Serotonin System Research Articles

Time-Dependent Effects of Buspirone versus Desipramine on the 5-Choice Serial Reaction Time Task in Rats Reared in Social Isolation: Implication of Early Life Experience and Motoric Impulsivity.

Early life social experience and the function of the central serotonin (5-Hydroxytryptophan, 5-HT) system are involved in development of behavioral impulsivity in which individuals act without forethought or before all necessary information is available. However, most of the evidence has been obtained from acute 5-HT manipulation, whereas, the present study aimed to investigate the effects of subchronic regimen targeting of 5-HT1A receptors on motoric waiting impulsivity in socially isolated rats. A two-week protocol of buspirone (0.5 mg/kg/day) and desipramine (2.5 mg/kg/day) was employed for rats following social isolation rearing (IR) to examine their behavioral performance in a 5-choice serial reaction time task (5-CSRTT) during the treatment regimen. Responses in any one of the apertures prior to an informative signal were recorded as a premature response. IR rats presented with more locomotor activity than socially reared (SR) rats. Buspirone progressively increased the baseline level of premature responding in a time-dependent manner that was not observed in IR rats. Both IR and SR rats exhibited less premature responding following acute buspirone challenge. For a subchronic desipramine regimen, IR rats followed the same trend of SR controls to increase the prematurity of baseline response. Buspirone but not desipramine-induced time-dependent effects of motoric waiting impulsivity can be reversed by IR, indicating a role for early life social experience on 5-HT1A receptor-associated ability to control impulsiveness.

BDE-47 Causes Depression-like Effects in Zebrafish Larvae via a Non-Image-Forming Visual Mechanism.

Depression is a high-incidence mood disorder that is frequently accompanied by sleep disturbances, which can be triggered by the non-image-forming (NIF) visual system. Therefore, we hypothesize that polybrominated diphenyl ethers are known to induce visual impairment that could promote depression by disrupting the NIF visual pathway. In this study, zebrafish larvae were exposed to BDE-47 at environmentally relevant concentrations (2.5 and 25 μg/L). BDE-47 caused melanopsin genes that dominate the NIF visual system that fell at night (p < 0.05) but rose in the morning (p < 0.05). Such bidirectional difference transmitted to clock genes and neuropeptides in the suprachiasmatic nucleus and impacted the adjacent serotonin system. However, indicative factors of depression, including serta, htr1aa, and aanat2, were unidirectionally increased 1.3- to 1.6-fold (p < 0.05). They were consistent with the increase in nighttime thigmotaxis (p < 0.05) and circadian hypoactivity (p < 0.05). The results of melanopsin antagonism also indicated that these consequences were possibly due to the combination of direct photoentrainment by melanopsin and circadian disruption originating from melanopsin. Collectively, our findings revealed that BDE-47 exposure disrupted the NIF visual pathway and resulted in depression-like effects, which may further exert profound health effects like mood disorders.

Alprazolam modulates persistence energy during emotion processing in first-degree relatives of individuals with schizophrenia: a network control study

Schizophrenia is marked by deficits in facial affect processing associated with abnormalities in GABAergic circuitry, deficits also found in first-degree relatives. Facial affect processing involves a distributed network of brain regions including limbic regions like amygdala and visual processing areas like fusiform cortex. Pharmacological modulation of GABAergic circuitry using benzodiazepines like alprazolam can be useful for studying this facial affect processing network and associated GABAergic abnormalities in schizophrenia. Here, we use pharmacological modulation and computational modeling to study the contribution of GABAergic abnormalities toward emotion processing deficits in schizophrenia. Specifically, we apply principles from network control theory to model persistence energy – the control energy required to maintain brain activation states – during emotion identification and recall tasks, with and without administration of alprazolam, in a sample of first-degree relatives and healthy controls. Here, persistence energy quantifies the magnitude of theoretical external inputs during the task. We find that alprazolam increases persistence energy in relatives but not in controls during threatening face processing, suggesting a compensatory mechanism given the relative absence of behavioral abnormalities in this sample of unaffected relatives. Further, we demonstrate that regions in the fusiform and occipital cortices are important for facilitating state transitions during facial affect processing. Finally, we uncover spatial relationships (i) between regional variation in differential control energy (alprazolam versus placebo) and (ii) both serotonin and dopamine neurotransmitter systems, indicating that alprazolam may exert its effects by altering neuromodulatory systems. Together, these findings provide a new perspective on the distributed emotion processing network and the effect of GABAergic modulation on this network, in addition to identifying an association between schizophrenia risk and abnormal GABAergic effects on persistence energy during threat processing.

