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1.
Bull Exp Biol Med ; 177(1): 10-14, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38954295

RESUMEN

Spatial learning, memory, and reactivity of the hypothalamic-pituitary-adrenocortical system (HPA axis) were studied in adult male rats, whose mothers during pregnancy were subjected to acute moderate normobaric hypoxia, or repeated injections of buspirone, an agonist of type 1A serotonergic receptors (5HT1A), or their combination. Prenatal treatment with buspirone in rats with prenatal hypoxia impaired learning ability during the first day of 5-day training. A decrease in the effectiveness of long-term memory in comparison with short-term memory was revealed in two groups of rats: prenatal treatment with buspirone in combination with hypoxia and injection of physiological saline without hypoxia. The effectiveness of long-term memory and the level of corticosterone in response to stress did not differ between the groups, which can indicate adaptation of the 5HT1A receptor and the HPA axis to the prenatal buspirone and normobaric hypoxia during ontogeny.


Asunto(s)
Buspirona , Sistema Hipotálamo-Hipofisario , Hipoxia , Efectos Tardíos de la Exposición Prenatal , Buspirona/farmacología , Animales , Embarazo , Femenino , Ratas , Masculino , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Hipoxia/fisiopatología , Hipoxia/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Corticosterona/sangre , Corticosterona/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Cognición/efectos de los fármacos , Cognición/fisiología , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Estrés Fisiológico/efectos de los fármacos
2.
Int J Mol Sci ; 25(11)2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38892382

RESUMEN

Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene, Freud-1/CC2D1A, a transcriptional repressor of human serotonin-1A (5-HT1A) and dopamine-D2 receptor genes. The altered expression of these Freud-1-regulated genes is implicated in mental illnesses such as major depression and schizophrenia. We hypothesized that Freud-1 is blocked by CaMK-induced phosphorylation. The incubation of purified Freud-1 with either CaMKIIα or CaMKIV increased Freud-1 phosphorylation that was partly prevented in Freud-1-Ser644Ala and Freud-1-Thr780Ala CaMK site mutants. In human SK-N-SH neuroblastoma cells, active CaMKIV induced the serine and threonine phosphorylation of Freud-1, and specifically increased Freud-1-Thr780 phosphorylation in transfected HEK-293 cells. The activation of purified CaMKIIα or CaMKIV reduced Freud-1 binding to its DNA element on the 5-HT1A and dopamine-D2 receptor genes. In SK-N-SH cells, active CaMKIV but not CaMKIIα blocked the Freud-1 repressor activity, while Freud-1 Ser644Ala, Thr780Ala or dual mutants were resistant to inhibition by activated CaMKIV or calcium mobilization. These results indicate that the Freud-1 repressor activity is blocked by CaMKIV-induced phosphorylation at Thr780, resulting in the up-regulation of the target genes, such as the 5-HT1A receptor gene. The CaMKIV-mediated inhibition of Freud-1 provides a novel de-repression mechanism to induce 5-HT1A receptor expression for the regulation of cognitive development, behavior and antidepressant response.


Asunto(s)
Calcio , Receptor de Serotonina 5-HT1A , Humanos , Fosforilación , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/genética , Células HEK293 , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/genética , Línea Celular Tumoral , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Regulación de la Expresión Génica , Proteínas de Unión al ADN
3.
Eur J Med Chem ; 275: 116564, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-38875810

RESUMEN

Depression is a common psychiatric disorder with an estimated global prevalence of 4.4 %. Here, we designed a series of new multimodal monoaminergic arylpiperazine derivatives using a pharmacophore hybrid approach and synthesized them for the treatment of depression. Molecular docking was employed to elucidate the differences in activity and selectivity of the corresponding compounds on SERT, NET, and DAT. In vitro experiments demonstrated that compound A3 has a relatively balanced multi-target activity profile with SERT reuptake inhibition (IC50 = 12 nM), NET reuptake inhibition (IC50 = 78 nM), DAT reuptake inhibition (IC50 = 135 nM), and 5-HT1AR agonism (EC50 = 34 nM). Pharmacokinetic experiments revealed that A3 exhibited excellent bioavailability and low clearance in mice. Subsequent behavioral experiments further confirmed its significant antidepressant effects. These results further highlight the rationality of our design strategy.


