Serotonergic Function Research Articles

Serotonin transporter polymorphism, depressive symptoms, and emotional impulsivity among advanced breast cancer patients.

This study tested a theory linking a marker of low serotonergic function to both depression and impulsivity in a sample of advanced breast cancer patients, among whom elevated depressive symptoms and difficulty regulating emotions are commonly reported. A total of 95 patients provided blood samples for serotonin transporter polymorphic region of the gene (5-HTTLPR) and completed questionnaires that measured depressive symptoms and emotional impulsivity. Structural equation modeling revealed that the s allele of 5-HTTLPR was related to greater depressive symptoms (β=.20, p<.042) but only marginally to greater emotional impulsivity (β=.19, p<.068). Depressive symptoms and emotional impulsivity were positively related (β=.33, p<.003). Further tests explored possible mediation from genotype to one psychological variable via the other. Results suggest that depressive symptoms, particularly perceived interpersonal rejection, may be a pathway linking genotype to emotional impulsivity. Findings provide the first evidence that low serotonergic function contributes to both depression and impulsivity within a clinically meaningful sample. Furthermore, the link of s allele of 5-HTTLPR to emotional impulsivity was mediated by depressive symptoms, particularly perceptions of social rejection. Findings have implications for advanced breast cancer patients' treatment decision.

Chronic antidepressant potentiates spontaneous activity of dorsal raphe serotonergic neurons by decreasing GABAB receptor-mediated inhibition of L-type calcium channels

Spontaneous activity of serotonergic neurons of the dorsal raphe nucleus (DRN) regulates mood and motivational state. Potentiation of serotonergic function is one of the therapeutic strategies for treatment of various psychiatric disorders, such as major depression, panic disorder and obsessive-compulsive disorder. However, the control mechanisms of the serotonergic firing activity are still unknown. In this study, we examined the control mechanisms for serotonergic spontaneous activity and effects of chronic antidepressant administration on these mechanisms by using modified ex vivo electrophysiological recording methods. Serotonergic neurons remained firing even in the absence of glutamatergic and GABAergic ionotropic inputs, while blockade of L-type voltage dependent Ca2+ channels (VDCCs) in serotonergic neurons decreased spontaneous firing activity. L-type VDCCs in serotonergic neurons received gamma-aminobutyric acid B (GABAB) receptor-mediated inhibition, which maintained serotonergic slow spontaneous firing activity. Chronic administration of an antidepressant, citalopram, disinhibited the serotonergic spontaneous firing activity by weakening the GABAB receptor-mediated inhibition of L-type VDCCs in serotonergic neurons. Our results provide a new mechanism underlying the spontaneous serotonergic activity and new insights into the mechanism of action of antidepressants.

Serotonin transporter density in binge eating disorder and pathological gambling: A PET study with [11C]MADAM

Behavioral addictions, such as pathological gambling (PG) and binge eating disorder (BED), appear to be associated with specific changes in brain dopamine and opioid function, but the role of other neurotransmitter systems is less clear. Given the crucial role of serotonin in a number of psychiatric disorders, we aimed to compare brain serotonergic function among individuals with BED, PG and healthy controls. Seven BED patients, 13 PG patients and 16 healthy controls were scanned with high-resolution positron emission tomography (PET) using the serotonin transporter (SERT) tracer [11C]MADAM. Both region-of-interest and voxel-wise whole brain analyses were performed. Patients with BED showed increased SERT binding in the parieto-occipital cortical regions compared to both PG and healthy controls, with parallel decreases in binding in the nucleus accumbens, inferior temporal gyrus and lateral orbitofrontal cortex. No differences between PG patients and controls were observed. None of the subjects were on SSRI medications at the time of imaging, and there were no differences in the level of depression between PG and BED patients. The results highlight differences in brain SERT binding between individuals with BED and PG and provide further evidence of different neurobiological underpinnings in behavioral addictions that are unrelated to the co-existing mood disorder. The results aid in the conceptualization of behavioral addictions by characterizing the underlying serotonin changes and provide a framework for additional studies to examine syndrome-specific pharmaceutical treatments.

