Low Serotonergic Activity Research Articles

Effect of age on amplitude of circulating catecholamine's change of healthy cyclic mares.

Catecholamines (CATs) are neurotransmitters and allostatic hormones whose plasma concentrations are physiologically modified in various species such as human, rats, mice and donkeys, with advancing age. However, currently these mechanisms are less well elucidated in horses and more specifically in mares. The hypothesis of this study was that, as in afore mentioned species, the CATs could experience physiological changes with advancing age. The objective of this study was to evaluate the concentrations of adrenaline (A), noradrenaline (NA), dopamine (DA), and serotonin (5-HT) in mares of different ages. Blood samples were drawn from 56 non-pregnant Spanish Purebred mares belonging to four different age groups: 6 to 9 years, 10 to 12 years, 13 to 16 years and > 16 years. The concentrations of A, NA, DA, and 5-HT were determined by competition EIA-Technical 3-CAt EIA, specifically validated for horses. Mares aged > 16 years showed lower A, DA, and 5-HT but higher NA concentrations than 6-9, 10-12, and 13-16 years (p < 0.05). Mares of 13-16 years showed lower A and higher NA than 6-9 and 10-12 years (p < 0.05). A and NA (r=-0.72; p < 0.05), and NA and 5-HT (r=-0.67; p < 0.05) were negatively correlated, and A and 5-HT (r = 0.74; p < 0.05) were positively correlated. Advanced age leads to a predominance of sympathetic nervous activity and lower serotonergic activity in non-pregnant mares.

Microbiome composition and central serotonergic activity in patients with depression and type 1 diabetes

The role of gut–brain axis functioning gains growing attention in research on the pathophysiology of major depressive disorders. Here, especially consequences of altered microbiota composition on tryptophan metabolism resulting in altered serotonergic neurotransmission in the central nervous system (CNS) have reached a central position. Previous research, however, mainly focused on either microbiota and peripheral serotonin levels or central serotonergic neurotransmission. The present study aimed to combine the analysis of microbiota composition and central serotonergic activity using a valid neurophysiological indicator. We recruited 19 adult patients with type 1 diabetes and depression (D + D; 7 males), 19 patients with type 1 diabetes (D-; 7 male), and 20 healthy participants (HC; 7 males). Next to the analysis of fecal microbiota regarding α- and β-diversity, the loudness dependence of auditory evoked potential (LDAEP) was investigated, a non-invasive measurement of central serotonergic activity. High α-diversity was associated with high LDAEP, i.e., low serotonergic activity, in patients with diabetes and additional depression. Furthermore, relative abundances of bacterial families belonging to Bacteroidetes, Proteobacteria and Firmicutes were shown to have an impact on central serotonergic activity. This finding was supported by a tendency indicating an association of central serotonergic activity with the Bacteroidetes–Firmicutes ratio in both patients’ groups. Together, this data suggests that the guts’ microbiota composition might play an important role in regulating the central serotonergic activity in the brain.

Endocannabinergic modulation of central serotonergic activity in healthy human volunteers

BackgroundThe serotonergic and the endocannabinoid system are involved in the etiology of depression. Depressive patients exhibit low serotonergic activity and decreased level of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2AG). Since the cannabinoid (CB) 1 receptor is activated by endogenous ligands such as AEA and 2AG, whose concentration are controlled by the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively, we investigated the effects on serotonergic utilization. In this study, we investigated the impact of the rs1049353 single-nucleotide polymorphism (SNP) of the cannabinoid receptor 1 (CNR1) gene, which codes the endocannabinoid CB1 receptor, and the rs324420 SNP of the FAAH gene on the serotonergic and endocannabinoid system in 59 healthy volunteers.MethodsSerotonergic activity was measured by loudness dependence of auditory-evoked potentials (LDAEP). Plasma concentrations of AEA, 2AG and its inactive isomer 1AG were determined by mass spectrometry. Genotyping of two SNPs (rs1049353, rs344420) was conducted by polymerase chain reaction (PCR) and differential enzymatic analysis with the PCR restriction fragment length polymorphism method.ResultsGenotype distributions by serotonergic activity or endocannabinoid concentration showed no differences. However, after detailed consideration of the CNR1-A-allele-carriers, a reduced AEA (A-allele-carrier M = 0.66, SD = 0.24; GG genotype M = 0.72, SD = 0.24) and 2AG (A-allele-carriers M = 0.70, SD = 0.33; GG genotype M = 1.03, SD = 0.83) plasma concentration and an association between the serotonergic activity and the concentrations of AEA and 2AG has been observed.ConclusionsOur results suggest that carriers of the CNR1-A allele may be more susceptible to developing depression.