Asunto(s)
Antidepresivos , Simulación del Acoplamiento Molecular , Piperazinas , Antidepresivos/farmacología , Antidepresivos/síntesis química , Antidepresivos/química , Animales , Piperazinas/química , Piperazinas/farmacología , Piperazinas/síntesis química , Ratones , Relación Estructura-Actividad , Humanos , Estructura Molecular , Masculino , Relación Dosis-Respuesta a Droga , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Depresión/tratamiento farmacológico , Receptor de Serotonina 5-HT1A/metabolismo
4.
Cereb Cortex ; 34(6)2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38904079

RESUMEN

Serotonin (5-HT) regulates working memory within the prefrontal cortex network, which is crucial for understanding obsessive-compulsive disorder. However, the mechanisms how network dynamics and serotonin interact in obsessive-compulsive disorder remain elusive. Here, we incorporate 5-HT receptors (5-HT1A, 5-HT2A) and dopamine receptors into a multistable prefrontal cortex network model, replicating the experimentally observed inverted U-curve phenomenon. We show how the two 5-HT receptors antagonize neuronal activity and modulate network multistability. Reduced binding of 5-HT1A receptors increases global firing, while reduced binding of 5-HT2A receptors deepens attractors. The obtained results suggest reward-dependent synaptic plasticity mechanisms may attenuate 5-HT related network impairments. Integrating serotonin-mediated dopamine release into circuit, we observe that decreased serotonin concentration triggers the network into a deep attractor state, expanding the domain of attraction of stable nodes with high firing rate, potentially causing aberrant reverse learning. This suggests a hypothesis wherein elevated dopamine concentrations in obsessive-compulsive disorder might result from primary deficits in serotonin levels. Findings of this work underscore the pivotal role of serotonergic dysregulation in modulating synaptic plasticity through dopamine pathways, potentially contributing to learned obsessions. Interestingly, serotonin reuptake inhibitors and antidopaminergic potentiators can counteract the over-stable state of high-firing stable points, providing new insights into obsessive-compulsive disorder treatment.


Asunto(s)
Trastorno Obsesivo Compulsivo , Corteza Prefrontal , Serotonina , Corteza Prefrontal/metabolismo , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/metabolismo , Serotonina/metabolismo , Humanos , Dopamina/metabolismo , Modelos Neurológicos , Receptores Dopaminérgicos/metabolismo , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatología , Simulación por Computador , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Serotonina/metabolismo , Plasticidad Neuronal/fisiología , Receptor de Serotonina 5-HT1A/metabolismo
5.
Biomed Pharmacother ; 176: 116937, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38870632

RESUMEN

The advent of general anesthesia (GA) has significant implications for clinical practice. However, the exact mechanisms underlying GA-induced transitions in consciousness remain elusive. Given some similarities between GA and sleep, the sleep-arousal neural nuclei and circuits involved in sleep-arousal, including the 5-HTergic system, could be implicated in GA. Herein, we utilized pharmacology, optogenetics, chemogenetics, fiber photometry, and retrograde tracing to demonstrate that both endogenous and exogenous activation of the 5-HTergic neural circuit between the dorsal raphe nucleus (DR) and basolateral amygdala (BLA) promotes arousal and facilitates recovery of consciousness from sevoflurane anesthesia. Notably, the 5-HT1A receptor within this pathway holds a pivotal role. Our findings will be conducive to substantially expanding our comprehension of the neural circuit mechanisms underlying sevoflurane anesthesia and provide a potential target for modulating consciousness, ultimately leading to a reduction in anesthetic dose requirements and side effects.


