Prepulse inhibition of the acoustic startle reflex impairment by 5-HT2A receptor activation in the inferior colliculus is prevented by GABAA receptor blockade in the pedunculopontine tegmental nucleus.

The relationship between serotonin dysfunction and schizophrenia commenced with the discovery of the effects of lysergic acid diethylamide (LSD) that has high affinity for 5-HT2A receptors. Activation of these receptors produces perceptual and behavioural changes such as illusions, visual hallucinations and locomotor hyperactivity. Using prepulse inhibition (PPI) of the acoustic startle, which is impaired in schizophrenia,we aimed to investigate:i) the existence of a direct and potentially inhibitory neural pathway between the inferior colliculus (IC) and the pedunculopontine tegmental nucleus (PPTg) involved in the mediation of PPI responses by a neural tract tracing procedure;ii) if the microinjection of the 5-HT2A receptors agonist DOI in IC would activate neurons in this structure and in the PPTg by a c-Fos protein immunohistochemistry study;iii) whether the deficits in PPI responses, observed after the administration of DOI in the IC, could be prevented by the concomitant microinjection of the GABAA receptor antagonist bicuculline in the PPTg.Male Wistar rats were used in this study. An IC-PPTg reciprocated neuronal pathway was identified by neurotracing. The number of c-Fos labelled cells was lower in the DOI group in IC and PPTg, suggesting that this decrease could be due to the high levels of GABA in both structures. The concomitant microinjections of bicuculline in PPTg and DOI in IC prevented the PPI deficit observed after the IC microinjection of DOI. Our findings suggest that IC 5-HT2A receptors may be at least partially involved in the regulation of inhibitory pathways mediating PPI response in IC and PPTg structures.

Role of 5-HT2A receptors in the effects of ayahuasca on ethanol self-administration using a two-bottle choice paradigm in male mice.

RATIONALE: Ayahuasca has been proposed as a potential treatment of alcohol (ethanol) use disorder (AUD). The serotonin 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) is the main psychoactive component of ayahuasca, suggesting that its therapeutic effects may be mediated by 5-HT2A receptors. OBJECTIVES: The aim of the present study was to investigate the effects of ayahuasca on the expression of ethanol self-administration using a two-bottle choice procedure and the role of 5-HT2A receptors in those effects. METHODS: Male mice had intermittent access to ethanol (10% v/v) in a two-bottle choice procedure for 30 days. Animals were then submitted to 3 treatment phases, each followed by ethanol re-exposure tests. During the treatment phase, every 3 days, animals received i.p. injections of either vehicle or the 5-HT2A receptor antagonist M100907 (M100, 1 mg/kg) followed by an i.g. (gavage) administration of vehicle or ayahuasca (100 mg/kg) and were exposed to the self-administration apparatus with no ethanol availability. During re-exposure tests, animals were submitted to the same conditions as during acquisition, with no treatments prior to those sessions. RESULTS: Treatment with ayahuasca blocked the expression of ethanol self-administration, decreasing ethanol intake and preference during re-exposure tests. Pretreatment with M100 blocked the effects of ayahuasca on ethanol drinking without significantly attenuating ethanol self-administration. CONCLUSIONS: Treatment with ayahuasca during alcohol abstinence blocked the expression of alcohol self-administration in mice, and 5-HT2A receptor activation is critical for those effects to emerge. Our findings support a potential for ayahuasca and other 5-HT2A receptor agonists as adjunctive pharmacotherapies for the treatment of AUD.

A partial least squares and artificial neural network study for a series of arylpiperazines as antidepressant agents.