The Role of Serotonergic Gene Methylation in Regulating Anxiety-Related Personality Traits in Chimpanzees.

While low serotonergic activity is often associated with psychological disorders such as depression, anxiety, mood, and personality disorders, variations in serotonin also contribute to normal personality differences. In this study, we investigated the role of blood DNA methylation levels at individual CpG sites of two key serotonergic genes (serotonin receptor gene 1A, HTR1A; serotonin transporter gene, SLC6A4) in predicting the personalities of captive chimpanzees. We found associations between methylation at 9/48 CpG sites with four personality dimensions: Dominance, Reactivity/Dependability, Agreeableness, and Openness. Directionality of effects were CpG location-dependent and confirmed a role of serotonergic methylation in reducing anxiety (Dominance) and aggression-related personality (Reactivity/Undependability) while simultaneously promoting prosocial (Agreeableness) and exploratory personalities (Openness). Although early-life adversity has been shown to impact serotonergic methylation patterns in other species, here, atypical early social rearing experiences only had a modest impact on CpG methylation levels in this chimpanzee sample. The precise environmental factors impacting serotonergic methylation in chimpanzees remain to be identified. Nevertheless, our study suggests a role in shaping natural variation in animal personalities. The results of this study offer a basis for future hypothesis-driven testing in additional populations and species to better understand the impact of ecology and evolution on complex behavioral traits.

Relationship Between Neuroanatomical and Serotonergic Hypotheses of Obsessive-Compulsive Disorder: A Combined Functional Magnetic Resonance Imaging-Evoked Potential Study.

The so-called neuroanatomical hypothesis (with an increased activity of orbitofrontal cortex [OFC]) and the serotonergic hypothesis (with low activity in this system) have been discussed regarding the pathogenesis of obsessive-compulsive disorder (OCD) for decades. This study aimed to look for a relationship between the 2 pathogenetic concepts. Nineteen OCD patients (8 female, 11 male, mean ± SD age = 33.37 ± 11.73 years, Yale-Brown Obsessive Compulsive Scale: 21.79 ± 6.59; diagnosed by ICD-10/DSM-IV-TR) were compared to 19 matched healthy controls (8 female, 11 male, mean ± SD age = 31.63 ± 10.79 years) and investigated (2012-2014) with the loudness dependence of auditory-evoked potentials (LDAEP) as a marker of the synaptic serotonergic activity and functional magnetic resonance imaging (fMRI) during the delay discounting paradigm, inducing OFC blood-oxygen level-dependent activity in the 2 groups. There were significant correlation coefficients between LDAEP (eLORETA right side) and fMRI OFC activities (anatomic region of interest) within the delay discounting paradigm (immediate vs control) in patients with OCD (r = -0.554; P = .014). LDAEP differed between the 2 groups with larger LDAEP at Cz in OCD patients indicating low serotonergic activity (0.28 ± 0.14 vs 0.20 ± 0.10 µV/10 dB, F₂,₃₅ = 4.66, P = .016). fMRI activations of dorsolateral and medial prefrontal cortex as well as ventral striatum (functional region of interest) were different between OCD and healthy volunteers. The 2 main pathophysiologic hypotheses of OCD seem to be related to each other as measured by LDAEP and fMRI OFC activity during the delay discounting task. This could be interpreted as a further hint that low serotonergic activity induces altered OFC responsivity, which has to be treated in each patient with OCD by a serotonin agonist.

