Serotonin System Research Articles

Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review.

BackgroundThe mechanisms underlying placebo effects of psychotropic drugs remain poorly understood. We carried out the first, to our knowledge, systematic review of functional neuroimaging correlates of placebo response in adults with anxiety/depressive disorders.MethodsWe systematically searched a large set of databases up to February 2021 based on a pre-registered protocol (PROSPERO CRD42019156911). We extracted neuroimaging data related to clinical improvement following placebo or related to placebo mechanisms. We did not perform a meta-analysis due to the small number of included studies and significant heterogeneity in study design and outcome measures.ResultsWe found 12 relevant studies for depressive disorders and 4 for anxiety disorders. Activity in the ventral striatum, rostral anterior cingulate cortex and other default mode network regions, orbitofrontal cortex, and dorsolateral prefrontal cortex correlated with placebo antidepressant responses. Activity in regions of the default mode network, including posterior cingulate cortex, was associated with placebo anxiolysis. There was also evidence for possible involvement of the endogenous opioid, dopamine, and serotonin systems in placebo antidepressant and anxiolytic effects.ConclusionsSeveral brain regions and molecular systems may be involved in these placebo effects. Further adequately powered studies exploring causality and controlling for confounders are required.

Translational PET Imaging of Spinal Cord Injury with the Serotonin Transporter Tracer [11C]AFM.

The descending raphespinal serotonin (5-HT) system contributes to neural activities required for locomotion. The presynaptic serotonin transporter (SERT) is a marker of 5-HT innervation. In this study, we explored the use of PET imaging with the SERT radioligand [11C]AFM as a biomarker of 5-HT axon damage after spinal cord injury (SCI) in a rodent model and its translation to imaging SCI in humans. PET imaging with [11C]AFM was performed in healthy rats under baseline and citalopram blocking conditions and a mid-thoracic transection rat model of SCI. The lumbar-to-cervical activity (L/C) ratio was calculated for the healthy and SCI animals to assess SERT binding decrease after SCI. Finally, translation of [11C]AFM PET was attempted to explore its potential to image SCI in humans. Intense uptake in the brain and intact spinal cord was observed at 30-60min post-injection of [11C]AFM in healthy rats. About 65% of [11C]AFM uptake in the spinal cord was blocked by citalopram. In the SCI rat model, the cervical uptake of [11C]AFM was similar to that in healthy rats, but the lumbar uptake was dramatically reduced, resulting in about half the L/C ratio in SCI rats compared to healthy rats. In contrast, [11C]AFM uptake in the human spinal cord showed no obvious decrease after treatment with citalopram. In the human subjects with SCI, decreases in [11C]AFM uptake were also not obvious in the section of spinal cord caudal to the injury point. [11C]AFM PET imaging of SERT provides a useful preclinical method to non-invasively visualize the rodent spinal cord and detect SERT changes in SCI rodent models. However, there appears to be little detectable specific binding signal for [11C]AFM in the human spinal cord. An SERT tracer with higher affinity and lower non-specific binding signal is needed to image the spinal cord in humans and to assess the axonal status in SCI patients.

Parkinson and depression: review and outlook.

Depression in Parkinson's Disorder (DPD) has been estimated to appear in up to 40% of people with PD and negatively impacts quality of life, motor and cognitive deficits and functional disability. Knowledge of the pathophysiology of DPD is unclear, DPD may be related to dysfunction in subcortical nuclei and the prefrontal cortex, striatal-thalamic-prefrontal and basotemporal limbic circuits, brainstem monoamine, and indolamine (i.e. dopamine, serotonin, and norepinephrine) systems. DPD is characterized by sadness, loss of interest, increased exhaustibility, feelings of helplessness, reduced drive, dysphoria, irritability, and pessimism about future. The diagnosis is complicated by overlap with PD symptoms, Detection of depression in PD should be made by psychometric depression scales. DPD is underrecognized and undertreated in clinical practice. Treatment mainly includes antidepressive medications and behavioral interventions as psychotherapy. Dopamine agonists showed some antidepressant effects, there are no sufficient numbers of RCTs. Important randomized clinical trials (RCTs) are summarized. SSRIs and SNRIs have a satisfying efficacy in DPD. TCAs are also good for improving depression. Side effects of different antidepressants (e.g. TCAs, SSRIs, SNRIs, bupropion, MAOIs) and potential interactions should be considered. In existing guidelines so far no statements, algorithms and recommendations are given for diagnosis and treatment of DPD. Methodologically adequate designed RCTs and comparative studies (NIS) which offer evidence-based results are urgently needed having the impact of DPD in mind.