Asunto(s)
Anestésicos por Inhalación , Complejo Nuclear Basolateral , Estado de Conciencia , Núcleo Dorsal del Rafe , Sevoflurano , Sevoflurano/farmacología , Animales , Núcleo Dorsal del Rafe/efectos de los fármacos , Núcleo Dorsal del Rafe/metabolismo , Estado de Conciencia/efectos de los fármacos , Anestésicos por Inhalación/farmacología , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Serotonina/metabolismo , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Receptor de Serotonina 5-HT1A/metabolismo , Optogenética
6.
Medicine (Baltimore) ; 103(24): e38496, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38875413

RESUMEN

As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target for antidepressants. The research groups focus on these area have tried to design novel compounds to alleviate depression by targeting 5-HT1A receptor. The heterocyclic structures is an important scaffold to enhance the antidepressant activity of ligands, including piperazine, piperidine, benzothiazole, and pyrrolidone. The current review highlights the function and significance of nitrogen-based heterocyclics 5-HT1AR represented by piperazine, piperidine, benzothiazole, and pyrrolidone in the development of antidepressant.


Asunto(s)
Antidepresivos , Receptor de Serotonina 5-HT1A , Agonistas del Receptor de Serotonina 5-HT1 , Humanos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Piperazinas/farmacología , Piperazinas/química , Benzotiazoles/farmacología , Benzotiazoles/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piperidinas/química , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéutico , Pirrolidinonas/química , Depresión/tratamiento farmacológico
7.
FASEB J ; 38(11): e23648, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38822661

RESUMEN

Previous studies on germ-free (GF) animals have described altered anxiety-like and social behaviors together with dysregulations in brain serotonin (5-HT) metabolism. Alterations in circulating 5-HT levels and gut 5-HT metabolism have also been reported in GF mice. In this study, we conducted an integrative analysis of various behaviors as well as markers of 5-HT metabolism in the brain and along the GI tract of GF male mice compared with conventional (CV) ones. We found a strong decrease in locomotor activity, accompanied by some signs of increased anxiety-like behavior in GF mice compared with CV mice. Brain gene expression analysis showed no differences in HTR1A and TPH2 genes. In the gut, we found decreased TPH1 expression in the colon of GF mice, while it was increased in the cecum. HTR1A expression was dramatically decreased in the colon, while HTR4 expression was increased both in the cecum and colon of GF mice compared with CV mice. Finally, SLC6A4 expression was increased in the ileum and colon of GF mice compared with CV mice. Our results add to the evidence that the microbiota is involved in regulation of behavior, although heterogeneity among studies suggests a strong impact of genetic and environmental factors on this microbiota-mediated regulation. While no impact of GF status on brain 5-HT was observed, substantial differences in gut 5-HT metabolism were noted, with tissue-dependent results indicating a varying role of microbiota along the GI tract.


Asunto(s)
Conducta Animal , Vida Libre de Gérmenes , Serotonina , Animales , Serotonina/metabolismo , Ratones , Masculino , Microbioma Gastrointestinal/fisiología , Encéfalo/metabolismo , Triptófano Hidroxilasa/metabolismo , Triptófano Hidroxilasa/genética , Ansiedad/metabolismo , Ansiedad/microbiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Ratones Endogámicos C57BL , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/genética , Colon/metabolismo , Colon/microbiología
8.
Brain Res ; 1838: 148996, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38744387

RESUMEN

INTRODUCTION: The excessive fat accumulation in obesity, resulting from an unbalanced diet, can lead to metabolic and neurological disorders and increase the risk of developing anxiety and depression. AIM: Assess the impact of dietary intervention (DI) on the serotonergic system, brain-derived neurotrophic factor (BDNF) expression and behaviors of obese mice. METHODS: Male C57BL/6 mice, 5 weeks old, received a high-fat diet (HFD) for 10 weeks for the induction of obesity. After this period, for 8 weeks, half of these animals received a control diet (CD), group obese (OB) + control diet (OB + CD, n = 10), and another half continued being fed HFD, group obese + HFD (OB + HFD, n = 10). At the end of the eighth week of intervention, behavioral tests were performed (sucrose preference test, open field, novel object recognition, elevated plus maze and tail suspension). Body weight and food intake were assessed weekly. Visceral adiposity, the hippocampal and hypothalamic protein expression of BDNF, 5-HT1A (5-HT1A serotonin receptor) and TPH2 (key enzyme in serotonin synthesis), were evaluated after euthanasia. RESULTS: The dietary intervention involved changing from a HFD to a CD over an 8-week period, effectively reduced body weight gain, adiposity, and anhedonia-like behavior. In the OB + HFD group, we saw a lower sucrose preference and shorter traveled distance in the open field, along with increased pro-BDNF expression in the hypothalamus compared to the OB + CD mice. However, the levels of TPH2 and 5-HT1A remained unchanged. CONCLUSION: The HFD model induced both obesity and anhedonia, but the dietary intervention successfully improved these conditions.