Brain cortisol receptor expression differs in Arctic charr displaying opposite coping styles

Individually consistent behavioral and physiological responses to stressful situations (often referred to as coping styles) has been reported in many animal species. Differences in hypothalamic-pituitary axis reactivity characterize individuals, and it has been proposed that the glucocorticoid (gr) and mineralocorticoid (mr) receptors are fundamental in regulating coping styles. We sorted individuals into reactive and proactive coping styles by collapsing behavioral outputs from net restraint and confinement stress tests in a principal component analysis. We then analyzed plasma cortisol levels, serotonin neurochemistry and the relative mRNA expression of gr1 and mr in stressed individuals per coping style. Proactive fish were characterized as having a lower serotonergic activity and being more active under stress. In addition, proactive fish had higher hypothalamic gr1 and mr abundance and a higher mr/gr1 ratio, compared to reactive fish. We found no significant differences in cortisol or telencephalic mRNA, gr1 and mr expression, or their ratio. Brain MR and GR have been proven to have an important role in the appraisal, coping and adaptation to stressful stimuli, so that a higher expression of these receptors in proactive fish suggests increased tolerance and performance under stress, compared to reactive individuals. We present evidence of a conserved neuroendocrine mechanism associated with coping styles in a fish species which is ecologically very diverse and considered to be the most cold-adapted fish in freshwater. We propose that this may be a first step into exploiting this model in order to better understand climate-change related effects in sub populations and ecophenotypes.

Serotonergic modulation of orbitofrontal activity and its relevance for decision making and impulsivity.

The orbitofrontal cortex seems to play a crucial role in reward-guided learning and decision making, especially for impulsive choice procedures including delayed reward discounting. The central serotonergic system is closely involved in the regulation of impulsivity, but how the serotonergic firing rate and release, best investigated by the loudness dependence of auditory evoked potentials (LDAEP), interact with orbitofrontal activity is still unknown. Twenty healthy volunteers (11 males, 9 females, 31.3 ± 10.6 years old) were studied in a 3T MRI scanner (Philips, Hamburg, Germany) during a delay discounting task, after their LDAEP was recorded using a 32 electrodes EEG machine (Brain Products, Munich, Germany). Significant positive correlations were only found between the LDAEP and the medial orbitofrontal part of the superior frontal gyrus (SFG/MO) [Δ immediate reward - delayed reward] for the right (r = 0.519; P = 0.019) and left side (r = 0.478; P = 0.033). This relationship was stronger for females compared with males. Orbitofrontal activity was also related to the Barratt Impulsivity Scale. This study revealed that low serotonergic activity as measured by a strong LDAEP was related to a high fMRI signal intensity of SFG/MO during immediate reward behavior which is related to impulsivity. Since this relationship was only found for the infralimbic medial and not for the middle or lateral part of the orbitofrontal cortex, an exclusive projection tract of the serotonergic system to this cortical region can be assumed to regulate impulsive reward-orientated decision making. Hum Brain Mapp 38:1507-1517, 2017. © 2016 Wiley Periodicals, Inc.

Diabolical effects of rabies encephalitis.

Rabies is an acute encephalomyelitis in humans and animals caused by rabies virus (RABV) infection. Because the neuropathological changes are very mild in rabies, it has been assumed that neuronal dysfunction likely explains the severe clinical disease. Recently, degenerative changes have been observed in neuronal processes (dendrites and axons) in experimental rabies. In vitro studies have shown evidence of oxidative stress that is caused by mitochondrial dysfunction. Recent work has shown that the RABV phosphoprotein (P) interacts with mitochondrial Complex I leading to overproduction of reactive oxygen species, which results in injury to axons. Amino acids at positions 139 to 172 of the P are critical in this process. Rabies vectors frequently show behavioral changes. Aggressive behavior with biting is important for transmission of the virus to new hosts at a time when virus is secreted in the saliva. Aggression is associated with low serotonergic activity in the brain. Charlton and coworkers performed studies in experimentally infected striped skunks with skunk rabies virus and observed aggressive behavioral responses. Heavy accumulation of RABV antigen was found in the midbrain raphe nuclei, indicating that impaired serotonin neurotransmission from the brainstem may account for the aggressive behavior. We now have an improved understanding of how RABV causes neuronal injury and how the infection results in behavioral changes that promote viral transmission to new hosts.