Understanding and assessing the antidepressant drug-associated risk of bleeding

Antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are the most commonly prescribed psychopharmacological drug group. Thus, a precise knowledge of the expected adverse drug reactions is indispensable. The increased risk of bleeding events is well documented, especially in patients treated with SSRIs. However, many other antidepressant drug groups have also been implicated in increasing the risk of bleeding. In the following review, the thrombocytic serotonin system and the respective targets of the different antidepressants are explained. Subsequently, the available literature on bleeding under the respective antidepressant classes or individual substances is presented, using data from meta-analyses whenever possible. In addition to the risk of bleeding in general, individual bleeding entities are also considered, such as gastrointestinal and cerebral hemorrhages. Finally, the effects of other drugs that increase the risk of bleeding (i. e., nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors and anticoagulants) in combination with antidepressant drugs are discussed. The information presented here is meant to guide practitioner's decision making regarding an appropriate antidepressant pharmacotherapy based on the patient's individual risk constellation.

Maternal LPS Exposure Enhances the 5-HT Level in the Prefrontal Cortex of Autism-like Young Offspring

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by reduced social interactions, impaired communication, and stereotyped behavior. The aim of this research is to investigate the changes in serotonin (5-HT) in the medial prefrontal cortex (PFC) of autism-like offspring induced by maternal lipopolysaccharide (LPS) exposure. Pregnant Sprague-Dawley rats were intraperitoneally injected with LPS to establish an autism-like model in their offspring. Offspring prenatally exposed to LPS showed autism-like behavior. The serotonin level in the mPFC of 2-week-old offspring was noticeably increased after maternal LPS exposure. Differentially expressed genes (DEGs) were enriched in pathways related to tryptophan metabolism and the serotonin system, as shown in RNA-seq findings. Consistently, tryptophan and serotonin metabolisms were altered in 2-week-old LPS-exposed offspring. The mRNA expression levels of 5-HT catabolic enzymes were remarkably reduced or tended to decrease. Moreover, maternal LPS exposure resulted in a higher serotonin 1B receptor (5-HT1BR) expression level in the mPFC but no difference in tryptophan hydroxylase 2 (TPH2) or serotonin reuptake transporter (SERT). The concentrations of 5-HT in serum and colon were increased in LPS-exposed offspring. Meanwhile, the expression level of tryptophan hydroxylase 1 (TPH1) in the colon was increased after maternal LPS treatment, whereas SERT was reduced. Furthermore, Golgi-Cox staining showed that neuronal dendritic length and spine density were significantly reduced in the mPFC of LPS-exposed offspring. The current study reveals that maternal LPS treatment resulted in an exaltation of the 5-HT of mPFC in ASD-like young rats, which may partly be caused by the abnormal elevation of 5-HT metabolism in its colon.

