ABSTRACT
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.
Subject(s)
Calcium , Receptor, Serotonin, 5-HT1A , Humans , Phosphorylation , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/genetics , HEK293 Cells , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 4/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 4/genetics , Cell Line, Tumor , Repressor Proteins/metabolism , Repressor Proteins/genetics , Gene Expression Regulation , DNA-Binding ProteinsABSTRACT
Alcohol use disorder is considered a chronic and relapsing disorder affecting the central nervous system. The serotonergic system, mainly through its influence on the mesolimbic dopaminergic reward system, has been postulated to play a pivotal role in the underlying mechanism of alcohol dependence. The study aims to analyse the association of the rs6295 polymorphism of the 5HTR1A gene in women with alcohol use disorder and the association of personality traits with the development of alcohol dependence, as well as the interaction of the rs6295, personality traits, and anxiety with alcohol dependence in women. The study group consisted of 213 female volunteers: 101 with alcohol use disorder and 112 controls. NEO Five-Factor and State-Trait Anxiety Inventories were applied for psychometric testing. Genotyping of rs6295 was performed by real-time PCR. We did not observe significant differences in 5HTR1A rs6295 genotypes (p = 0.2709) or allele distribution (p = 0.4513). The AUD subjects scored higher on the anxiety trait (p < 0.0001) and anxiety state (p < 0.0001) scales, as well as on the neuroticism (p < 0.0001) and openness (p = 0134) scales. Significantly lower scores were obtained by the AUD subjects on the extraversion (p < 0.0001), agreeability (p < 0.0001), and conscientiousness (p < 0.0001) scales. Additionally, we observed a significant effect of 5HTR1A rs6295 genotype interaction and alcohol dependency, or lack thereof, on the openness scale (p = 0.0016). In summary, this study offers a comprehensive overview of alcohol dependence among women. It offers valuable insights into this complex topic, contributing to a more nuanced understanding of substance use among this specific demographic. Additionally, these findings may have implications for developing prevention and intervention strategies tailored to individual genetic and, most importantly, personality and anxiety differences.
Subject(s)
Alcoholism , Anxiety , Personality , Polymorphism, Single Nucleotide , Receptor, Serotonin, 5-HT1A , Humans , Female , Receptor, Serotonin, 5-HT1A/genetics , Alcoholism/genetics , Alcoholism/psychology , Personality/genetics , Adult , Anxiety/genetics , Middle Aged , Genotype , Genetic Predisposition to Disease , Alleles , Genetic Association Studies , Case-Control StudiesABSTRACT
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.
Subject(s)
Behavior, Animal , Germ-Free Life , Serotonin , Animals , Serotonin/metabolism , Mice , Male , Gastrointestinal Microbiome/physiology , Brain/metabolism , Tryptophan Hydroxylase/metabolism , Tryptophan Hydroxylase/genetics , Anxiety/metabolism , Anxiety/microbiology , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Mice, Inbred C57BL , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/genetics , Colon/metabolism , Colon/microbiologyABSTRACT
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.
Subject(s)
5-Methoxytryptamine , Anti-Anxiety Agents , Antidepressive Agents , Methoxydimethyltryptamines , Receptor, Serotonin, 5-HT1A , Receptor, Serotonin, 5-HT2A , Animals , Humans , Male , Mice , 5-Methoxytryptamine/analogs & derivatives , 5-Methoxytryptamine/chemistry , 5-Methoxytryptamine/pharmacology , 5-Methoxytryptamine/therapeutic use , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Cryoelectron Microscopy , Hallucinogens , Lysergic Acid Diethylamide/chemistry , Lysergic Acid Diethylamide/pharmacology , Methoxydimethyltryptamines/chemistry , Methoxydimethyltryptamines/pharmacology , Methoxydimethyltryptamines/therapeutic use , Models, Molecular , Receptor, Serotonin, 5-HT1A/chemistry , Receptor, Serotonin, 5-HT1A/genetics , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/ultrastructure , Receptor, Serotonin, 5-HT2A/chemistry , Receptor, Serotonin, 5-HT2A/genetics , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2A/ultrastructure , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Serotonin Receptor Agonists/therapeutic use , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Hippocampus , Neural Stem Cells , Receptors, Serotonin , Stress, Psychological , Animals , Neural Stem Cells/metabolism , Female , Hippocampus/metabolism , Male , Mice , Receptors, Serotonin/metabolism , Receptors, Serotonin/genetics , Stress, Psychological/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1A/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Sex Characteristics , Mice, Inbred C57BL , Serotonin/metabolismABSTRACT