Asunto(s)
Adiposidad , Anhedonia , Peso Corporal , Factor Neurotrófico Derivado del Encéfalo , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Obesidad , Serotonina , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Anhedonia/fisiología , Serotonina/metabolismo , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Adiposidad/fisiología , Ratones , Peso Corporal/fisiología , Ratones Obesos , Hipocampo/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Triptófano Hidroxilasa/metabolismo , Conducta Animal/fisiología , Hipotálamo/metabolismo , Patrones Dietéticos
9.
Nature ; 630(8015): 237-246, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38720072

RESUMEN

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1-3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens5, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads6. Although 5-HT1A is a validated therapeutic target7,8, little is known about how psychedelics engage 5-HT1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT1A agonists. We show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.


Asunto(s)
5-Metoxitriptamina , Ansiolíticos , Antidepresivos , Metoxidimetiltriptaminas , Receptor de Serotonina 5-HT1A , Receptor de Serotonina 5-HT2A , Animales , Humanos , Masculino , Ratones , 5-Metoxitriptamina/análogos & derivados , 5-Metoxitriptamina/química , 5-Metoxitriptamina/farmacología , 5-Metoxitriptamina/uso terapéutico , Ansiolíticos/química , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Antidepresivos/química , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Microscopía por Crioelectrón , Alucinógenos , Dietilamida del Ácido Lisérgico/química , Dietilamida del Ácido Lisérgico/farmacología , Metoxidimetiltriptaminas/química , Metoxidimetiltriptaminas/farmacología , Metoxidimetiltriptaminas/uso terapéutico , Modelos Moleculares , Receptor de Serotonina 5-HT1A/química , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/ultraestructura , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/ultraestructura , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Agonistas de Receptores de Serotonina/uso terapéutico , Relación Estructura-Actividad
10.
J Affect Disord ; 359: 109-116, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38768823

RESUMEN

BACKGROUND: Inter-hemispheric cooperation is a prominent feature of the human brain, and previous neuroimaging studies have revealed aberrant inter-hemispheric cooperation patterns in patients with major depressive disorder (MDD). Typically, inter-hemispheric cooperation is examined by calculating the functional connectivity (FC) between each voxel in one hemisphere and its anatomical (structurally homotopic) counterpart in the opposite hemisphere. However, bilateral hemispheres are actually asymmetric in anatomy. METHODS: In the present study, we utilized connectivity between functionally homotopic voxels (CFH) to investigate abnormal inter-hemispheric cooperation in 96 MDD patients compared to 173 age- and sex-matched healthy controls (HCs). In addition, we analyzed the spatial correlations between abnormal CFH and the density maps of 13 neurotransmitter receptors and transporters. RESULTS: The CFH values in bilateral orbital frontal gyri and bilateral postcentral gyri were abnormally decreased in patients with MDD. Furthermore, these CFH abnormalities were correlated with clinical symptoms. In addition, the abnormal CFH pattern in MDD patients was spatially correlated with the distribution pattern of 5-HT1AR. LIMITATIONS: drug effect; the cross-sectional research design precludes causal inferences; the neurotransmitter atlases selected were constructed from healthy individuals rather than MDD patients. CONCLUSION: These findings characterized the abnormal inter-hemispheric cooperation in MDD using a novel method and the underlying neurotransmitter mechanism, which promotes our understanding of the pathophysiology of depression.