Feeding motivation as a personality trait in Nile tilapia (Oreochromis niloticus): role of serotonergic neurotransmission.

Consistent individual variation in behaviour and physiology (i.e. animal personality or coping style) has emerged as a central topic in many biological disciplines. Yet, underlying mechanisms of crucial personality traits like feeding behaviour in novel environments remain unclear. Comparative studies, however, reveal a strong degree of evolutionary conservation of neural mechanisms controlling such behaviours throughout the vertebrate lineage. Previous studies have indicated duration of stress-induced anorexia as a consistent individual characteristic in teleost fishes. This study aims to determine to what degree brain 5-hydroxytryptamine (5-HT, serotonin) activity pertains to this aspect of animal personality, as a correlate to feed anticipatory behaviour and recovery of feed intake after transfer to a novel environment. Crucial to the definition of animal personality, a strong degree of individual consistency in different measures of feeding behaviour (feeding latency and feeding score), was demonstrated. Furthermore, low serotonergic activity in the hypothalamus was highly correlated with a personality characterized by high feeding motivation, with feeding motivation represented as an overall measure incorporating several behavioural parameters in a Principle Component Analyses (PCA). This study thus confirms individual variation in brain 5-HT neurotransmission as a correlate to complex behavioural syndromes related to feeding motivation.

Environmental enrichment induces changes in brain monoamine levels in gilthead seabream Sparus aurata

It is generally accepted that environmental enrichment enhances the performance and improves welfare of animals kept in captivity. Similar results have been obtained for fish. It has been previously reported that the presence of Blue or Red-Brown Substrate (BS and RBS respectively) on tank bottom resulted in growth enhancement and suppression of aggressive behavior of gilthead seabream Sparus aurata compared to Green Substrate (GS) and tanks without modifications (Control-C). In an attempt to identify the underlying mechanisms, in the present study the effects of this environmental enrichment on brain monoamine neurotransmitters and fatty acids of gilthead seabream were evaluated. BS and RBS fish had lower serotonergic activity (5-HIAA/5-HT), resulting mainly from lower 5-hydroxyindoleacetic acid (5-HIAA) levels. BS fish also had lower serotonin levels compared to all other treatments. Brain noradrenaline (NA) levels did not show significant differences between substrate treatments and control. Brain dopamine (DA) levels were lowest in BS and RBS fish, higher in GS fish and highest in C fish. No differences were observed for dopamine metabolites or dopaminergic activity. Moreover, brain NA was negatively correlated with body weight in BS fish and positively correlated in RBS and C fish. A positive correlation was also observed for brain DA with body weight in RBS fish. No differences were observed for brain fatty acids. Present results support the hypothesis that the beneficial effects of the presence of BS and RBS are related to altered social interactions and indicate the establishment of a less stressful social organization in enriched-reared fish groups.

The association between suicidality and serotonergic dysfunction in depressed patients

The loudness dependence of auditory evoked potentials (LDAEP) has been proposed as a reliable indicator of central serotonin system activity in animal and some human studies. Since low central serotonergic activity is related to suicidality, it is possible that the LDAEP can be used to predict suicidality. The aim of the present study was to determine whether there is an association between suicidality and LDAEP in a depressed Korean population. Data from 38 depressive subjects (10 males, 28 females; mean age: 40.79 years) were analyzed. The subjects were divided into two groups: with prior suicide attempts (SA; n=17) and no prior suicide attempts (NSA; n=21). The LDAEP was evaluated by measuring auditory event-related potentials. Peak-to-peak N1/P2 amplitudes were calculated at five stimulus intensities, and the LDAEP was calculated as the slope of the linear-regression curve. The LDAEP values differed significantly between the SA and NSA groups. Depressed subjects with a history of suicide attempts seem to be characterized by large LDAEP values, indicating low serotonergic activity. The findings of the present study support the view that low serotonergic activity is related to the suicidality of depressed subjects. Thus, LDAEP, which can reflect serotonergic activity, may be a practical biological marker for suicidality.