17.1 Serotonergic Function and Early Adulthood Outcomes in Children With Disruptive Behavior Disorders

17.1 Serotonergic Function and Early Adulthood Outcomes in Children With Disruptive Behavior Disorders

Altered serotonergic and GABAergic neurotransmission in a mice model of obsessive-compulsive disorder

There is ample evidence that obsessive-compulsive disorder (OCD) is based on reduced serotonergic function. Replicated bidirectional selection for thermoregulatory nest-building behavior in the laboratory house mouse (Mus musculus) resulted in compulsive-like, non-compulsive-like and randomly bred control mice that represent a non-induced animal model of OCD. The present study aimed at investigating the neurochemical patterns in specific brain regions of compulsive-like (HA) versus non-compulsive-like (LA) and normal (CA) mice. The neurochemical investigation of several brain regions of the corticostriato-thalamocortical circuity, i.e., nucleus caudatus (CPU), nucleus accumbens (NAc), globus pallidus (GP), hippocampus (HPC), amygdala (AM), ventral tegmental area (VTA) and substantia nigra (SN) was performed by electrochemical (serotonin and dopamine) and fluorescence (glutamate and GABA) HPLC detection. HA mice displayed significantly decreased 5-HT concentrations in the mPFC and LA mice displayed a significant increase in GABA concentrations in the mPFC. This supports the pathophysiological relevance of serotonin in the manifestation of OCD and adding to the construct validity of the non-induced mouse model of OCD.

Neural correlates of placebo effect: Review and future implications

Experimental and clinical research has documented expectancy related symptom improvement in a variety of conditions, leading to a growing interest in the placebo effect. Despite significant treatment outcomes, placebo-induced effects have been regarded as nonspecific psychological factors associated with the subjective experience of healing that operates different than the actual drug agent . However, neuroimaging research revealed more complex regulation of the placebo response, which indicates a top-down regulation of the symptom improvement enhanced by the expectancy effects. It appears that, placebo response is not solely function of higher order control processes, but also involves diverse disease-specific neurobiological mechanisms. In the current review, neural mechanisms underlying placebo effect have been addressed focusing on the analgesia, Parkinson’s disease and major depression. Along with the opiate system, dopaminergic and serotonergic functions in the brain are discussed in relation with the three target conditions. Last, potential implications of the placebo research are discussed with respect to experimental and clinical practice.

Serotonin and self-control: A genetically moderated stress sensitization effect

PurposeThe current study seeks to examine how two widely studied serotonergic polymorphisms, MAOA-uVNTR and 5-HTTLPR, interact with early and later life stressors to explain between-individual variation in low self-control in a genetically moderated stress sensitization model (G×E×E). MethodsUsing a sample of male undergraduate students (n=190), regression analyses were performed to examine three-way interactions of distal and proximal stress by MAOA-uVNTR and 5-HTTLPR separately, while controlling for age, race, parenting, and peer delinquency. ResultsResults suggest that MAOA-uVNTR and 5-HTTLPR polymorphisms moderate individual stress sensitization in the explanation of self-control. ConclusionOur findings highlight the need to study the etiology of self-control from both developmental and biological perspectives by demonstrating that molecular genetic variation related to serotonergic function interacts with distal stressors to increase reactivity to proximal stressors.

Loudness- and time-dependence of auditory evoked potentials is blunted by the NMDA channel blocker MK-801

Amplitudes of auditory evoked potentials (AEP) increase with the intensity/loudness of sounds (loudness-dependence of AEP, LDAEP), and the time between adjacent sounds (time-dependence of AEP, TDAEP). Both, blunted LDAEP and blunted TDAEP are markers of altered auditory function in schizophrenia (SZ). However, while blunted LDAEP has been attributed to altered serotonergic function, blunted TDAEP has been linked to altered NMDA receptor function. Despite phenomenological similarities of the two effects, no common pharmacological underpinnings have been identified. To test whether LDAEP and TDAEP are both affected by NMDA receptor blockade, two rhesus macaques passively listened to auditory clicks of 5 different intensities presented with stimulus-onset asynchronies ranging between 0.2 and 6.4s. 8 AEP components were analyzed, including the N85, the presumed human N1 homolog. LDAEP and TDAEP were estimated as the slopes of AEP amplitude with intensity and the logarithm of stimulus-onset asynchrony, respectively. On different days, AEPs were collected after systemic injection of MK-801 or vehicle. Both TDAEP and LDAEP of the N85 were blunted by the NMDA blocker MK-801 and recapitulate the SZ phenotype. In summary, LDAEP and TDAEP share important pharmacological commonalities that may help identify a common pharmacological intervention to normalize both electrophysiological phenotypes in SZ.