Chapter 8 - Sudden unexpected death in epilepsy: Respiratory mechanisms

Epilepsy is one of the most common chronic neurologic diseases, with a prevalence of 1% in the US population. Many people with epilepsy live normal lives, but are at risk of sudden unexpected death in epilepsy (SUDEP). This mysterious comorbidity of epilepsy causes premature death in 17%-50% of those with epilepsy. Most SUDEP occurs after a generalized seizure, and patients are typically found in bed in the prone position. Until recently, it was thought that SUDEP was due to cardiovascular failure, but patients who died while being monitored in hospital epilepsy units revealed that most SUDEP is due to postictal central apnea. Some cases may occur when seizures invade the amygdala and activate projections to the brainstem. Evidence suggests that the pathophysiology is linked to defects in the serotonin system and central CO2 chemoreception, and that there is considerable overlap with mechanisms thought to be involved in sudden infant death syndrome (SIDS). Future work is needed to identify biomarkers for patients at highest risk, improve ascertainment, develop methods to alert caregivers when SUDEP is imminent, and find effective approaches to prevent these fatal events.

Molecular pathways of serotoninergic neurons regulation in murine brain in metabolic syndrome of various etiologies

Serotonin system participates in control of feeding behavior and energy balance jointly with hypothalamic neurohormonal systems. Tryptophan hydroxylase-2 (TPH2) is a key enzyme in serotonin biosynthesis in CNS. We compared TPH2 level in the hypothalamus and the midbrain and to evaluate neuroprotective mechanisms activated in metabolic syndrome.

Anti-osteoporotic medication and scleroderma

Scleroderma (systemic sclerosis) represents a challenging condition, usually requiring a multi-disciplinary team due to multi-organ involvement; it is mostly considered an autoimmune disease; the signature of the malady is the extensive fibrosis at the level of skin and multiple organs, associating endothelial/vessel damage and anomalies of immune response. We point out a few aspects concerning scleroderma-related osteoporosis. This is a literature review. Patients might associate low bone mineral density (the underling mechanisms are not entirely understood), thus an increased risk of fractures; so early recognition and treatment is mandatory for a better outcome. Some data showed that particularly vertebral fractures are prone to the condition. Almost half of individuals with the malady have osteoporosis (female prevalence, especially post-menopausal) and one third of them have an osteoporotic fracture. Older age and associated vitamin D deficiency increases the risk of fracture. Vitamin D has pleomorphic distribution, also targeting the immune modulation, cytokines puzzle, and the muscle-bone crosstalk in scleroderma. Hypovitaminosis D might be expected in these patients, while general D-supplementation has controversial benefits effects. Chronic inflammatory rheumatic conditions might benefit from the TBS use as fracture risk indicator through micro-architecture evaluation. It seems that patients with systemic sclerosis and malnutrition have lower TBS; high Dkk-1 serum levels (Dickkopf-1) is correlated with reduced TBS and advanced disease; TBS is correlated to the extent of microvascular complications; exposure to glucocorticoids (certain high-dose regimes) supplementary lowers TBS. Gastrointestinal complications are presented in 90% of patients with systemic sclerosis, involving fibrosis at any level which is a poor prognostic factor; malabsorption of nutrients and weight loss correlates with reduced bone formation while esophageal and gastric anomalies contraindicate the use of oral bisphosphonates for osteoporosis. Other abnormal elements of skeleton frame include: premature ovarian failure, serotonin system anomalies, chronic inflammation, potential side effects of immunosuppressant drugs. In patients with systemic sclerosis, the choices of medication targeting osteoporosis are limited; the use of intravenous bisphosphonates remains first line option (if renal function is adequate); the consideration of skin and esophageal anomalies is mandatory in the management of osteoporosis. Overall, the landscape of bone domain in systemic sclerosis is multi-leveled and some areas are still waiting for clear answers.