Aripiprazole Partial Agonism at 5-HT2C

5-HT2C receptor antagonists are thought to contribute toward increased appetite and obesity. Aripiprazole acts as a partial agonist at the 5-HT2C receptor; hence, it is thought to cause little or no significant weight gain when used alone. We theorize that, in the presence of antidepressants with high serotonergic activity, aripiprazole acts as an antagonist at the 5-HT2C receptor, thus increasing the potential for weight gain. Conversely, in environments with low serotonergic activity, aripiprazole acts as an agonist at the 5-HT2C receptor, therefore having less potential for weight gain. A retrospective electronic medical record chart review of the Veterans Integrated Service Network 22 Veterans Affairs database was performed comparing patients' weight and body mass index (BMI) while taking aripiprazole alone (n = 1,177), versus aripiprazole plus a high-serotonergic antidepressant (citalopram, fluoxetine, paroxetine, sertraline, or venlafaxine) (n = 145), versus aripiprazole plus a low-serotonergic antidepressant (bupropion) (n = 77) for a minimum continuous duration of 6 months of aripiprazole monotherapy or combination treatment. The study was conducted from January 2010 through June 2011. In our patient population, only the aripiprazole plus high-serotonergic antidepressants group had a statistically significant increase in weight (P = .0027) and BMI (P = .0016). Our data suggest that, in the presence of antidepressants with high serotonergic activity, aripiprazole may act as an antagonist at the 5-HT2C receptor, resulting in weight gain. Conversely, when aripiprazole is used in the presence of antidepressants with low serotonergic activity, it may act as an agonist and result in little or no weight gain. This varying effect at the 5-HT2C receptor may explain why aripiprazole has not been associated with significant weight gain in previous studies focusing on schizophrenia and bipolar disorder.

Serotonergic neurotransmission in early Parkinson's disease: A pilot study to assess implications for depression in this disorder

Objectives. Depression, a disease usually accompanied by a serotonergic deficit, has been observed in about 40% of patients suffering from Parkinson's disease (PD). Thus, a serotonergic dysfunction in PD can be assumed. We aimed to investigate the interaction between serotonergic (5-HT) and dopaminergic activity in early PD. We hypothesized a serotonergic as well as a dopaminergic deficit in PD patients. We also assumed a correlation between these neurotransmitters indicating a relationship between dopaminergic and serotonergic function in PD. Methods. Nine unmedicated PD patients before and 12 weeks after l-dopa treatment and nine healthy subjects were examined using the loudness dependence of auditory evoked potentials (LDAEP), a promising indicator of central serotonergic function. Dopaminergic transporters (DAT) were collected using 123I-FP-CIT and single photon emission computer tomography (SPECT). LDAEP values were correlated with 123I-FP-CIT SPECT data. Results. A significant difference between LDAEP of controls and patients (P= 0.05) suggested lower serotonergic activity in PD. Twelve weeks after initiation of l-dopa treatment this difference was lost between patients and controls (P= 0.20). There was a trend towards a correlation between LDAEP and DAT (r= 0.65; P = 0.057) of the unmedicated patients, suggesting a low serotonergic activity may be related to a dopamine deficit in PD. Conclusions. Our results support the hypothesis that serotonergic neurotransmission is decreased in untreated PD and suggest that a low serotonergic activity may be related to the dopamine pathology in PD. This could be related to the high prevalence of depression in PD.