Neuroprotective role of GABAB receptor modulation against streptozotocin-induced behavioral and biochemical abnormalities in rats

Stimulation as well as inhibition of GABAB (Gamma amino butyric acid) receptors has been reported to show beneficial effects in Alzheimer’s disease (AD). Experimental evidences suggest that the use of GABAergic agents could influence learning and memory. The present study was designed to investigate the possible role of GABAB receptors in streptozotocin (STZ)-induced behavioral and biochemical abnormalities in rats. Herein STZ was infused (3mg/kg) bilaterally on alternate days (day 1 and day 3) to produce experimental dementia in rats. STZ-infused rats were then treated with baclofen (GABABR agonist) 5 and 10mg/kg i.p. and CGP35348 (GABABR antagonist) 25 and 50mg/kg i.p. one week following STZ infusion for 15days. Cognitive functions were assessed by using Morris water maze (MWM) and object recognition task (ORT). Levels of malondialdehyde (MDA.), reduced glutathione (GSH), andacetylcholinesterase (AChE) were determined to evaluate oxidative stress and cholinergic function. STZ-infused rats showed decreased memory retention, elevated levels of MDA, increased AChE activity, reduced GSH levels. The combination of STZ with increasing doses of Baclofen further induced a higher decrease in memory retention and increase in oxidative stress. CGP35348 restored cognitive functions and AChE activity in STZ-infused rats. The cognitive enhancement following CGP35348 may be due to its ability to restore cholinergic, serotonergic and dopaminergic function, and its antioxidant activity. Therefore, it would be safe to conclude that the pharmacological blockade of GABAB receptors would be therapeutic in the management of cognitive disorders such as Alzheimer’s disease.

Brain responses to sound intensity changes dissociate depressed participants and healthy controls

Depression is associated with bias in emotional information processing, but less is known about the processing of neutral sensory stimuli. Of particular interest is processing of sound intensity which is suggested to indicate central serotonergic function. We tested weather event-related brain potentials (ERPs) to occasional changes in sound intensity can dissociate first-episode depressed, recurrent depressed and healthy control participants. The first-episode depressed showed larger N1 amplitude to deviant sounds compared to recurrent depression group and control participants. In addition, both depression groups, but not the control group, showed larger N1 amplitude to deviant than standard sounds. Whether these manifestations of sensory over-excitability in depression are directly related to the serotonergic neurotransmission requires further research. The method based on ERPs to sound intensity change is fast and low-cost way to objectively measure brain activation and holds promise as a future diagnostic tool.

Biomarkers of Suicide Attempt Behavior: Towards a Biological Model of Risk.

The rising suicide rate in the USA will not be reversed without improved risk assessment and prevention practices. To date, the best method for clinicians to assess a patient's risk for suicide is screening for past suicide attempts in the patient and their family. However, neuroimaging, genomic, and biochemical studies have generated a body of findings that allow description of an initial heuristic biological model for suicidal behavior that may have predictive value. We review studies from the past 3years examining potential biological predictors of suicide attempt behavior. We divide findings into two major categories: (1) structural and functional brain imaging findings and (2) biochemical and genomic findings encompassing several systems, including major neurotransmitters (serotonin, catecholamines, GABA, and glutamate), the hypothalamic pituitary adrenal (HPA) axis, the inflammasome, lipids, and neuroplasticity. The biomarkers that appear promising for assessing suicide risk in clinical settings include indices of serotonergic function, inflammation, neuronal plasticity, and lipids.