Asunto(s)
Trastorno Depresivo Mayor , Imagen por Resonancia Magnética , Humanos , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/metabolismo , Femenino , Masculino , Adulto , Persona de Mediana Edad , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Neurotransmisores/metabolismo , Estudios Transversales , Estudios de Casos y Controles , Lateralidad Funcional/fisiología , Receptores de Neurotransmisores/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo
11.
Behav Brain Res ; 469: 115051, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38777263

RESUMEN

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Conducta Exploratoria , Reconocimiento en Psicología , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Emociones/efectos de los fármacos , Emociones/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Ratas Wistar
12.
BMC Complement Med Ther ; 24(1): 198, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773460

RESUMEN

BACKGROUND: Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. METHODS: A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. RESULTS: Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5 µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. CONCLUSION: This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the serotonin receptors, to produce analgesia.


Asunto(s)
Analgésicos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Dolor Postoperatorio , Animales , Ratones , Medicamentos Herbarios Chinos/farmacología , Masculino , Dolor Postoperatorio/tratamiento farmacológico , Analgésicos/farmacología , Serotonina/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Administración Oral , Ratones Endogámicos ICR
13.
Neuropsychopharmacology ; 49(8): 1227-1235, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38671147

RESUMEN

Stress affects brain serotonin (5HT) and dopamine (DA) function, and the effectiveness of 5HT and DA to regulate stress and emotional responses. However, our understanding of the long-term impact of early life adversity (ELA) on primate brain monoaminergic systems during adolescence is scarce and inconsistent. Filling this gap in the literature is critical, given that the emergence of psychopathology during adolescence has been related to deficits in these systems. Here, we use a translational nonhuman primate (NHP) model of ELA (infant maltreatment by the mother) to examine the long-term impact of ELA on adolescent 5HT1A, 5HT2A and D2 receptor systems. These receptor systems were chosen based on their involvement in stress/emotional control, as well as reward and reinforcement. Rates of maternal abuse, rejection, and infant's vocalizations were obtained during the first three postnatal months, and hair cortisol concentrations obtained at 6 months postnatal were examined as early predictors of binding potential (BP) values obtained during adolescence using positron emission tomography (PET) imaging. Maltreated animals demonstrated significantly lower 5HT1A receptor BP in prefrontal cortical areas as well as the amygdala and hippocampus, and lower 5HT2A receptor BP in striatal and prefrontal cortical areas. Maltreated animals also demonstrated significantly lower D2 BP in the amygdala. None of the behavioral and neuroendocrine measurements obtained early in life predicted any changes in BP data. Our findings suggest that early caregiving experiences regulate the development of brain 5HT and DA systems in primates, resulting in long-term effects evident during adolescence.


Asunto(s)
Encéfalo , Tomografía de Emisión de Positrones , Receptor de Serotonina 5-HT1A , Receptor de Serotonina 5-HT2A , Receptores de Dopamina D2 , Estrés Psicológico , Animales , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , Masculino , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D2/metabolismo , Femenino , Receptor de Serotonina 5-HT1A/metabolismo , Estrés Psicológico/metabolismo , Macaca mulatta , Modelos Animales de Enfermedad , Hidrocortisona/metabolismo , Privación Materna
14.
Cell Rep ; 43(5): 114140, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38656873

RESUMEN

Women are more vulnerable to stress and have a higher likelihood of developing mood disorders. The serotonin (5HT) system has been highly implicated in stress response and mood regulation. However, sex-dependent mechanisms underlying serotonergic regulation of stress vulnerability remain poorly understood. Here, we report that adult hippocampal neural stem cells (NSCs) of the Ascl1 lineage (Ascl1-NSCs) in female mice express functional 5HT1A receptors (5HT1ARs), and selective deletion of 5HT1ARs in Ascl1-NSCs decreases the Ascl1-NSC pool only in females. Mechanistically, 5HT1AR deletion in Ascl1-NSCs of females leads to 5HT-induced depolarization mediated by upregulation of 5HT7Rs. Furthermore, repeated restraint stress (RRS) impairs Ascl1-NSC maintenance through a 5HT1AR-mediated mechanism. By contrast, Ascl1-NSCs in males express 5HT7R receptors (5HT7Rs) that are downregulated by RRS, thus maintaining the Ascl1-NSC pool. These findings suggest that sex-specific expression of distinct 5HTRs and their differential interactions with stress may underlie sex differences in stress vulnerability.