Effects of chronic combined treatment with ketanserin and fluoxetine in B6.CBA-D13Mit76C recombinant mice with abnormal 5-НТ&lt;sub&gt;1a&lt;/sub&gt; receptor functional activity

The recombinant B6.CBA-D13Mit76C mouse strain is characterized by altered sensitivity of 5-HT1A receptors and greater Htr1a gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced pro-depressive effect in a forced swim test. Since 5-HT2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT1A and 5-HT2A receptors, serotonin turnover, and transcription of principal genes of the serotonin system in the brain of B6.CBA-D13Mit76C mice. Ketanserin did not reverse the pro-depressive effect of fluoxetine. Fluoxetine, ketanserin, and fluoxetine + ketanserin decreased functional activity of 5-HT1A receptors and Htr1a gene transcription in the midbrain and hippocampus. Additionally, all the tested drug regimens decreased mRNA levels of Slc6a4 and Maoa in the midbrain. These changes were not accompanied by a significant shift in the levels of serotonin and its metabolite 5-HIAA. Notably, ketanserin upregulated enzymatic activity of tryptophan hydroxylase 2 (TPH2). Thus, despite some benefits (reduced Htr1a, Slc6a4, and Maoa transcription and increased TPH2 activity), prolonged blockade of 5-HT2A receptors failed to ameliorate the adverse effect of fluoxetine during abnormal functioning of 5-HT1A receptors.

Impact of Stress Exposure on Mental and Physical Health across the Life Span: Molecular mechanisms, Neurobiological abnormalities, and Novel Pathways for Intervention

Stress exposures across the lifespan are known to have potent and long-lasting negative effects on mental health, and on the vulnerability to develop several metabolic dysfunctions. Importantly, the outcomes depend on the timing of the exposure as stress experienced at different neurodevelopmental windows (early in life, adolescence, adulthood, and old age) can lead to different negative outcomes via the involvement of distinct molecular and neurobiological mechanisms. Therefore, this symposium will integrate behavioural, immunological, and molecular findings from preclinical studies and clinical cohorts to dissect biological pathways that are involved in the effect of stress exposure at different stages and that can explain the onset of different negative outcomes. Moreover, we will also discuss promising new targets for preventing the negative effects of stress on brain function, cognition, affective behaviours, and physical health. Dr. Christoph Anacker will present data on how the serotonin system modulates neuroinflammatory responses to early life adversity in the mouse hippocampus across the lifespan, including adolescence, adulthood, and old age. He will show that rescuing impairments in serotonin signalling that result from early life adversity reduces neuroinflammation in the hippocampus, as well as associated deficits in neural signalling. Dr. Cattaneo will show data on inflammation related pathways as main biological systems affected by exposure to stress early in life both in animal models as well as in humans across lifespan and she will also discuss how this can also drive comorbidities between mental and physical diseases. She will also show how stress occurring at a different life period, at adulthood, enhance the risk for psychopathology by activating a different set of inflammatory pattern drive by specific and distinct epigenetic signatures. Dr. Nikolaos Daskalakis will show data on effects due to exposure to adversities at different ages (early in life and adolescence) and their additive effect on stress responses and vulnerability based on genetic background. He will show how animals exposed to early in life stress, upon exposure to adolescence-onset social isolation, exhibit sensorimotor gating deficits linked to hippocampus gene expression signature. He will also show human hippocampal post-mortem data of childhood trauma survivors with and without genetic susceptibility for stress.

Interactions between early adversity and the serotonin system determine lifespan immune responses in the hippocampus

Early Life Adversity (ELA) is a major risk factor for psychiatric disorders, but the neurobiological mechanisms that mediate the long-lasting effects of ELA are largely unknown. One candidate process implicated in stress-induced psychiatric disorders that is also increased by ELA, is neuroinflammation. Reducing neuroinflammation may thus be a promising new strategy to rescue the impact of ELA on brain function and mental health. To test this hypothesis, we exposed mice to ELA (limited bedding and nesting material from postnatal day (PND)3 to PND10). We then tested their behavior in a fear discrimination task and collected brains at PND35 (adolescence), PND56 (adulthood), and at 18 months of age (old age). While ELA did not alter adolescent behavior, we find that ELA causes fear discrimination deficits in female mice from adulthood (PND56; n=12, p=0.009) that last into old age (18 months; n=5, p=0.02). At the neurobiological level, we used immunohistochemistry for CD68+/Iba1+ to determine the number of activated microglia. We found a strong and long-lasting increase in the number of activated microglia in the hippocampus of ELA-exposed mice in adulthood and in old age (n=6; p<0.001). We then used a transgenic mouse line to increase hippocampal serotonin (5-HT) by knockdown of the 5-HT1A autoreceptor, and found that adolescent 5-HT1A knockdown can rescue ELA effects on fear discrimination and neuroinflammation later on. Our findings provide new insight into the potential of targeting the 5-HT system to prevent the neuroinflammatory and behavioral deficits resulting from ELA.

Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo

Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.e. monoamine concentrations) were shown to affect MAO-A levels. We assessed the effect of MAOA (rs1137070, rs2064070, rs6323) and TPH2 (rs1386494, rs4570625) variants associated with risk for depression and related clinical phenomena on global MAO-A distribution volume (VT) using [11C]harmine PET in 51 participants (21 individuals with seasonal affective disorder (SAD) and 30 healthy individuals (HI)). Statistical analyses comprised general linear models with global MAO-A VT as dependent variable, genotype as independent variable and age, sex, group (individuals with SAD, HI) and season as covariates. rs1386494 genotype significantly affected global MAO-A VT after correction for age, group and sex (p < 0.05, corr.), with CC homozygotes showing 26% higher MAO-A levels. The role of rs1386494 on TPH2 function or expression is poorly understood. Our results suggest rs1386494 might have an effect on either, assuming that TPH2 and MAO-A levels are linked by their common product/substrate, 5-HT. Alternatively, rs1386494 might influence MAO-A levels via another mechanism, such as co-inheritance of other genetic variants. Our results provide insight into how genetic variants within serotonin turnover translate to the cerebral serotonin system. Clinicaltrials.gov Identifier: NCT02582398. EUDAMED Number: CIV-AT-13-01-009583.

Parkinson's Disease: A Narrative Review on Potential Molecular Mechanisms of Sleep Disturbances, REM Behavior Disorder, and Melatonin.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. There is a wide range of sleep disturbances in patients with PD, such as insomnia and rapid eye movement (REM) sleep behavior disorder (or REM behavior disorder (RBD)). RBD is a sleep disorder in which a patient acts out his/her dreams and includes abnormal behaviors during the REM phase of sleep. On the other hand, melatonin is the principal hormone that is secreted by the pineal gland and significantly modulates the circadian clock and mood state. Furthermore, melatonin has a wide range of regulatory effects and is a safe treatment for sleep disturbances such as RBD in PD. However, the molecular mechanisms of melatonin involved in the treatment or control of RBD are unknown. In this study, we reviewed the pathophysiology of PD and sleep disturbances, including RBD. We also discussed the potential molecular mechanisms of melatonin involved in its therapeutic effect. It was concluded that disruption of crucial neurotransmitter systems that mediate sleep, including norepinephrine, serotonin, dopamine, and GABA, and important neurotransmitter systems that mediate the REM phase, including acetylcholine, serotonin, and norepinephrine, are significantly involved in the induction of sleep disturbances, including RBD in PD. It was also concluded that accumulation of α-synuclein in sleep-related brain regions can disrupt sleep processes and the circadian rhythm. We suggested that new treatment strategies for sleep disturbances in PD may focus on the modulation of α-synuclein aggregation or expression.

Effects of Chronic Combined Treatment with Ketanserin and Fluoxetine in B6.CBA-D13Mit76C Recombinant Mice with Abnormal 5-HT1A Receptor Functional Activity.