Serum total cholesterol correlates positively to central serotonergic turnover in male but not in female subjects

Reduced central serotonergic activity and low total serum cholesterol have been related to increased aggression, violent behavior, and suicidality. Searching for a correlation between them, we estimated serum total cholesterol and CSF levels of the main serotonin metabolite 5-HIAA in medication free male and female subjects for whom diagnostic lumbar puncture was performed. To eliminate age influence, we included in the study subjects in the age range 26 to 45 years. In a group of 62 subjects (30 males), found negative after diagnostic neurological examination, the correlation was not significant for the whole group, but after sex stratification, a significant positive correlation was revealed for males but not for females. These results were replicated in a second group of 76 subjects (31 males) with clinical and laboratory findings suggestive of multiple sclerosis (clinically isolated syndrome). The results link low cholesterol to low serotonergic activity only in males, predisposing them for violent and risky behaviors. This phenomenon could be seen as an evolutionary trait, possibly a result of the distinct role of males in a hunter–gatherer environment of evolutionary adaptedness, and may contribute to the understanding of the higher incidence of violent behavior observed in males.

Gene × environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict

BackgroundSerotonin genes have been hypothesized to play a role in the etiology of attention-deficit hyperactivity disorder (ADHD); prior work suggests that serotonin may interact with psychosocial stressors in ADHD, perhaps via mechanisms involved in emotional dysregulation. Because the development of behavioral and emotional regulation depends heavily both on the child's experience within the family context and the child's construals of that experience, children's appraisals of inter-parental conflict are a compelling candidate potentiator of the effects of variation within the serotonin transporter gene promoter polymorphism (5HTTLPR) on liability for ADHD.Method304 youth from the local community underwent a multi-informant diagnostic assessment procedure to identify ADHD cases and non-ADHD controls. Youth also completed the Children's Perception of Inter-Parental Conflict (CPIC) scale to assess appraisals of self-blame in relation to their parents' marital disputes. The trialleic configuration of 5HTTLPR (long/short polymorphism with A> G substitution) was genotyped and participants were assigned as having high (La/La N = 78), intermediate (La/Lg, La/short, N = 137), or low (Lg/Lg, Lg/short, short/short, N = 89) serotonin transporter activity genotypes. Teacher reported behavior problems were examined as the target outcome to avoid informant overlap for moderator and outcome measures.ResultsHierarchical linear regression analyses indicated significant 5HTTLPR × self-blame interactions for ADHD symptoms. Examination of the interactions indicated positive relations between reports of self-blame and ADHD symptoms for those with the high and low serotonin activity genotypes. There was no relation between self-blame and ADHD for those with intermediate activity 5HTTLPR genotypes.ConclusionBoth high and low serotonergic activity may exert risk for ADHD when coupled with psychosocial distress such as children's self-blame in relation to inter-parental conflict. Results are discussed in relation to the role of serotonin in the etiology of the ADHD and related externalizing behaviors.

Serotonergic functioning as measured by the loudness dependence of auditory evoked potentials is related to a haplotype in the brain-derived neurotrophic factor (BDNF) gene

Objectives The serotonergic system plays an important pathophysiological role in various psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is involved in the differentiation and survival of serotonergic neurons. A previous study showed that low serum BDNF levels were associated with strong loudness dependence of auditory evoked potentials (LDAEP) as a reflection of low central serotonergic activity. To evaluate the genetic basis of this relationship, we studied whether the LDAEP is correlated with genetic variants within the BDNF gene. Methods Ninety five healthy subjects (41 males, 54 females) received electrophysiological recording of LDAEP and blood drawing for BDNF genotyping. Three BDNF markers (including the single nucleotide polymorphism rs6265(Val66Met)) were analyzed. Results Haplotype analysis revealed stronger LDAEP values in carriers of the G(Val)-C-T [rs6265(Val66Met)-rs2030324-rs1491850] haplotype within the BDNF gene in comparison to other haplotype carriers. These findings were demonstrated for the LDAEP of both left and right primary auditory cortices as well as for the vertex electrode (Cz). Conclusion Subjects with the BDNF haplotype G(Val)-C-T seem to be characterized by low serotonergic activity as well as possibly by low serum BDNF levels. These findings need replication in independent samples.

