabolismo , Adulto JovemRESUMO
The present study used the whole isolated urinary bladder of Suncus murinus, to investigate the effect of exogenously added serotonin (5-HT) and electrical field stimulation (EFS) in the absence and presence of methysergide, a 5-HT1/2/7 receptor antagonist or the selective 5-HT7 receptor antagonist, SB269970. Further experiments investigated the involvement of potassium channel, cholinergic and purinergic systems in mediating the contractile response to EFS. Pre-treatment with methysergide reduced and increased the contractile responses to 5-HT and EFS, respectively. Pre-treatment with SB269970 increased the responses to 5-HT without modifying the EFS-induced contractions. EFS-induced contractions were not modified by pre-treatment with atropine (10µM), α-ß-methylene ATP or glibenclamide. EFS-induced contractions were attenuated by cromakalim (10µM) or atropine (0.1 µM). In conclusion, the 5-HT2 receptors are likely to play a role in mediating the contractile response to 5-HT in detrusor muscle. Furthermore, EFS-induced contractions are mediated through cholinergic and an unknown neurotransmitter which is modulated by K(ATP) channels in the detrusor muscle of Suncus murinus.
Assuntos
Receptores de Serotonina/fisiologia , Serotonina/farmacologia , Bexiga Urinária/efeitos dos fármacos , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Atropina/farmacologia , Cromakalim/farmacologia , Estimulação Elétrica , Feminino , Glibureto/farmacologia , Masculino , Metisergida , Contração Muscular/efeitos dos fármacos , Fenóis/farmacologia , Antagonistas da Serotonina/farmacologia , Musaranhos , Sulfonamidas/farmacologia , Bexiga Urinária/fisiologiaRESUMO
AIMS: To better understand the effects of the selective 5-HT7 receptor agonist 4-[2-(Methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide hydrochloride (LP44) on micturition in spinal cord injury (SCI) rats. METHODS: Female Sprague-Dawley rats weighing 200-275 g were used. SCI was produced in 8 of the 16 rats by transection at the T10 level; cystometric study occurred 8-12 weeks post-transection. Intravesical pressure was monitored in urethane-anesthetized animals via a transvesical catheter. The selective 5-HT7 antagonist (R)-3-[2-[2-(4-Methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl] phenol hydrochloride (SB-269970) was administered after each LP44 dose-response curve (all drugs were administered intravenously, i.v). RESULTS: Compared to controls, SCI rats had a higher bladder capacity and residual volume, and a lower voiding efficiency. In SCI rats, LP44 (0.003-0.3 mg/kg, i.v) induced significant dose-dependent increases in micturition volume, significant dose-dependent decreases in residual volume, resulting in significant increases in voiding efficiency. CMG measurements showed a dose-dependent increase of the high-frequency oscillation (HFO) activity, including the number of small oscillation per voiding. This was correlated with the improved voiding efficiency. SB-269970 (0.1 mg/kg, i.v) partially or completely reversed all LP44-induced changes. CONCLUSIONS: HFOs seems to be correlated with external urethral sphincter (EUS) bursting activity during voiding. Both the bladder voiding efficiency and the periodic EUS activity were decreased in SCI rats. 5-HT7 receptor agonist can enhance HFO activity, thereby improving voiding efficiency. Whether or not these results may have implications for the future treatment of voiding dysfunction in SCI patients remains to be studied.