The recombinant B6.CBA-D13Mit76C mouse strain is characterized by an altered sensitivity of 5-HT1A receptors and upregulated 5-HT1A gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced the pro-depressive effect in a forced swim test. Since 5-HT2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT1A and 5-HT2A receptors, serotonin turnover, and transcription of principal genes of the serotonin system in the brain of B6.CBA-D13Mit76C mice. Ketanserin did not reverse the pro-depressive effect of fluoxetine, while fluoxetine, ketanserin, and fluoxetine + ketanserin decreased the functional activity of 5-HT1A receptors and Htr1a gene transcription in the midbrain and hippocampus. All tested drug regimens decreased the mRNA levels of Slc6a4 and Maoa in the midbrain. These changes were not accompanied by a significant shift in the levels of serotonin and its metabolite 5-HIAA. Notably, ketanserin upregulated enzymatic activity of tryptophan hydroxylase 2 (TPH2). Thus, despite some benefits (reduced Htr1a, Slc6a4, and Maoa transcription and increased TPH2 activity), prolonged blockade of 5-HT2A receptors failed to ameliorate the adverse effect of fluoxetine in the case of abnormal functioning of 5-HT1A receptors.

A Role for the Serotonin Transporter in the Largely Unknown Molecular Pathophysiology of Premenstrual Dysphoric Disorder

Despite a prevalence of approximately 5% in females, premenstrual dysphoric disorder (PMDD) suffers from a lack of investigation at the neurochemical level in humans. The preferred fundamental study design in PMDD is to investigate neurobiology across the menstrual cycle, which inherently rules out direct brain tissue assays from postmortem study that are unable to be repeated in the same participant. Therefore, molecular imaging methods applicable for longitudinal designs are highly relevant for creating advances in PMDD. SEE CORRESPONDING ARTICLE ON PAGE 1081 SEE CORRESPONDING ARTICLE ON PAGE 1081 Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging StudyBiological PsychiatryVol. 93Issue 12PreviewPremenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle. Full-Text PDF

Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex.

3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission, and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short-echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. Chronic MDMA users showed elevated GLX levels in the striatum but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short-echo-time PRESS and thus provided more robust results. Our findings suggest that MDMA use affects not only serotonin but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users.

(051) Gut Microbiota and Sexual Desire Disorder in Women

Abstract Introduction Hyposexual desire disorder (HSDD) is a common female sexual health problem. HSDD mainly refers to women's continuous lack of sexual fantasy or desire for sexual activities, accompanied by obvious personal pain or affecting the partnership. In humans, sexual desire is regulated by a variety of neurotransmitters in key areas of the brain. Norepinephrine, dopamine, melanocortin, oxytocin and vasopressin mediate excitability, while serotonin, opioids, prolactin and endogenous cannabinoid system mediate inhibition. HSDD may be related to neuropsychological state of increased inhibition or decreased excitation, or both. There is a close relationship between gut microbiota and a variety of mental and neurological diseases. The changes of gut microbiota richness and diversity affect the functions of 5-hydroxytryptamine, norepinephrine and dopaminergic nervous systems in the brain, and these pathways and molecules have been proved to be closely related to the level of human sexual desire. At present, the understanding of the role of gut microbiota in the regulation of sexual desire and the mechanism of HSDD is limited. Objective In order to study the composition of gut microbiota and fecal metabolites in HSDD women, and increase the understanding of the possible relationship between low sexual desire and intestinal microbiota, this study hypothesized that the composition of intestinal microorganisms and fecal metabolites in HSDD patients was different from that in normal people. Methods We recruited and diagnosed HSDD women through Case-Control study, and performed the 16S rRNA sequencing, non targeted LC-MS metabonomics detection and targeted SCFAs quantitative detection of intestinal microorganisms to explore and evaluate the differences of gut microbiota and fecal metabolites composition between HSDD women and control group. Results In this study, 24 women with HSDD and 22 women without history of sexual dysfunction (NHSD) were included. The 16S rRNA gene sequencing of 46 fecal samples showed that the richness and diversity of intestinal flora in HSDD women were higher than those in NHSD women, and there were significant differences in the composition of gut microbiota between the two groups. At the genus level, Bifidobacterium, Lactobacillus, Sphingomonas, Phenylbacillus, Corynebacterium and some unclassified actinomycetes were enriched in the feces of HSDD women, while Ruminococcus were enriched in the feces of NHSD women. The results of non-targeted metabonomics of fecal samples showed that there were significant differences between HSDD and NHSD women in fecal metabolic phenotype. The main metabolites included histamine, deoxycorticosterone, tryptamine, tyramine, 6-methylquinoline, etc. The results of targeted SCFAs quantitative analysis showed that the content of butyric acid in feces of HSDD group was significantly higher than that of NHSD group. Spearman correlation analysis showed that the difference of gut microbiota and fecal metabolites between the two groups were associated with clinical characteristics including FSFI-D score. Conclusions The composition of gut microbiota and metabolites in HSDD women is different from that in NHSD women. The effect of characteristic bacteria and metabolites on the function of neurotransmitter system may be part of the pathogenesis of HSDD. Further studies may bring new theories of the gut microbiota brain sexual desire axis. Disclosure No