Clozapine modulation of zebrafish swimming behavior and gene expression as a case study to investigate effects of atypical drugs on aquatic organisms

Mental illnesses affect more than 150 million people in Europe and lead to an increasing consumption of neuroactive drugs during the last twenty years. The antipsychotic compound, clozapine, is one of the most used psychotropic drugs worldwide, with potentially negative consequences for the aquatic environment. Hence, the objectives of the study presented here were the quantification of clozapine induced changes in swimming behavior of exposed Danio rerio embryos and the elucidation of the molecular effects on the serotonergic and dopaminergic systems. Yolk-sac larvae were exposed to different concentrations (0.2 mg/L, 0.4 mg/L, 0.8 mg/L, 1.6 mg/L, 3.2 mg/L and 6.4 mg/L) of clozapine for 116 h post-fertilization, and changes in the swimming behavior of the larvae were assessed. Further, quantitative real-time PCR was performed to analyze the expression of selected genes. The qualitative evaluation of changes in the swimming behavior of D. rerio larvae revealed a significant decrease of the average swimming distance and velocity in the light-dark transition test, with more than a 36% reduction at the highest exposure concentration of 6.4 mg/L. Furthermore, the total larval body length was reduced at the highest concentration. An in-depth analysis based on expression of selected target genes of the serotonin (slc6a4a) and dopamine (drd2a) system showed an upregulation at a concentration of 1.6 mg/L and above. In addition, a lower increase in expression was detected for biomarkers of general stress (adra1a and cyp1a2). Our data show that exposure to clozapine during development inhibits swimming activity of zebrafish larvae, which could, in part, be due to disruption of the serotonin- and dopamine system.

Rewiring of the Serotonin System in Major Depression.

Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive impairment. Chronic treatment with antidepressants that amplify 5-HT action, such as selective serotonin reuptake inhibitors (SSRIs), appears to accelerate the rewiring of the 5-HT system by mechanisms that may be critical to the behavioral and cognitive improvements induced in these models. In this review, we survey the possible 5-HT receptor mechanisms that could mediate 5-HT rewiring and assess the evidence that 5-HT-mediated brain rewiring is impacting recovery from mental illness. By amplifying 5-HT-induced rewiring processes using SSRIs and selective 5-HT agonists, more rapid and effective treatments for injury-induced mental illness or cognitive impairment may be achieved.

Effects of a Cc2d1a/Freud-1 Knockdown in the Hippocampus on Behavior, the Serotonin System, and BDNF.

The serotonin 5-HT1A receptor is one of the most abundant and widely distributed brain serotonin (5-HT) receptors that play a major role in the modulation of emotions and behavior. The 5-HT1A receptor gene (Htr1a) is under the control of transcription factor Freud-1 (also known as Cc2d1a/Freud-1). Here, using adeno-associated virus (AAV) constructs in vivo, we investigated effects of a Cc2d1a/Freud-1 knockdown in the hippocampus of C57BL/6J mice on behavior, the brain 5-HT system, and brain-derived neurotrophic factor (BDNF). AAV particles carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a short-hairpin RNA targeting mouse Cc2d1a/Freud-1 mRNA had an antidepressant effect in the forced swim test 5 weeks after virus injection. The knockdown impaired spatiotemporal memory as assessed in the Morris water maze. pAAV_H1-2_shRNA-Freud-1_Syn_EGFP decreased Cc2d1a/Freud-1 mRNA and protein levels. Furthermore, the Cc2d1a/Freud-1 knockdown upregulated 5-HT and its metabolite 5-hydroxyindoleacetic acid but not their ratio. The Cc2d1a/Freud-1 knockdown failed to increase mRNA and protein levels of Htr1a but diminished a 5-HT1A receptor functional response. Meanwhile, the Cc2d1a/Freud-1 knockdown reduced Creb mRNA expression and CREB phosphorylation and upregulated cFos mRNA. The knockdown enhanced the expression of a BDNF precursor (proBDNF protein), which is known to play a crucial part in neuroplasticity. Our data indicate that transcription factor Cc2d1a/Freud-1 is implicated in the pathogenesis of depressive disorders not only via the 5-HT1A receptor and transcription factor CREB but also through an influence on BDNF.