Introduction and objectives: Premature ejaculation (PE) is characterized by shorter intravaginal ejaculation latency time than it is acceptable for the patient or partner. It is thought that lifelong PE is a neurobiological dysfunction associated with genetic predisposition and with central serotonin neurotransmission dysfunction in receptors. To contribute to the understanding the genetic etiology of lifelong PE, it was planned to compare the 5-HT2C receptor gene rs3813929, rs518147, 5-HT1A receptor gene rs6295, 5-HT1B receptor gene rs11568817 of lifelong PE patients to healthy controls. Materials and methods: For this purpose, 100 patients with premature ejaculation and 100 healthy controls were included in the study. Blood samples for DNA extraction were obtained. Appropriate procedures were applied to the probes (rs3813929, rs518147, rs6295, rs11568817) suitable for the DNA studied. Results: A statistically significant relationship was found between the rs11568817 polymorphism (p=0.019) in the 5-HT1B receptor gene and the rs518147 polymorphism (p=0.016) in the 5-HT2C receptor gene. Also, no statistically significant relationship was found between 5-HT1A receptor gene rs6295 polymorphism and 5-HT2C receptor gene rs3813929 polymorphism and lifelong PE. Conclusions: The relationship between rs3813929 and rs11568817 polymorphisms with lifelong PE was confirmed. Repeating the study in larger sample groups could be useful in determining the genetic etiology of PE. (AU)
Introducción y objetivos: La eyaculación precoz (EP) se caracteriza por un tiempo de latencia de eyaculación intravaginal más corto de lo que es aceptable para el paciente o para la pareja. Se cree que la EP de por vida es una disfunción neurobiológica asociada con la predisposición genética y con la disfunción central de la neurotransmisión de serotonina en los receptores. Para contribuir a la comprensión de la etiología genética de la EP de por vida, se planificó comparar el gen del receptor 5-HT2C rs3813929, rs518147, el gen del receptor 5-HT1A rs6295 y el gen del receptor 5-HT1B rs11568817 de pacientes con EP de por vida con controles sanos. Materiales y métodos: Para este propósito, se incluyeron en el estudio 100 pacientes con eyaculación precoz y 100 controles sanos. Se obtuvieron muestras de sangre para extracción de ADN. Se aplicaron procedimientos apropiados a las sondas (rs3813929, rs518147, rs6295, rs11568817) adecuadas para el ADN estudiado. Resultados: Se encontró una relación estadísticamente significativa entre el polimorfismo rs11568817 (p=0,019) en el gen del receptor 5-HT1B y el polimorfismo rs518147 (p=0,016) en el gen del receptor 5-HT2C. Además, no se encontró una relación estadísticamente significativa entre el polimorfismo del gen del receptor 5-HT1A rs6295 y el polimorfismo del gen del receptor 5-HT2C rs3813929 y la EP de por vida. Conclusiones: Se confirmó la relación entre los polimorfismos rs3813929 y rs11568817 con EP de por vida. Repetir el estudio en grupos de muestra más grandes podría ser útil para determinar la etiología genética de la EP. (AU)
Subject(s)
Humans , Male , Young Adult , Adult , Middle Aged , Premature Ejaculation/etiology , Polymorphism, Genetic , Serotonin , Receptor, Serotonin, 5-HT1A/genetics , Receptor, Serotonin, 5-HT1B/genetics , Receptor, Serotonin, 5-HT2C/geneticsABSTRACT
Abstract This study aimed to investigate if SNP rs6313, SNP rs2770304, SNP rs4941573, and SNP rs1923884 of the 5-HT2A receptor gene and SNP rs6295 of the 5-HT1A receptor gene are associated with bruxism etiology. Methodology This systematic review was registered in PROSPERO (CRD42018094561). A search was conducted for articles published in or before May 2021. To qualify for eligibility in this review, the studies had to be case-controls, cohort or cross-sectional. The inclusion criteria were the articles with a group of patients with bruxism and a control group in which the presence of these SNPs was evaluated. The exclusion criteria were the investigations of other polymorphisms, the studies that did not consider a control group for comparison, case reports, and reviews. The NOS and JBI were used to evaluate the methodological quality of studies. Results We conducted this study with databases, such as Web of Science, Scopus, Embase, PubMed/MEDLINE, and ProQuest. We considered four studies eligible. A total of 672 participants were included,187 with sleep bruxism, 105 with awake bruxism, 89 with sleep and awake bruxism, and 291 controls. One study found a strong association between the SNPs rs6313, rs2770304 and rs4941573 of the 5-HT2A receptor gene and sleep bruxism. In one study, we considered the C allele of the SNP rs2770304 a risk factor for sleep bruxism. We found no significant results of other SNPs in sleep bruxers compared to controls. We found no positive association concerning the SNPs and groups of awake bruxism and sleep and awake bruxism. Conclusion The different results regarding the SNPs in sleep bruxers could be explained by the genetic distinction between Chilean, Mexican, Japanese, and Polish population. More clinical trials and prospective studies must be conducted with larger sample size and in different ethnicities to confirm the results of this review.