Effects of Escitalopram on the Functional Neural Circuits in an Animal Model of Adolescent Depression.

Although escitalopram is known to be an effective drug for adult depression, its disease-modifying efficacy on adolescents remains controversial. The present study aimed to evaluate the therapeutic effect of escitalopram on behavioral aspects as well as functional neural circuits by means of positron emission tomography. To generate the animal models of depression, restraint stress was used during the peri-adolescent period (RS group). Thereafter, escitalopram was administered after the end of stress exposure (Tx group). We performed NeuroPET studies of glutamate, glutamate, GABA, and serotonin systems. The Tx group showed no body weight change compared to the RS group. In the behavioral tests, the Tx group also displayed the similar time spent in open arms and immobility time to those for RS. In the PET studies, brain uptake values for the Tx group revealed no significant differences in terms of glucose, GABAA, and 5-HT1A receptor densities, but lower mGluR5 PET uptake compared to the RS group. In the immunohistochemistry, the Tx group showed the significant loss of neuronal cells in the hippocampus compared to the RS group. The administration of escitalopram had no therapeutic effect on the adolescent depression.

Seizures Cause Prolonged Impairment of Ventilation, CO2 Chemoreception and Thermoregulation.

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1a R1407X/+ (Dravet syndrome; DS) and Scn8a N1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with para-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone.SIGNIFICANCE STATEMENT There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO2 chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.

Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

Obsessive-compulsive disorder: Etiology, neuropathology, and cognitive dysfunction.

This review provides an overview of obsessive-compulsive disorder (OCD) symptoms, including the four partially distinct subtypes of the disorder, current diagnostic criteria, and common comorbidities. Critically, it focuses on the etiology of OCD, including its underlying neuropathology, and examines cognitive dysfunction in OCD. This review study was conducted by library method. We show how dysfunction in cortico-striato-thalamo-cortical (CSTC) circuits may underpin symptoms; and shed light on the putative neurochemistry within these loops such as the role of serotonin, dopamine, and glutamate systems. We also show how OCD is characterized by cognitive dysfunction including problems in cognitive flexibility, visuospatial memory, response inhibition, and goal-directed behavior, linked to aberrant activity within CSTC circuits. In brief, research questions we shed light on include (1) what are the symptoms in OCD; (2) what is the etiology of the disorder and do existing models explain OCD; and (3) what are key cognitive deficits in OCD and do these improve with treatment?