P.0576 Knockdown of 5-HT1A receptor silencer Freud-2 in the frontal cortex affected the behavior and the serotonin system in mice

P.0576 Knockdown of 5-HT1A receptor silencer Freud-2 in the frontal cortex affected the behavior and the serotonin system in mice

P.0548 Tryptophan hydroxylase 2 deficiency modifies the effects of chronic fluoxetine treatment on the brain serotonin system and behavior in zebrafish

P.0548 Tryptophan hydroxylase 2 deficiency modifies the effects of chronic fluoxetine treatment on the brain serotonin system and behavior in zebrafish

The circadian clock in the mouse habenula is set by catecholamines.

Circadian rhythms are those variations in behavioral and molecular processes of organisms that follow roughly 24h cycles in the absence of any external cue. The hypothalamic suprachiasmatic nucleus (SCN) harbors the principal brain pacemaker driving circadian rhythms. The epithalamic habenula (Hb) contains a self-sustained circadian clock functionally coupled to the SCN. Anatomically, the Hb projects to the midbrain dopamine (DA) and serotonin (5-HT) systems, and it receives inputs from the forebrain, midbrain, and brainstem. The SCN is set by internal signals such as 5-HT or melatonin from the raphe nuclei and pineal gland, respectively. However, how the Hb clock is set by internal cues is not well characterized. Hence, in the present study, we determined whether DA, noradrenaline (NA), 5-HT, and the neuropeptides orexin (ORX) and vasopressin influence the Hb circadian clock. Using PER2::Luciferase transgenic mice, we found that the amplitude of the PER2 protein circadian oscillations from Hb explants was strongly affected by DA and NA. Importantly, these effects were dose-and region (rostral vs. caudal) dependent for NA, with a main effect in the caudal part of the Hb. Furthermore, ORX also induced a significant change in the amplitude of PER2 protein oscillations in the caudal Hb. In conclusion, catecholaminergic (DA, NA) and ORXergic transmission impacts the clock properties of the Hb clock likely contributing to the circadian regulation of motivated behaviors. Accordingly, pathological conditions that lead in alterations of catecholamine or ORX activity (drug intake, compulsive feeding) might affect the Hb clock and conduct to circadian disturbances.

Psychophysiology and psychopharmacology of aggression

The article is devoted to the psychophysiological mechanisms of aggressive behavior and its psychopharmacological correction. 3 main symptoms associated with aggression: hypoperfusion of the frontal and temporal lobes, dysfunction of serotonin system, dysfunction of glucose metabolism in temporal cortex.

5-HT2C receptor perturbation has bidirectional influence over instrumental vigour and restraint

The serotonin (5-HT) system, particularly the 5-HT2C receptor, has consistently been implicated in behavioural control. However, while some studies have focused on the role 5-HT2C receptors play in regulating motivation to work for reward, others have highlighted its importance in response restraint. To date, it is unclear how 5-HT transmission at this receptor regulates the balance of response invigoration and restraint in anticipation of future reward. In addition, it remains to be established how 5-HT2C receptors gate the influence of internal versus cue-driven processes over reward-guided actions. To elucidate these issues, we investigated the effects of administering the 5-HT2C receptor antagonist SB242084, both systemically and directly into the nucleus accumbens core (NAcC), in rats performing a Go/No-Go task for small or large rewards. The results were compared to the administration of d-amphetamine into the NAcC, which has previously been shown to promote behavioural activation. Systemic perturbation of 5-HT2C receptors—but crucially not intra-NAcC infusions—consistently boosted rats’ performance and instrumental vigour on Go trials when they were required to act. Concomitantly, systemic administration also reduced their ability to withhold responding for rewards on No-Go trials, particularly late in the holding period. Notably, these effects were often apparent only when the reward on offer was small. By contrast, inducing a hyperdopaminergic state in the NAcC with d-amphetamine strongly impaired response restraint on No-Go trials both early and late in the holding period, as well as speeding action initiation. Together, these findings suggest that 5-HT2C receptor transmission, outside the NAcC, shapes the vigour of ongoing goal-directed action as well as the likelihood of responding as a function of expected reward.