Depression affects more than 300 million people around the world and can lead to suicide. About 30% of patients on treatment for depression drop out of therapy due to side effects or to latency time associated to therapeutic effects. 5-HT receptor, known as serotonin, is considered the key in depression treatment. Arylpiperazine compounds are responsible for several pharmacological effects and are considered as ligands in serotonin receptors, such as the subtype 5-HT2a. Here, in silico studies were developed using partial least squares (PLSs) and artificial neural networks (ANNs) to design new arylpiperazine compounds that could interact with the 5-HT2a receptor. First, molecular and electronic descriptors were calculated and posteriorly selected from correlation matrixes and genetic algorithm (GA). Then, the selected descriptors were used to construct PLS and ANN models that showed to be robust and predictive. Lastly, new arylpiperazine compounds were designed and their biological activity values were predicted by both PLS and ANN models. It is worth to highlight compounds G5 and G7 (predicted by the PLS model) and G3 and G15 (predicted by the ANN model), whose predicted pIC50 values were as high as the three highest values from the arylpiperazine original set studied here. Therefore, it can be asserted that the two models (PLS and ANN) proposed in this work are promising for the prediction of the biological activity of new arylpiperazine compounds and may significantly contribute to the design of new drugs for the treatment of depression.

Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action.

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

Effects of combined 5-HT2A and cannabinoid receptor modulation on a schizophrenia-related prepulse inhibition deficit in mice.

RATIONALE: Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. OBJECTIVES: To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. RESULTS: WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. CONCLUSIONS: WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.

Characterization of the serotonin 2A receptor selective PET tracer (R)-[18F]MH.MZ in the human brain.

PURPOSE: The serotonin receptor subtype 2A antagonist (5-HT2AR) (R)-[18F]MH.MZ has in preclinical studies been identified as a promising PET imaging agent for quantification of cerebral 5-HT2ARs. It displays a very similar selectivity profile as [11C]MDL 100907, one of the most selective compounds identified thus far for the 5-HT2AR. As [11C]MDL 100907, (R)-[18F]MH.MZ also displays slow brain kinetics in various animal models; however, the half-life of fluorine-18 allows for long scan times and consequently, a more precise determination of 5-HT2AR binding could still be feasible. In this study, we aimed to evaluate the potential of (R)-[18F]MH.MZ PET to image and quantify the 5-HT2AR in the human brain in vivo. METHODS: Nine healthy volunteers underwent (R)-[18F]MH.MZ PET at baseline and four out of these also received a second PET scan, after ketanserin pretreatment. Regional time-activity curves of 17 brain regions were analyzed before and after pretreatment. We also investigated radiometabolism, time-dependent stability of outcomes measures, specificity of (R)-[18F]MH.MZ 5-HT2AR binding, and performance of different kinetic modeling approaches. RESULTS: Highest uptake was determined in 5-HT2AR rich regions with a BPND of approximately 1.5 in cortex regions. No radiometabolism was observed. 1TCM and 2TCM resulted in similar outcome measure, whereas reference tissue models resulted in a small, but predictable bias. (R)-[18F]MH.MZ binding conformed to the known distribution of 5-HT2AR and could be blocked by pretreatment with ketanserin. Moreover, outcomes measures were stable after 100-110 min. CONCLUSION: (R)-[18F]MH.MZ is a suitable PET tracer to image and quantify the 5-HT2AR system in humans. In comparison with [11C]MDL 100907, faster and more precise outcome measure could be obtained using (R)-[18F]MH.MZ. We believe that (R)-[18F]MH.MZ has the potential to become the antagonist radiotracer of choice to investigate the human 5-HT2AR system.

5-Hydroxytryptamine 2A receptors of the dorsal raphe nucleus modulate panic-like behaviours and mediate fear-induced antinociception elicited by neuronal activation in the central nucleus of the inferior colliculus.

It has been established that chemical stimulation of the inferior colliculus (IC) of laboratory animals evokes fear-related defensive responses, which are considered panic attack-like behaviours. In addition, there is evidence that defensive reactions provoked by chemical stimulation of midbrain tectum neurons may induce an antinociceptive response. Morphologically, the IC receives projections from other mesencephalic structures, such as the dorsal raphe nucleus (DRN), a region rich in serotonergic neurons that play a critical role in the control of defensive behaviours. Moreover, this monoaminergic brainstem reticular nucleus is suggested to comprise the endogenous pain modulatory system. The aim of the present study was to investigate the role of DRN 5-hydroxytryptamine 2A (5-HT2A) receptors in Wistar rats by local microinjection of R-96544 (a selective antagonist of the 5-HT2A receptor) at doses of 5, 10 or 15 nM on defensive reactions and fear-induced antinociception evoked by chemical stimulation of the central nucleus of the IC with NMDA (6, 9 or 12 nmol). Behavioural responses were analysed for 10 min, and then the nociceptive threshold was measured at 10 min intervals for 70 min. The dose of 12 nmol of NMDA was the most effective in causing panic attack-like defensive behaviours and much higher hypoalgesia. In addition, both effects were attenuated by pretreatment of the DRN with R-96544. These findings suggest the critical participation of DRN 5-HT2A receptors in the modulation of panic attack-like defensive behaviour and unconditioned fear-induced antinociception organised by neurons in the central nucleus of the IC.