Treadmill exercise alleviates depressive symptoms in rotenone-induced Parkinson disease rats

Parkinson disease (PD) is characterized by selective loss of the dopaminergic neurons. The symptoms of depression following PD are closely associated with reduced activity of the serotonergic system in the dorsal raphe. We explored the antidepressive effect of exercise and its possible mechanism using the rotenone-induced PD rats. PD rats were induced by subcutaneously injection with rotenone for 14 days. The rats in the exercise groups were made to run on a treadmill for 30 min once a day during 14 consecutive days. Forced swimming test, immunohistochemistry for serotonin (5-hydroxytryptamine, 5-HT), tryptophan hydroxylase (TPH), and western blot for serotonin 1A (5-HT1A) receptor were conducted. Injection of rotenone induced PD rats. PD rats showed depressive state and treadmill exercise ameliorated this depressive state. 5-HT, TPH, and 5-HT1A receptor expressions in the dorsal raphe were suppressed by rotenone injection and treadmill exercise increased the expressions of 5-HT, TPH, and 5-HT1A receptor in the rotenone-injected rats. The present results show that treadmill exercise ameliorated depressive symptoms in the rotenone-induced PD rats. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe.

Opposite effects of 5-HT/AKH and octopamine on the crop contractions in adult Drosophila melanogaster: Evidence of a double brain-gut serotonergic circuitry.

This study showed that in adult Drosophila melanogaster, the type of sugar—either present within the crop lumen or in the bathing solution of the crop—had no effect on crop muscle contraction. What is important, however, is the volume within the crop lumen. Electrophysiological recordings demonstrated that exogenous applications of serotonin on crop muscles increases both the amplitude and the frequency of crop contraction rate, while adipokinetic hormone mainly enhances the crop contraction frequency. Conversely, octopamine virtually silenced the overall crop activity. The present study reports for the first time an analysis of serotonin effects along the gut-brain axis in adult D. melanogaster. Injection of serotonin into the brain between the interocellar area shows that brain applications of serotonin decrease the frequency of crop activity. Based on our results, we propose that there are two different, opposite pathways for crop motility control governed by serotonin: excitatory when added in the abdomen (i.e., directly bathing the crop) and inhibitory when supplied within the brain (i.e., by injection). Finally, our results point to a double brain-gut serotonergic circuitry suggesting that not only the brain can affect gut functions, but the gut can also affect the central nervous system. On the basis of our results, and data in the literature, a possible mechanism for these two discrete serotonergic functions is suggested.

Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome is an inherited monogenic disorder in which mutations to the 7-dehydrocholesterol (7-DHC) reductase (Dhcr7) gene lead to deficits in cholesterol synthesis. As a result, many patients suffer from gross physiological and neurological deficits. The purpose of this study was to identify a potential abnormal behavioral phenotype in a compound mutant mouse model for Smith-Lemli-Opitz disease (Dhcr7 Δ3-5/T93M ) to further validate the model and to provide potential targets for future therapeutic interventions. We also sought to identify some of the underlying changes in brain function that may be responsible for behavioral differences among groups. The Dhcr7 compound mutant mice were smaller than their single mutant littermates. Both single and compound heterozygous mice made fewer ultrasonic vocalizations when separated from the dam, which may suggest a communication deficit in these animals. Striking increases of the highly oxidizable 7-DHC were observed in the compound mutant mice. 7-Dehydrocholesterol is the precursor to cholesterol and builds up because of decreased function of the mutated Dhcr7 enzyme. Additionally, several differences were noted in the serotonergic system including increased expression of the serotonin transporter and increased uptake of serotonin by isolated synaptosomes. We propose that changes to the oxidative environment during development can have a significant impact on the development of serotonergic function and that this contributes to behavioral differences observed in the mutant mice.

Treadmill exercise improves depression-like symptoms by enhancing serotonergic function through upregulation of 5-HT1A expression in the olfactory bulbectomized rats.