Heat stress affects fetal brain and intestinal function associated with the alterations of placental barrier in late pregnant mouse

High ambient temperature-induced heat stress (HS) during pregnancy may affect the placental function and fetal development. Late gestation is a critical period of the developing fetal brain and intestine. The study aimed to investigate the effects of HS during late pregnancy on the function of placenta, fetal brain and intestine in a mouse model. We found that the number of stillborn fetal mice were increased due to maternal HS. Transcriptome analysis revealed that the expression of genes enriched in nutrients transport and metabolism of HS group were up-regulated in the placenta, but down-regulated in the fetal duodenum and jejunum. Interestingly, the concentration of triglyceride (TG) in the HS group was raised in the placenta, but reduced both in the fetal duodenum and jejunum compared with the thermal-neutral (TN) group. Additionally, maternal HS also reduced total cholesterol (TC) contents in the fetal duodenum. The mRNA expression and protein levels of placental fatty acid binding protein 2 and 4 (fabp2 and fabp4) were not affected by maternal HS, but the mRNA expression and protein levels of cluster of differentiation 36 (CD36) and diacylglycerol acyltransferase-2 (Dgat2) were decreased in the fetal intestine. Furthermore, maternal HS reduced the mRNA expression and protein levels of the placental 11beta-hydroxysteroid dehydrogenase type 2 (Hsd11b2) and 5-hydroxytryptamine receptor 1D (Htr1d). The concentrations of corticosterone and the expression of heat shock protein 90 beta family member 1 (hsp90b1), hypoxia up-regulated 1 (hyou1) and corticotropin releasing hormone receptor 1 (crhr1) enriched in response to glucocorticoids in the fetal brain were increased by maternal HS. Taken together, our findings demonstrated that maternal HS disrupted the placental glucocorticoid barrier and serotonin system associated with the raised corticosterone levels in the fetal brain, which might contribute to the decreased capacity of nutrients transport and metabolism in the fetal intestine.

Advances in Imaging Genetics of Suicidal Behavior

Suicide,a major public health problem,is the death caused by injuring oneself with the intent to die.In this paper,we reviewed the genes encoding serotonin system,calcium voltage-gated channel subunit alpha1 C,γ-aminobutyric acid,and spindle and kinetochore associated complex subunit 2,as well as their related brain regions,from the perspective of imaging genetics,aiming to provide new ideas for the research and intervention on suicidal behavior.

No Association Between the 5-HTTLPR Polymorphism and Diurnal Preference in Koreans

Objective: Recent studies have extended the study of diurnal preferences to the genetic level. Most studies have focused on clock genes, but some studies have searched for the possibilities of other genes associated with the circadian rhythm. Considering that the circadian rhythm is associated with the serotonergic system, investigating the association between major genes of the serotonin system and the diurnal preference phenotype is essential. In this study, we evaluated whether the 5-HTTLPR polymorphism is associated with diurnal preference in a Korean population.Methods: In total, 509 healthy subjects were genotyped for the 5-HTTLPR polymorphism. The Korean version of the Composite Scale of Morningness (CSM) was used to measure the phenotype patterns of diurnal preference. In addition, scores of three subscales—morningness, activity planning, and morning alertness—were extracted from the CSM.Results: No significant associations were observed between CSM scores and the 5-HTTLPR genotype or allele carrier status.Conclusion: The results of this study suggests that 5-HTTLPR has no effect on diurnal preference in a healthy Korean population. Further studies with a large number of subjects from multiple ethnicities are necessary to fully evaluate the association between 5-HTTLPR and diurnal preference.

Ересек егеуқұйрықтардың жүрегінің оң жақ қарынша миокардының жиырылғыштығына серотонин мен адреналиннің жоғарылаған концентрацияларының əсері

Соңғы жылдары ағзаның физиологиялық жəне патологиялық процестеріне серотониннің(5-HT) рөлі мен оның əсер ету механизмдеріне аса көңіл бөлініп келеді. Серотониндік жүйенің қалыпты жағдайдан ауытқуы атеросклероз, артериялық гипертензия, жүректің ишемиялық ауруын тудыруына себепболатыны кеңінен талқылануда. Бүгінгі таңда сүтқоректілер мен адамдардың миокардында анықталған серотонин рецепторларының екі түрі белгілі— 5-НТ2 жəне5-НТ4. Жүрек қызметін басқаратын негізгі механизмдердің бірі кардиомиоциттердің адренорецепторларына катехоламиндердің əсер етуімен байланысты. Адам мен жануарлардың жүрегінде кардиомиоциттердің жиырылуына β1, β4 жəне α1A адренорецепторлары қатысады. Серотонин мен адреналин физиологиялық процестерін реттеуші модуляторлары болып, патология жағдайында аурудың дамуына ықпал ететін факторларға айналады. Ересек ұрғашы егеуқұйрықтардың миокардының серотонин мен адреналиннің түрлі концентрацияларына жиырылу күшін in vitro зерттеу барысында анықтадық. Нəтижесінде, серотониннің концентрациясының жоғарылауымен оң қарыншаның миокардында дозаға тəуелді оң инотропты əсер байқалды. Серотониннің соңғы концентрациясына оң жақ қарыншаның жиырылу күші алғашқы концентрациясымен салыстырғанда 48,3 % жоғарылаған. Алайда, адреналин концентрациясының жоғарылауымен оң инотропты реакция əлсірейді. Адреналиннің максималды10,0 mM концентрациясына алдыңғы концентрациясымен салыстырғанда10,4 % теріс инотропты əсер байқалды. Осылайша, жүректегі серотониндік рецепторлардың таралуы мен функционалды рөлі адренергиялық рецепторлармен сəйкес болса да, кардиомиоциттердің серотонин мен адреналинге инотропты реакциясы əртүрлі болды.