Striatal serotonin transporter gain-of-function in L-DOPA-treated, hemi-parkinsonian rats

L-DOPA is the standard treatment for Parkinson’s disease (PD), but chronic treatment typically leads to L-DOPA-induced dyskinesia (LID). LID involves a complex interaction between the remaining dopamine (DA) system and the semi-homologous serotonin (5-HT) system. Since serotonin transporters (SERT) have some affinity for DA uptake, they may serve as a functional compensatory mechanism when DA transporters (DAT) are scant. DAT and SERT’s functional contributions in the dyskinetic brain have not been well delineated. The current investigation sought to determine how DA depletion and L-DOPA treatment affect DAT and SERT transcriptional processes, translational processes, and functional DA uptake in the 6-hydroxydopamine-lesioned hemi-parkinsonian rat. Rats were counterbalanced for motor impairment into equally lesioned treatment groups then given daily L-DOPA (0 or 6 mg/kg) for 2 weeks. At the end of treatment, the substantia nigra was processed for tyrosine hydroxylase (TH) and DAT gene expression and dorsal raphe was processed for SERT gene expression. The striatum was processed for synaptosomal DAT and SERT protein expression and ex vivo DA uptake. Nigrostriatal DA loss severely reduced DAT mRNA and protein expression in the striatum with minimal changes in SERT. L-DOPA treatment, while not significantly affecting DAT or SERT alone, did increase striatal SERT:DAT protein ratios. Using ex vivo microdialysis, L-DOPA treatment increased DA uptake via SERT when DAT was depleted. Overall, these results suggest that DA loss and L-DOPA treatment uniquely alter DAT and SERT, revealing implications for monoamine transporters as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.

5HT1AR-FGFR1 Heteroreceptor Complexes Differently Modulate GIRK Currents in the Dorsal Hippocampus and the Dorsal Raphe Serotonin Nucleus of Control Rats and of a Genetic Rat Model of Depression.

The midbrain raphe serotonin (5HT) neurons provide the main ascending serotonergic projection to the forebrain, including hippocampus, which has a role in the pathophysiology of depressive disorder. Serotonin 5HT1A receptor (R) activation at the soma-dendritic level of serotonergic raphe neurons and glutamatergic hippocampal pyramidal neurons leads to a decrease in neuronal firing by activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels. In this raphe-hippocampal serotonin neuron system, the existence of 5HT1AR-FGFR1 heteroreceptor complexes has been proven, but the functional receptor-receptor interactions in the heterocomplexes have only been investigated in CA1 pyramidal neurons of control Sprague Dawley (SD) rats. In the current study, considering the impact of the receptor interplay in developing new antidepressant drugs, the effects of 5HT1AR-FGFR1 complex activation were investigated in hippocampal pyramidal neurons and in midbrain dorsal raphe serotonergic neurons of SD rats and of a genetic rat model of depression (the Flinders Sensitive Line (FSL) rats of SD origin) using an electrophysiological approach. The results showed that in the raphe-hippocampal 5HT system of SD rats, 5HT1AR-FGFR1 heteroreceptor activation by specific agonists reduced the ability of the 5HT1AR protomer to open the GIRK channels through the allosteric inhibitory interplay produced by the activation of the FGFR1 protomer, leading to increased neuronal firing. On the contrary, in FSL rats, FGFR1 agonist-induced inhibitory allosteric action at the 5HT1AR protomer was not able to induce this effect on GIRK channels, except in CA2 neurons where we demonstrated that the functional receptor-receptor interaction is needed for producing the effect on GIRK. In keeping with this evidence, hippocampal plasticity, evaluated as long-term potentiation induction ability in the CA1 field, was impaired by 5HT1AR activation both in SD and in FSL rats, which did not develop after combined 5HT1AR-FGFR1 heterocomplex activation in SD rats. It is therefore proposed that in the genetic FSL model of depression, there is a significant reduction in the allosteric inhibition exerted by the FGFR1 protomer on the 5HT1A protomer-mediated opening of the GIRK channels in the 5HT1AR-FGFR1 heterocomplex located in the raphe-hippocampal serotonin system. This may result in an enhanced inhibition of the dorsal raphe 5HT nerve cell and glutamatergic hippocampal CA1 pyramidal nerve cell firing, which we propose may have a role in depression.