Asunto(s)
Hipocampo , Células-Madre Neurales , Receptores de Serotonina , Estrés Psicológico , Animales , Células-Madre Neurales/metabolismo , Femenino , Hipocampo/metabolismo , Masculino , Ratones , Receptores de Serotonina/metabolismo , Receptores de Serotonina/genética , Estrés Psicológico/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Caracteres Sexuales , Ratones Endogámicos C57BL , Serotonina/metabolismo
15.
Elife ; 132024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38573820

RESUMEN

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.


Asunto(s)
Trombocitopenia , Clorhidrato de Vilazodona , Ratones , Animales , Clorhidrato de Vilazodona/efectos adversos , Clorhidrato de Vilazodona/metabolismo , Pez Cebra , Receptor de Serotonina 5-HT1A/metabolismo , Plaquetas/metabolismo , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/metabolismo , Megacariocitos/metabolismo , Trombopoyesis
16.
Environ Sci Technol ; 58(17): 7577-7587, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38630542

RESUMEN

The serotonin signaling system plays a crucial role in regulating the ontogeny of crustaceans. Here, we describe the effects of different concentrations of the 5-hydroxytryptamine 1A receptor antagonist (WAY-100635) on the induced antipredation (Rhodeus ocellatus as the predator), morphological, behavioral, and life-history defenses of Daphnia magna and use transcriptomics to analyze the underlying molecular mechanisms. Our results indicate that exposure to WAY-100635 leads to changes in the expression of different defensive traits in D. magna when faced with fish predation risks. Specifically, as the length of exposure to WAY-100635 increases, high concentrations of WAY-100635 inhibit defensive responses associated with morphological and reproductive activities but promote the immediate negative phototactic behavioral defense of D. magna. This change is related to the underlying mechanism through which WAY-100635 interferes with gene expression of G-protein-coupled GABA receptors by affecting GABBR1 but promotes serotonin receptor signaling and ecdysteroid signaling pathways. In addition, we also find for the first time that fish kairomone can significantly activate the HIF-1α signaling pathway, which may lead to an increase in the rate of immediate movement. These results can help assess the potential impacts of serotonin-disrupting psychotropic drugs on zooplankton in aquatic ecosystems.


Asunto(s)
Daphnia , Transcriptoma , Animales , Daphnia/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Conducta Predatoria/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Daphnia magna
17.
Sci Rep ; 14(1): 9878, 2024 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-38684848

RESUMEN

Chronic stress is associated with major depressive disorder (MDD). Increased glucocorticoid levels caused by uncontrolled release through the hypothalamic‒pituitary‒adrenal (HPA) axis can cause changes in the lipid content of the cellular plasma membrane. These changes are suspected to be involved in the development of depressive disorders. St. John's wort extract (SJW) Ze 117 has long been used as an alternative to synthetic antidepressants. Part of its effect may be due to an effect on the cellular lipid composition and thus on the properties of plasma membranes and receptor systems embedded therein. In this study, we investigated the effect of Ze 117 on that of dexamethasone and simvastatin. Dexamethasone increases the fluidity of C6 cell plasma membranes. This effect is counteracted by administration of Ze 117. Here we demonstrate that this is not due to a change in C16:1/16:0 and C18:1/18:0 ratios in C6 cell fatty acids. On the other hand, Ze 117 increased the cellular cholesterol content by 42.5%, whereas dexamethasone reduced cholesterol levels similarly to simvastatin. Lowering cholesterol levels by dexamethasone or simvastatin resulted in decreased ß-arrestin 2 recruitment to the 5-HT1a receptor. This effect was counterbalanced by Ze 117, whereas the SJW extract had little effect on ß-arrestin 2 recruitment in non-stressed cells. Taken together, in C6 cells, Ze 117 induces changes in membrane fluidity through its effect on cellular cholesterol metabolism rather than by affecting fatty acid saturation. This effect is reflected in an altered signal transduction of the 5-HT1a receptor under Ze 117 administration. The current in vitro results support the hypothesis that Ze 117 addresses relevant parts of the cellular lipid metabolism, possibly explaining some of the antidepressant actions of Ze 117.