The olfactory bulbectomy (OBX) is a well-known method inducing animal model of depression. Depression is associated with dysfunction of serotonin (5-hydroxytryptamine, 5-HT) system. In the present study, antidepressive effect of treadmill exercise was investigated using olfactory bulbectomized rats. After bilateral bulbectomy, the rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day during 28 days. Increased immobility time and decreased fast time in the forced swim test were observed in the olfactory bulbectomized rats. Sucrose preference in the sucrose preference test was decreased and activity in the open field test was also increased in the olfactory bulbectomized rats. Treadmill exercise decreased immobility time and activity and increased fast time and sucrose preference in the olfactory bulbectomized rats. Expressions of 5-HT and tryptophan hydroxylase (TPH) in the dorsal raphe of rats were suppressed by OBX and treadmill exercise increased the expressions of 5-HT and TPH in the olfactory bulbectomized rats. Serotonin receptor type 1A (5-HT1A) expression in the dorsal raphe was reduced by OBX and treadmill exercise increased 5-HT1A expression in the olfactory bulbectomized rats. In the present study, treadmill exercise ameliorated OBX-induced depressive symptoms. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe.

A Tph2GFP Reporter Stem Cell Line To Model in Vitro and in Vivo Serotonergic Neuron Development and Function.

Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2GFP, in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene. Tph2GFP mES cells selectively express GFP upon in vitro differentiation toward the serotonergic fate, they synthesize serotonin, possess excitable membranes, and show the typical morphological, morphometrical, and molecular features of in vivo serotonergic neurons. Thanks to the vital reporter GFP, we highlighted by time-lapse video microscopy several dynamic processes such as cell migration and axonal outgrowth in living cultures. Finally, we demonstrated that predifferentiated Tph2GFP cells are able to terminally differentiate, integrate, and innervate the host brain when grafted in vivo. On the whole, the present study introduces the Tph2GFP mES cell line as a useful tool allowing accurate developmental and dynamic studies and representing a reliable platform for the study of serotonergic neurons in health and disease.

Medicinal Plants Effective on Serotonin Level: A Systematic Review

In recent years, the prevalence of depression and mood disorders has been on the rise. With regards to increased popularity of traditional medicine and medicinal plants, we conducted this review to identify and study the action mechanisms of the medicinal plants that are effective on serotonin, as one of the neurotransmitters of happiness and mood, and depression symptoms. To conduct this systematic review, the key words of interest were used to retrieve articles from the Information Sciences Institute (ISI) and the PubMed. The articles, published between 2010 and 2017, about the medicinal plants’ and their products’ potential effects on serotonin and brain serotonergic system were analyzed. Plants and their derivatives may not only exert therapeutic effects on mild depression but also exhibit suitable therapeutic response in treating severe disorders such as major depressive disorder (MDD) to improve mood conditions and eliminate depressed mood through affecting the serotonergic system. Plants and their compounds affect serotonergic system function through anti-inflammatory mechanisms, inhibiting noradrenaline and serotonin reuptake, inhibiting monoamine oxidase (MAO), and increasing expression of serotonin transporter (5-HTT) and hepatic tryptophan 2, 3-dioxygenase. They can therefore be used as options for discovering new drugs effective on happiness and depression.

Serum serotonin as a potential risk factor in female suicide attempts by poisoning, in different menstrual cycle phases

Background Suicide is a major public and mental health concern worldwide today. It lies behind exceeding numbers of deaths every year. This necessitates studying the causes and risk factors involved in suicidal behavior. Suicide attempts are found to be more common in women, with higher risk during the low estrogen phases of the menstrual cycle. Serotonin is a neurotransmitter that is proved by many studies to be involved in suicidal behavior. A relation between circulating estrogen levels and serotonergic function is supposed by some studies to explain the link between female suicide attempts and low estrogen phases of the menstrual cycle. Aim The aim of this work was to study serum serotonin level as a potential risk factor in female suicide attempts in the different menstrual cycle phases. Also, this study aimed to investigate the potential correlation between serum serotonin and estrogen levels. Patients and methods This cross-sectional study was carried out on two groups: the suicidal group that included women with suicide attempts who came to Tanta Poison-Control Center during the period from the beginning of July 2015 to the end of December 2015, and the control group that included 25 nonsuicidal apparently healthy female volunteers. The menstrual cycle phase was assessed for those women; the serum serotonin level was estimated by specific ELISA techniques, and the suicidal intent of the suicidal group was assessed by Pierce’s suicidal intent scale. Results and conclusion This study demonstrated that the suicide attempters had significantly lower serum serotonin levels. This significance was observed to be in the menstrual and the whole luteal phases. A significant inverse correlation was found between serum serotonin levels and Pierce’s suicidal intent scale for the women who attempted suicide in the late luteal and menstrual phases. Also, a significant positive correlation was found between serum estrogen and serotonin levels.