Behavioral Effects of Systemic, Infralimbic and Prelimbic Injections of a Serotonin 5-HT2A Antagonist in Carioca High- and Low-Conditioned Freezing Rats.

The role of serotonin (5-hydroxytryptamine [5-HT]) and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]). The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM). In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL) and prelimbic (PL) cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices. Highlights -CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more "anxious" phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF) or increased (CLF) anxiety-like behavior.-PL injections either decreased (CHF) anxiety-like behavior or had no effect (CLF).

25I-NBOH: a new potent serotonin 5-HT2A receptor agonist identified in blotter paper seizures in Brazil.

A new potent serotonin 5-HT2A receptor agonist was identified in blotter papers by several state level forensic laboratories in Brazil. The 25I-NBOH is a labile molecule, which fragments into 2C-I when analyzed by routine seized material screening gas chromatography (GC) methods. GC-mass spectrometry (MS), liquid chromatography-quadrupole time-of-flight-MS, and Fourier transform infrared and nuclear magnetic resonance analyses were performed to complete molecular characterization. Individual doses range from 300 to 1000 µg. Despite its being a potent 5-HT2A receptor agonist, 25I-NBOH is neither registered in the United Nations Office on Drugs and Crime (UNODC) nor classified as a scheduled substance in most countries. Sweden and Brazil seem to be the only countries to control 25I-NBOH. To our knowledge, this is the first scientific report dealing with identification of 25I-NBOH in actual seizures.

Culture as a mediator of gene-environment interaction: Cultural consonance, childhood adversity, a 2A serotonin receptor polymorphism, and depression in urban Brazil.

Research on gene-environment interaction was facilitated by breakthroughs in molecular biology in the late 20th century, especially in the study of mental health. There is a reliable interaction between candidate genes for depression and childhood adversity in relation to mental health outcomes. The aim of this paper is to explore the role of culture in this process in an urban community in Brazil. The specific cultural factor examined is cultural consonance, or the degree to which individuals are able to successfully incorporate salient cultural models into their own beliefs and behaviors. It was hypothesized that cultural consonance in family life would mediate the interaction of genotype and childhood adversity. In a study of 402 adult Brazilians from diverse socioeconomic backgrounds, conducted from 2011 to 2014, the interaction of reported childhood adversity and a polymorphism in the 2A serotonin receptor was associated with higher depressive symptoms. Further analysis showed that the gene-environment interaction was mediated by cultural consonance in family life, and that these effects were more pronounced in lower social class neighborhoods. The findings reinforce the role of the serotonergic system in the regulation of stress response and learning and memory, and how these processes in turn interact with environmental events and circumstances. Furthermore, these results suggest that gene-environment interaction models should incorporate a wider range of environmental experience and more complex pathways to better understand how genes and the environment combine to influence mental health outcomes.

Serotonin 2a Receptor and Serotonin 1a Receptor Interact Within the Medial Prefrontal Cortex During Recognition Memory in Mice.

Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR) one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a (-/-)) with wild type (htr2a (+/+)) littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex.