Asunto(s)
Colesterol , Dexametasona , Hypericum , Fluidez de la Membrana , Extractos Vegetales , Simvastatina , Hypericum/química , Extractos Vegetales/farmacología , Colesterol/metabolismo , Fluidez de la Membrana/efectos de los fármacos , Dexametasona/farmacología , Línea Celular Tumoral , Simvastatina/farmacología , Glioma/metabolismo , Glioma/tratamiento farmacológico , Glioma/patología , Animales , Ratas , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Ácidos Grasos/metabolismo
18.
Int J Mol Sci ; 25(8)2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38673988

RESUMEN

In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.


Asunto(s)
Hipercapnia , Enfermedad de Parkinson , Receptor de Serotonina 5-HT1A , Receptor de Serotonina 5-HT2A , Animales , Masculino , Ratas , Modelos Animales de Enfermedad , Dopamina/metabolismo , Hipercapnia/metabolismo , Hipercapnia/fisiopatología , Norepinefrina/metabolismo , Norepinefrina/farmacología , Oxidopamina/farmacología , Enfermedad de Parkinson/metabolismo , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Respiración/efectos de los fármacos , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología
19.
Cell ; 187(9): 2194-2208.e22, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38552625

RESUMEN

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.


Asunto(s)
Quimioinformática , Diseño de Fármacos , Polifarmacología , Animales , Ratones , Humanos , Quimioinformática/métodos , Ligandos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/química , Masculino , Sitios de Unión
20.
Behav Brain Res ; 466: 114975, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38552745

RESUMEN

Painful invasive procedures are often performed on newborns admitted to intensive care units (ICU). The acute and long-term effects caused by these stimuli can be investigated in animal models, such as newborn rats. Previous studies have shown that animals subjected to nociceptive stimuli in the neonatal period show sex-specific behavioral changes such as signs of anxiety or depression. Under the same conditions, neonatal stimuli also provoke an increase in the rate of neurogenesis and cell activation in the hippocampal dentate gyrus. So, this study aims to identify the possible roles of central monoamines, receptor expression (5-HT1A), and signaling factors (p-CREB) underlying the long-term effects of neonatal nociceptive stimulation. For this, noxious stimulation was induced by intra-plantar injection of Complete Freund´s adjuvant (CFA) on the postnatal day 1 (P1) or 8 (P8). Control animals were not stimulated. On P75 the behavioral tests were conducted (hotplate and elevated plus maze), followed by sacrifice and molecular studies. Our results showed that neonatal nociceptive stimulation alters pain sensitization specially in females, while stimulation on P1 increases pain threshold, P8-stimulated animals respond with reduced pain threshold (P < 0.001). Hippocampal expression of 5-HT1A receptor and p-CREB were reduced in P8 F group (P < 0.001) in opposition to the increased utilization rate of dopamine and serotonin in this group (P < 0.05). This study shows sex- and age-specific responses of signaling pathways within the hippocampus accompanied by altered behavioral repertoire, at long-term after neonatal painful stimulation.


Asunto(s)
Animales Recién Nacidos , Hipocampo , Umbral del Dolor , Receptor de Serotonina 5-HT1A , Animales , Femenino , Masculino , Ratas , Conducta Animal/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Adyuvante de Freund , Hipocampo/metabolismo , Nocicepción/fisiología , Dolor/metabolismo , Dolor/fisiopatología , Umbral del Dolor/fisiología , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo
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