Serotonin, social status and sex change in the bluebanded goby Lythrypnus dalli

In a variety of vertebrates, highly aggressive individuals tend to have high social status and low serotonergic function. In the sex changing fish Lythrypnus dalli, serotonin (5-HT) may be involved as a mediator between the social environment and the reproductive system because social status is a critical cue in regulating sex change. Subordination inhibits sex change in L. dalli, and it is associated with higher serotonergic activity in other species. We tested the hypothesis that high serotonergic activity has an inhibitory effect on sex change. In a social situation permissive to sex change, we administered to the dominant female implants containing the serotonin precursor 5-hydroxytryptophan (5-HTP). In a social situation not conducive to sex change, we administered either the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) or the 5-HT 1A receptor antagonist p-MPPI. After three weeks we used HPLC to measure brain levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). We also performed PCPA, p-MPPI and fluoxetine injections in size-matched pairs of females to assess its effect on dominance status. Males and newly sex changed fish showed a trend for higher levels of 5-HIAA and 5-HT/5-HIAA ratio than females. The different implants treatments did not affect the probability of sex change. Interestingly, this species does not seem to fit the pattern seen in other vertebrates where dominant individuals have lower serotonergic activity than subordinates.

Association of 5‐HT1B receptor polymorphisms with the loudness dependence of auditory evoked potentials in a community‐based sample of healthy volunteers

The terminal autoreceptor 5-HT1B is centrally involved in the regulation of the brain serotonergic system and in several psychiatric disorders including depression, addiction, and obsessive-compulsive disorder. The loudness dependence of the auditory evoked N1/P2-component (LDAEP; primary auditory cortex) is currently considered as one of best-validated indicators of serotonergic neurotransmission, especially for synaptically released serotonin. Since the 5-HT1B receptor is involved in the release of serotonin at terminal endings of cortical neurons, this study addressed the question whether single nucleotide polymorphism (SNP) in the gene coding for this receptor (HTR1B) are related to LDAEP of the primary auditory cortex (tangential dipole) investigating a community-based sample of 127 healthy subjects randomly selected from the general population. In this carefully recruited sample, a G-G haplotype (rs1213368-rs6296) and the respective G-alleles were found to be related to a strong LDAEP response of the left tangential dipole, indicating low serotonergic activity. Apart from the fact that this is the first study which relates HTR1B SNPs to a measure of serotonergic function, it can be speculated that LDAEP may reflect parts of the release mechanism of serotonin at cortical synapses, although the lateralized finding cannot be entirely explained. Carriers of the G-alleles may be characterized by a particularly strong feedback inhibition of serotonin release at cortical terminals in the primary auditory cortex, possibly mediated by higher sensitivity of 5-HT1B receptors associated with low serotonergic activity.

The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis

BackgroundLow serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC).MethodsOur sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach.ResultsIn the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described.DiscussionA genetic influence on monoaminergic involvement in impulsivity shown by children with ADHD was found. There were trends for separate and overlapping influences on impulsive-aggressive behavior and cognitive impulsivity, where an association with PNMT (and arousal mechanisms affected by its activity) was more clearly involved in the latter. Serotonergic and dopaminergic mechanisms were implicated in both forms of impulsivity with a wider range of serotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity. These preliminary results should be followed up with an examination of environmental influences and associations with performance on tests of impulsivity in the laboratory.

Acute levodopa administration reduces cortisol release in patients with Parkinson’s disease

Levodopa (LD) application improves motor symptoms in patients with Parkinson's disease (PD) patients. Little is known on further effects of LD, which induced lower plasma levels of cortisol and lower serotonergic activity in certain brain areas of fish. Objectives of this trial were to analyse levels of cortisol, LD and 3-O-methyldopa (3-OMD) after administration of LD/benserazide in long term treated PD patients. 12 PD patients, taken off their regular treatment for at least 12 hours, received soluble 200 mg LD/50 mg benserazide under stress free conditions. Motor symptoms improved, LD and 3-OMD levels increased, whereas cortisol concentrations started to decrease significantly 30 minutes after LD intake. This reduced cortisol release may result from an overflow of exogenous LD in the brainstem. This hypothetically causes an reduced 5-HT content in neurons projecting to the hypothalamic structures, which are involved in the partial 5-HT dependent central regulation of peripheral cortisol release.