Orexin, serotonin, and energy balance.

The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these behaviors. Evidence points to lateral hypothalamic orexin neurons as modulators of feeding and SPA. These neurons affect a broad range of systems, and project to multiple brain regions such as the dorsal raphe nucleus, which contains serotoninergic neurons (DRN) important to energy homeostasis. Physical activity is comprised of intentional exercise and SPA. These are opposite ends of a continuum of physical activity intensity and structure. Non‐goal‐oriented behaviors, such as fidgeting, standing, and ambulating, constitute SPA in humans, and reflect a propensity for activity separate from intentional activity, such as high‐intensity voluntary exercise. In animals, SPA is activity not influenced by rewards such as food or a running wheel. Spontaneous physical activity in humans and animals burns calories and could theoretically be manipulated pharmacologically to expend calories and protect against obesity. The DRN neurons receive orexin inputs, and project heavily onto cortical and subcortical areas involved in movement, feeding and energy expenditure (EE). This review discusses the function of hypothalamic orexin in energy‐homeostasis, the interaction with DRN serotonin neurons, and the role of this orexin‐serotonin axis in regulating food intake, SPA, and EE. In addition, we discuss possible brain areas involved in orexin–serotonin cross‐talk; the role of serotonin receptors, transporters and uptake‐inhibitors in the pathogenesis and treatment of obesity; animal models of obesity with impaired serotonin‐function; single‐nucleotide polymorphisms in the serotonin system and obesity; and future directions in the orexin–serotonin field.This article is categorized under:Metabolic Diseases > Molecular and Cellular Physiology

Nano-TiO2 aggravates bioaccumulation and developmental neurotoxicity of triphenyl phosphate in zebrafish larvae

This study explored the combined effects of titanium dioxide nanoparticles (nano-TiO2) and triphenyl phosphate (TPhP) on the neurodevelopment of zebrafish larvae as well as the underlying mechanisms. With this regard, zebrafish embryos were exposed to nano-TiO2 of 100 μg·L−1, TPhP of 0, 8, 24, 72, and 144 μg·L−1, or their combinations until 120 h post-fertilization (hpf). Results indicated 100 μg·L−1 nano-TiO2 alone to be nontoxic to zebrafish larvae. However, obvious developmental toxicity manifested as inhibition of surviving rate, heart rate and body length as well as increased malformation was observed in the higher concentrations of TPhP (72 and 144 μg·L−1) alone and the co-exposure groups. Additionally, results suggested that nano-TiO2 significantly enhanced the bioaccumulation of TPhP in zebtafish larvae, and thus aggravated the abnormities of spontaneous movement and swimming behavior in zebrafish larvae induced by TPhP. Nano-TiO2 also exacerbated the TPhP-induced inhibition of the axonal growth on the secondary motor neuron, and aggravated the TPhP-induced decrease on expressions of neuron-specific green fluorescent protein (GFP) and neuronal marker genes (ngn1 and elavl3). Further, the content of neurotransmitter serotonin was not altered by TPhP alone exposure, but was decreased significantly in the co-exposure group of 144 μg·L−1 TPhP and nano-TiO2. Our data indicated that nano-TiO2 might aggravate the neuron abnormities and serotonin system dysfunction by enhancing the TPhP accumulation, leading to exacerbated abnormal locomotors in zebrafish larvae.