Moody microbes: Do Microbes Influence our Behavior?

A growing body of literature indicates that our “second genome”- the genes in our resident microorganisms (microbiome) - affects many aspects of our physiology. From this perspective, we are “supraorganisms” coated and inhabited by a number of microbial cells that are 10 times greater than the sum of all our human somatic and germ cells, carrying150 fold more genetic information than our own human genome. The intestine contains the largest collection of microbes among all of our body “habitats” (sites for microbial colonization). Together, gut microbes form a community, or microbiota, that has a major impact on health through interactions with host cells (including components of the innate and adaptive immune systems), extraction of nutrients and energy from the diet, and complex biotransformations of a variety of ingested compounds, including potential carcinogens. Shifts in microbiome composition occur at different stages in life, from infancy, through puberty and gestation, to old age. Changes in the composition of the gut microbiome (dysbiosis) have also been associated with different disease states such as obesity, inflammatory bowel disease (IBD), diabetes, and metabolic syndrome.It is also becoming widely known that our gut microbiome has important effects on our moods and behavior. Studies have linked gut bacterial composition with risk taking, anxiety, stress, mating and sexual preferences in animals. These are concurrent with alterations found in serotonin levels, levels of brain derived neurotrophic factor (BDNF), and exaggerated corticosterone release in response to stress. Germ free animals also provide an important tool to study the contribution of the microbiota as they have altered serotonergic function in the central nervous system and different behavioral patterns. Taken together, the data indicates the important roles of microbiota in host behavior.

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

The adult brain shows remarkable neuroplasticity in response to hormones and the socioemotional modifications that they influence. In females with reproductive and maternal experience, this neuroplasticity includes the birth and death of cells in several forebrain regions involved in maternal caregiving and postpartum affective state. Such plasticity in midbrain sites critical for these behavioral and emotional processes has never been examined, though. By visualizing bromodeoxyuridine (BrdU) to label mitotic cells, NeuroD for neuronal precursors, and TUNEL to identify dying cells, we found that the midbrain dorsal raphe nucleus (DR, the source of most ascending serotoninergic projections) exhibited significant neuroplasticity in response to motherhood. Specifically, BrdU analyses revealed that DR newborn cell survival (but not proliferation) was regulated by reproductive state, such that cells born early postpartum were less likely to survive 12 days to reach the late postpartum period compared to cells born during late pregnancy that survived 12 days to reach the early postpartum period. Many of the surviving cells in the DR were NeuN immunoreactive, suggesting a neuronal phenotype. Consistent with these findings, late postpartum rats had fewer NeuroD-immunoreactive DR cells than early postpartum rats. Maternal experience contributed to the late postpartum reduction in DR newborn cell survival because removing the litter at parturition increased cell survival as well as reduced cell death. Unlike cytogenesis in the maternal hippocampus, which is reduced by circulating glucocorticoids, DR newborn cell survival was unaffected by postpartum adrenalectomy. These effects of reproductive state and motherhood on DR plasticity were associated with concurrent changes in DR levels of serotonin's precursor, 5-HTP, and its metabolite, 5-HIAA. Our results demonstrate for the first time that cytogenesis occurs in the midbrain DR of any adult mammal, that DR plasticity is influenced by female reproductive state and maternal experience, and that this plasticity is accompanied by changes in DR serotonergic function. Because serotonin is critical for postpartum caregiving behaviors and maternal affective state, plasticity in the DR may contribute to the neurochemical changes necessary for successful motherhood.