Subject(s)
Humans , Sleep Bruxism/genetics , Receptor, Serotonin, 5-HT1A/genetics , Polymorphism, Single NucleotideABSTRACT
INTRODUCTION AND OBJECTIVES: Lifelong premature ejaculation (LPE) is identified as the inability to delay ejaculation for more than 1min after vaginal penetration occurring on all or almost all sexual experiences together with feelings of frustration of both the patient and his partner with avoidance of sexual intimacy. Recently, a role for (HTR1A)-C (1019) G gene polymorphism in patients with LPE was postulated. MATERIALS AND METHODS: Three hundred and fifty participants were prospectively enrolled in this study. They were recruited from the outpatient clinic of Andrology & STDs Department Cairo University from December 2015 to January 2017. Two hundred and forty-five of them were suffering from lifelong premature ejaculation joined this study, in addition to 105 controls. We instructed the wives of the patients to measure the intra-vaginal ejaculation latency time (IELT) of the first intercourse only using a stopwatch for 1 month. Genotyping was performed at the end of the study. RESULTS: The results showed that the majority of the patients were CG, while; the controls were GG. This difference revealed a statistically significant association (p-value<0.001). A highly significant statistical association was found between the studied gene polymorphisms and the IELT among cases (p-values=0.001). CONCLUSION: The study replicated the potential role of 5HT-1A receptor gene polymorphisms in patients with lifelong premature ejaculation
INTRODUCCIÓN Y OBJETIVOS: La eyaculación precoz permanente (LPE) se identifica como la incapacidad para retrasar la eyaculación más de 1min después de la penetración vaginal, que en todas o casi todas las experiencias sexuales provoca sentimientos de frustración tanto en el paciente como en su pareja y conduce a la abstención de las relaciones sexuales. Recientemente, se ha propuesto que el polimorfismo del gen (HTR1A)-C (1019) G tiene un papel en pacientes con LPE. MATERIALES Y MÉTODOS: Se incluyó a 350 participantes en este estudio. Se los reclutó en la clínica ambulatoria del Departamento de Andrología y ETS de la Universidad del Cairo entre diciembre de 2015 y enero de 2017. Doscientos cuarenta y cinco de ellos con eyaculación precoz permanente se incorporaron a este estudio, además de 105 controles. Instruimos a las esposas de los pacientes para medir el tiempo de latencia de la eyaculación (TLE) intravaginal de la primera relación sexual utilizando solamente un cronómetro durante 1 mes. La genotipificación se realizó al final del estudio. RESULTADOS: Los resultados mostraron que la mayoría de los pacientes fueron CG, mientras los controles fueron GG. Esta diferencia reveló una asociación estadísticamente significativa (valor de p < 0,001). Se encontró una asociación estadística muy significativa entre los polimorfismos de los genes estudiados y el TLE entre casos (valores de p = 0,001). CONCLUSIÓN: El estudio reprodujo el papel potencial de los polimorfismos del gen del receptor de 5-HT1A en pacientes con eyaculación precoz permanente
Subject(s)
Humans , Male , Young Adult , Adult , Polymorphism, Genetic , Premature Ejaculation/genetics , Receptor, Serotonin, 5-HT1A/genetics , Premature Ejaculation/physiopathology , Prospective StudiesABSTRACT
PURPOSE: Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs. MATERIALS AND METHODS: Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations. RESULTS: Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively. CONCLUSIONS: Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.
Subject(s)
Adolescent , Adult , Aged , Humans , Male , Middle Aged , Young Adult , Body Mass Index , Cytochrome P-450 CYP2D6/genetics , Leptin/blood , Mutation , Paroxetine/administration & dosage , Polymorphism, Genetic , Premature Ejaculation/drug therapy , Receptor, Serotonin, 5-HT1A/genetics , Risk Factors , Selective Serotonin Reuptake Inhibitors/administration & dosage , Time Factors , Treatment OutcomeABSTRACT
PURPOSE: Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs. MATERIALS AND METHODS: Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations. RESULTS: Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively. CONCLUSIONS: Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.