Neurociencias y aplicaciones psicoterapéuticas en el renacimiento de la investigación con psicodélicos / Neurosciences and psycotherapeutic applications in the psychedelic research renaissaince

The main scope of this review is to expose the main advances regarding recent research of psychedelic substances in the neurociences and their potential psychotherapeutic applications. Psilocybin, a 5-HT2A receptor agonist has been associated with reduced activity in the Default-Mode Network (commonly activated during introspection and self-reflection), enhanced access to biographical memories, positive emotional attentional bias and a reduction on anxiety and mood symptoms. The administration of 3,4-methylenedioxy-N-methylamphetamine (MDMA) could significantly aid the psychotherapeutic process in patients with Post-Traumatic Stress Disorder by strengthening the therapeutic alliance through the release of oxytocin, as well as facilitating emotional regulation from frontal areas to the amygdala during the recollection of traumatic memories. Furthermore, the administration of ayahuasca (an amazonic beverage containing dimethyltryptamine, which binds with the 5-HT2A receptor) and ketamine (a NMDA receptor agonist) in pilot studies has resulted in reduced problematic use of cocaine, heroine, alcohol and tobacco, as well as reported reduction in craving in addiction. While modern research with substances containing psychedelic properties is still young, initial findings suggest the need of expanding the number of studies in order to further clarify their potential risks, benefits and action mechanisms associated to their administration.

El objetivo de esta revisión consiste en exponer los principales avances en la investigación reciente con sustancias psicodélicas en las neurociencias y sus aplicaciones psioterapéuticas. La acción de la psilocibina, un agonista del receptor 5-HT2A, ha sido asociada a una desactivación en la Default Mode Network (activada durante la introspección y pensamientos auto-referentes), un mayor acceso a la memoria autobiográfica, un sesgo atencional emocionalmente positivo y a reducciones en la sintomatología de trastornos de ansiedad y de ánimo. Se ha planteado que la 3,4-metilendioximetanfetamina (MDMA) podría asistir de forma significativa el proceso terapéutico en casos con Trastorno por Estrés Postraumático al fortalecer la alianza terapéutica y permitir una reelaboración de recuerdos traumáticos con menores conductas de evitación. Sus mecanismos terapéuticos se han asociado a la liberación de oxitocina y a una mayor regulación desde áreas frontales hacia la amígdala. Adicionalmente, la administración de ayahuasca (brebaje de origen amazónico que contiene dimetiltriptamina, la cual actúa sobre el receptor 5-HT2A) y ketamina (agonista de receptores NMDA) en estudios iniciales ha resultado en reducción de uso problemático de cocaína, heroína, alcohol, tabaco como también en el "craving" asociado a su consumo. Si bien la investigación moderna de substancias con propiedades psicodélicas es reciente, resultados iniciales fomentan un mayor número de investigaciones para dilucidar los potenciales riesgos, beneficios y mecanismos de acción asociados a su administración.

The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5-HT2A and 5-HT2C serotonergic receptors in post-ictal antinociception.

The periaqueductal gray matter (PAG) consists in a brainstem structure rich in 5-hydroxytryptamine (5-HT) inputs related to the modulation of pain. The involvement of each of the serotonergic receptor subtypes found in PAG columns, such as the dorsomedial (dmPAG) and the ventrolateral (vlPAG) columns, regarding post-ictal antinociception have not been elucidated. The present work investigated the participation of the dmPAG and vlPAG columns in seizure-induced antinociception. Specifically, we studied the involvement of serotonergic neurotransmission in these columns on antinociceptive responses that follow tonic-clonic epileptic reactions induced by pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl(-) influx antagonist. Microinjections of cobalt chloride (1.0 mM CoCl2 /0.2 µL) into the dmPAG and vlPAG caused an intermittent local synaptic inhibition and decreased post-ictal antinociception that had been recorded at various time points after seizures. Pretreatments of the dmPAG or the vlPAG columns with the nonselective serotonergic receptors antagonist methysergide (5.0 µg/0.2 µL) or intramesencephalic microinjections of ketanserin (5.0 µg/0.2 µL), a serotonergic antagonist with more affinity to 5-HT2A/2C receptors, decreased tonic-clonic seizure-induced antinociception. Both dmPAG and vlPAG treatment with either the 5-HT2A receptor selective antagonist R-96544 (10 nM/0.2 µL), or the 5-HT2C receptors selective antagonist RS-102221 (0.15 µg/0.2 µL) also decrease post-ictal antinociception. These findings suggest that serotonergic neurotransmission, which recruits both 5-HT2A and 5-HT2C serotonergic receptors in dmPAG and vlPAG columns, plays a critical role in the elaboration of post-ictal antinociception.

Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as homologues of the antipsychotic lead compound LASSBio-579.

In an attempt to increase the affinity of our antipsychotic lead compound LASSBio-579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; (2)) for the 5-HT(2A) receptor, we synthesized five new N-phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of (2) proved to be appropriated since the affinity of these compounds increased 3-10-fold for the 5-HT(2A) receptor, with no relevant change in the affinity for the D2-like and 5-HT(1A) receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1H-pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) (6) has the expected efficacy at the 5-HT(2A) receptors, acting as an antagonist. Intraperitoneal administration of (6) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that (6) could be considered as a new antipsychotic lead compound.

Polymorphisms in the 5-HTR2A gene related to obstructive sleep apnea syndrome / Polimorfismos no gene HTR2A relacionados à síndrome da apneia obstrutiva do sono

Obstructive sleep apnea syndrome (OSAS) is one of the most complex disorders of sleep; it involves several genetic factors that contribute to the phenotype. Serotonin (5-HT) regulates a variety of visceral and physiological functions, including sleep. Gene 5-HTR2A polymorphisms may change the transcription of several receptors in the serotoninergic system, thereby contributing to OSAS. AIM: To investigate the prevalence of T102C and -1438G/A polymorphisms in the 5-HTR2A gene of patients with and without OSAS . MATERIAL AND METHOD: A molecular study of 100 index-cases and 100 controls of both genders. DNA was extracted from blood leukocytes samples and the regions that enclose both polymorphisms were amplified with PCR-RFLP. STUDY DESIGN: A cross-sectional case study. RESULTS: There was a significant prevalence of males in index cases compared to controls (p<0.0001). No significant genotypic differences between cases and controls were found in T102C polymorphisms (p=1.000).There were significant differences between the AA genotype of -1438G/A polymorphisms and patients with OSAS (OR:2.3; CI95 percent:1.20-4.38, p=0.01). CONCLUSION: Serotonergic mechanisms may be related to OSAS. There were no differences in the prevalence of T102C polymorphisms in patients with OSAS and the control group. There is evidence of an association between the -1438G /A polymorphism and OSAS.

A síndrome da apneia obstrutiva do sono (SAOS) é um dos distúrbios mais complexos do sono, envolvendo múltiplos fatores genéticos contribuintes para o fenótipo. A serotonina (5-HT) está envolvida na regulação de uma variedade de funções viscerais e fisiológicas, inclusive o sono. Polimorfismos no gene 5-HTR2A podem alterar a transcrição, afetando o número de receptores do sistema serotoninérgico, contribuindo para a SAOS. OBJETIVO: Investigar a prevalência dos polimorfismos T102C e -1438G/A no gene HTR2A em pacientes com e sem SAOS. MATERIAL E MÉTODO: Estudo molecular em 100 pacientes como casos-índice e em 100 como grupo controle, de ambos os gêneros. O DNA foi extraído de leucócitos de sangue periférico e realizada a amplificação das regiões que abrangem ambos os polimorfismos pelas técnicas da PCR-RFLP. DESENHO DO ESTUDO: Estudo de caso/controle em corte transversal. Resultados: Houve prevalência significativa do gênero masculino nos casos-índice em relação aos controles (p<0,0001). Para o polimorfismo T102C, não houve diferença genotípica significante entre casos e controles (p=1,000). Houve diferença significativa entre o genótipo AA do polimorfismo -1438G/A e pacientes com SAOS (OR:2,3; IC95 por cento:1,20-4,38; p=0,01). CONCLUSãO: Os mecanismos serotoninérgicos parecem estar relacionados a SAOS. Não há diferenças na prevalência do polimorfismo T102C entre os pacientes com SAOS e o grupo controle. Há evidências de associação entre o polimorfismo -1438G/A e a SAOS.

Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence?

The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A) has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravataí-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 ± 6.35 years (60-100 years), with 16.9 percent males and 83.1 percent females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78 percent, the CT genotype frequency was 55.24 percent and the TT genotype frequency was 22.98 percent. We found an independent significant association between the TT genotype (35.7 percent) and urinary incontinence (OR = 2.06, 95 percentCI = 1.16-3.65). Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings.