Psychology
Genetic Research on Serotonin
Genetic research on serotonin focuses on understanding how variations in genes related to serotonin production and regulation may influence behavior, mood, and mental health. By studying these genetic factors, researchers aim to uncover potential links between serotonin and conditions such as depression, anxiety, and other mood disorders. This research has the potential to inform personalized treatment approaches and interventions for individuals with these conditions.
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12 Key excerpts on "Genetic Research on Serotonin"
eBook - ePubThe Serotonin System
History, Neuropharmacology, and Pathology
- Mark Tricklebank, Eileen Daly(Authors)
- 2019(Publication Date)
- Academic Press(Publisher)
Chapter SixEndocrine and genetic moderation of serotonin systems and the psychopathology of affective disorders
Mark D. Tricklebank1 and Eileen Daly2 ,1 Department of Neuroimaging Sciences, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom,2 Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United KingdomAbstract
The selective serotonin reuptake inhibitors (SSRIs) have taught us much about the pathophysiology of depression particularly about the impact that polymorphisms in the transporter gene seemed to have on susceptibility to depression have that seemed to explain the association between early life trauma and subsequent development of depression. Neuroimaging studies lent strong support for this hypothesis: finding a strong amplification of the activation of the amygdala in response to anger or fear-provoking stimuli in healthy short (S) allele carriers compared to those carrying the long (L) allele. Preclinical studies using transgenic animals carrying the S or L alleles, exposed to an SSRI in early life, suggested that amygdaloid reactivity is developmentally determined. The story is yet more complicated as further studies have identified a further 10 polymorphisms in the serotonin transporter whose functional consequences and interaction with environmental events are currently unknown.
- (Author)
- 2020(Publication Date)
- Academic Press(Publisher)
Chapter 48Functional pharmacogenetics of serotonin receptors in psychiatric drug action
Olga O. McGowan1and Gavin P. Reynolds2,∗1 Leverndale Hospital, Glasgow, United Kingdom2 Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, United Kingdom∗ Corresponding author.Abstract
There is substantial evidence for the importance of serotonin system dysfunction in the biology of mood, anxiety disorders, and psychotic illness, as well as in the behavioral disturbances associated with neurodegenerative disorders. Interactions with serotonin receptors are likely to contribute to the mechanisms of action of many psychiatric drugs. There is substantial individual difference in response to drug treatment—not all patients show benefit, the treatment is often inadequate, and adverse effects of drugs may reduce their tolerability. Genetic factors are likely to contribute substantially to this individual variability; variability in serotonin receptor genes can influence both response to drug treatment and the emergence of adverse effects. This chapter concentrates on the functional pharmacogenetics of the main serotonin receptors involved in psychiatric drug action. The 5-HT1A , 5-HT2A , and 5-HT2C receptors are the main focus; however, 5-HT1B , 5-HT4 , 5-HT6 , and 5-HT7
eBook - PDF- Despina Sanoudou(Author)
- 2012(Publication Date)
- IntechOpen(Publisher)
The ultimate goal of this scientific field is to provide “tailor-made” pharmacotherapies based on the genetic constitution of the individual. Importantly, genetic prediction of antidepressant response has the potential to facilitate an informed choice of agent and a patient-tailored dose in order for response rates to be significantly improved and adverse effects to be alleviated. Recent pharmacogenetic research on the impact of sex on antidepressant treatment has focused mostly on SSRIs, because these drugs represent the first-choice of pharmacological intervention for the treatment of major depression worldwide. Given that not all patients respond sufficiently to the initial treatment with an SSRI, non-response has been associated with individual differences in pharmacodynamic processes and in this context has been partly attributed to the polymorphic nature of certain genes related to the metabolism of monoamines, to the serotonergic and other neurobiological systems (Steimer et al. , 2001). Multiple genes influencing central monoaminergic neurotransmission have served as targets of vast pharmacogenetic screening. Among these are the rate-limiting enzyme of 5-HT biosynthesis, tryptophan hydroxylase 1 & 2 (TPH1 & TPH2), inactivation enzymes monoamine oxidases A & B (MAO-A; MAO-B) and catechol-O-methyl-transferase (COMT), as well as 5-HT’s protein-targets, such as the 5-HT 1A receptor (Drago et al. , 2009). In humans, there are two distinct TPH genes located on chromosomes 11 and 12, coding for two different homologous enzymes, with TPH2 being the predominant isoform in the CNS (Walther & Bader, 2003). Therefore, sedulous research on whether/which DNA polymorphisms are somehow involved in SSRI responsiveness and if these vary between the two sexes, is of great importance for improving the clinical care of depressed patients.
eBook - PDFBiological Child Psychiatry
Recent Trends and Developments
- T. Banaschewski, L. A. Rohde, W. P. Kaschka, W. F. Gattaz(Authors)
- 2008(Publication Date)
- S. Karger(Publisher)
Risk factors for the pathogenesis of depression in childhood and youth 58 Bark Resch Various attempts have been made to discover the genetic and psychosocial causes of neurotransmitter imbalance. Several psychosocial risk factors are mainly discussed such as sexual abuse, physical and psychological negligence, and loss of a loved per-son. However there is still a lack of knowledge on the neural mechanisms connecting social factors and transmitter systems. The neurobiological systems evolve signifi-cantly during childhood and may play different roles in the genesis of depression dur-ing childhood and adulthood. Implication of the Serotonergic System in the Genesis of Affective Disorders and Its Influence on Suicidal Behavior Serotonergic neurons are localized in the raphe nuclei, they form connections to different areas of the brain, the cortex, hippocampus and basal ganglia. The level of serotonergic neurotransmission is influenced by the 5-HT transporter (5-HTT). The positive effect of fluoxetine in childhood depression in contrast to the inefficiency of tricyclics indicates the involvement of the serotonergic system in the genesis of depression in childhood [7]. Children and adolescents suffering from affective disor-ders have lower levels of 5-HT in blood compared to patients with other psychiatric disorders [8]. Children with hyperactive behavior have higher levels of 5-HT in blood than children suffering from affective disorders. With regard to the blood level of 5-HT, no differences have been found when comparing depressive children with a healthy control group. There is a significant negative correlation between the plasma 5-HT levels and suicidal behavior in adolescents [9]. However there is a negative cor-relation between the level of 5-hydroxyindolacetoacetate in cerebrospinal fluid, a metabolite of 5-HT, and aggressive behavior [10].
eBook - PDF- Francisco Lopez-Munoz, Cecilio Alamo(Authors)
- 2011(Publication Date)
- CRC Press(Publisher)
Recently, serotonin neurons have been classified based on genetic lineages. Specifically, sero-tonin neuronal progenitors can be subdivided into subsets defined by rhombomeres (r1, r2, r3, r5), which are discriminated by differing genetic cues (transcription factors) during development (Jensen et al. 2008). The broad functions of serotonin in the central nervous system include its involvement in the modulation of aggression, sleep, appetite, mood, thermoregulation, and sexual function; however, serotonin levels in the brain account for only 10% of the total serotonin in the body (Berger et al. 2009). In the periphery, serotonin is predominantly found in enterochromaffin cells of the gut, where it functions in smooth muscle contraction and gut motility (Spiller 2008). Additionally, sero-tonin is taken up into platelets, where it is released to cause vasoconstriction and is involved in cardiovascular regulation (Ramage and Villalon 2008). Serotonin is also found in lymphocytes and monocytes and is associated with immune system function (Gordon and Barnes 2003). Peripheral tissues express SERT and multiple serotonin receptors, and thus possess many of the components of the central serotonin system (Berger et al. 2009). As will be discussed later, correlations between central and peripheral serotonin system components are important for advances in depression research, whereby peripheral cells might be used as diagnostic tools to study treatment responses in cases where direct brain measurements are not feasible. 7.3 THE MONOAMINE HYPOTHESIS OF DEPRESSION 7.3.1 D ISCOVERY OF THE R OLE OF S EROTONIN Early evidence for the involvement of monoamine neurotransmitters, including serotonin, in depres-sion and other affective disorders arose serendipitously. Reserpine ( Rauwolfia serpentina ) was first used as an ayurvedic treatment for insanity, producing calming effects and lowering blood pres-sure (Sen and Bose 1931; Gupta et al. 1947; Vakil 1949).
eBook - ePubCompendium Of In Vivo Monitoring In Real-time Molecular Neuroscience - Volume 1: Fundamentals And Applications
Volume 1: Fundamentals and Applications
- George S Wilson, Adrian C Michael(Authors)
- 2014(Publication Date)
- WSPC(Publisher)
CHAPTER 12 PROBING SEROTONIN NEUROTRANSMISSION: IMPLICATIONS FOR NEUROPSYCHIATRIC DISORDERS Kevin M. Wood, David Cepeda and Parastoo Hashemi Wayne State University 12.1 INTRODUCTIONSerotonin is a unique neurotransmitter. About 98% of the body’s serotonin is located outside of the brain (Cooper et al., 2003), however, as a neuromodulator it plays important, expansive roles. Serotonin is thought to control many essential processes including appetite, sleep, mood, memory, cognition, movement and reward. Imbalances in the serotonergic system are associated with many neuropsychiatric disorders.Autism (Chugani et al., 1997; Sutcliffe et al., 2005), post-traumatic stress disorder (PTSD) (Lee et al., 2005), anxiety (Lesch et al., 1996; Sen et al., 2004; Ramboz et al., 1998), schizophrenia (Inayama et al., 1996; Laruelle et al., 1993), bipolar disorder (Furlong et al., 1998; Young et al., 1994), and addiction (Muller et al. 2007; Sellers et al., 1992) all display distinct deregulations of the serotonergic system.The most notorious of serotonin’s associations, however, is depression. Depression debilitates millions of Americans every year; it is a mental illness that can destroy feelings of joy gained from previous exciting activities. Fatigue, hopelessness, irritability, and excessive sadness can plague the sufferer. In 2011, antidepressants and antipsychotics dominated the pharmaceutical market (Lindsley, 2012).Modern antidepressants typically exaggerate serotonin’s effects in the synapse by slowing down its reuptake. Despite their mainstream usage, antidepressants generate controversy because of variable clinical efficacy (Smith et al., 2002; Cipriani et al., 2009) and systemic side effects (Ferguson, 2001; Masand and Gupta, 2002). Moreover, it is common for patients to take antidepressants for 3–4 weeks without experiencing therapeutic benefit (Gelenberg and Chesen, 2000; Onder and Tural, 2003). During this period patients can experience heightened depression and suicidal tendencies (Stone et al., 2009).
eBook - ePub- (Author)
- 2020(Publication Date)
- Wiley-Blackwell(Publisher)
2016 ). Collectively, these data suggest that unlike the antidepressant effects of increasing synaptic serotonin by blocking the 5‐HTT in adults, elevations of serotonin during prenatal development, and potentially into childhood, may increase risk for depression during adolescence and/or adulthood. Taken together, these findings suggest that the 5‐HTTLPR short allele, which is associated with reduced 5‐HTT efficiency and greater synaptic 5‐HT levels, may increase risk for depression through exposure to elevated serotonin throughout development.5‐HTTLPR: Potential Neural Mechanisms UnderlyingAssociations with Stress‐Related Depression
Amygdala and Neuroticism
Imaging genetics is a research strategy that examines associations between both genetic and epigenetic variation and variability in brain structure, function, and connectivity, as well as risk for psychopathology (Bogdan et al., 2017 ). Imaging genetics provide a unique approach to mechanistically relate differences in 5‐HTTLPR genotype to neural systems that mediate cognition, emotion, and behavior in health and disease (Hariri & Holmes, 2006 ). Most commonly, 5‐HTTLPR imaging genetic studies have investigated amygdala responsivity to threatening information. Broadly, the amygdala and its connections are necessary for recognizing possible threat in the environment and then generating and regulating physiologic and behavioral reactions. Elevated amygdala response to threat is a hallmark of various forms of psychopathology and in particular stress‐related disorder (Bogdan, Pagliaccio, Baranger, & Hariri, 2016 ). Amygdala function is regulated by serotonin (Holmes & Hariri, 2003 ), and Hariri and colleagues (Hariri et al., 2002 ) linked the short allele to elevated amygdala reactivity in one of the first imaging genetic studies. This finding has not been consistently replicated across studies, with meta‐analyses concluding that a small effect may be present (Munafo, Brown, & Hariri, 2008 ; Murphy et al., 2013 but see also Bastiaansen et al., 2014 ). As such, heightened amygdala reactivity associated with the short allele remains a plausible mechanism, among many (e.g., hypothalamic–pituitary–adrenal axis function; Gotlib, Joormann, Minor, &Hallmayer, 2008 ) through which the 5‐HTTLPR polymorphism may confer vulnerability to the depressogenic effects of stress. Indeed, recent evidence that elevated amygdala reactivity prospectively predicts elevated depression symptoms following stressful life event exposure provides support for this speculation (Swartz, Knodt, Radtke, & Hariri, 2015 ). A related interpretation is that given the links between amygdala reactivity and neuroticism (Cunningham, Arbuckle, Jahn, Mowrer, & Abduljalil, 2010 ), it is plausible that elevated amygdala reactivity among short allele carriers contributes to neuroticism, which itself moderates the impact of stressful life events on the development of depression (Kendler, Kuhn, & Prescott, 2004 ). Future adequately powered prospective longitudinal studies employing structural equation models alongside convergent nonhuman animal models are needed to evaluate these putative mechanisms (Bogdan et al., 2016
eBook - PDFHandbook of Depression and Anxiety
A Biological Approach, Second Edition
- Siegfried Kasper, Johan A. den Boer, J.M. Ad Sitsen(Authors)
- 2003(Publication Date)
- CRC Press(Publisher)
There may be a higher concentration of patients with genetically based abnormalities of drug metabolism in hospitals and tertiary care facilities than in the com-munity. This could be due to the fact that patients in such centers are more likely to be nonresponders or to have suffered adverse effects. 647 Pharmacogenetics of Mood Disorders IV. PHARMACODYNAMIC FACTORS IN ANTIDEPRESSANT RESPONSE The serotonin transporter (5HTT) is located on the presynaptic neuron of serotonergic nerve terminals and is the site of action of SSRIs and other antidepressants that block the uptake of serotonin. Therefore, it is an important potential candidate for pharmacogenetic studies of antidepressants. The 5HTT is encoded by a single gene, SLC6A4 on chromo-some 17, and includes 14 exons spanning approximately 35 kb. There are two common polymorphisms in SLC6A4. One is in the promoter region and is termed 5HTTLPR (5HT transporter-linked polymorphic region). It consists of a 44-base pair insertion or deletion. The long [l] variant has been reported to generate more gene transcription than the shorter variant(s) [21]. The other polymorphism in SLC6A4 consists of a variable number of tandem repeats (VNTR) in the second intron. It has three alleles (STin2*9, Stin2*10, Stin2*12) represented by different numbers of repeats. 5HTTLPR was reported to be asso-ciated with personality traits [21] and has been extensively studied as a candidate gene for mood disorders with variable results [22]. Association of the intron 2 VNTR polymor-phism with mood disorders is also variable [23]. An association between the serotonin transporter gene and response to antidepres-sants was first reported by Smeraldi et al. [24] (Table 1). One-hundred-two patients with DSM-IV major depression and psychotic features received fluvoxamine pindolol or fluvoxamine placebo in a 6-week double-blind controlled study. Response to the study drugs was compared among the patients grouped according to 5HTTLPR genotype.
eBook - PDFPsychiatric Disorders
Trends and Developments
- Toru Uehara(Author)
- 2011(Publication Date)
- IntechOpen(Publisher)
& Manji, H. (2006). Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet, Vol.78, No.5, (May 2006), pp. 804-814. Meaney, M.J. (2001). Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci, Vol.24, 2001), pp. 1161-1192. Merali, Z., Lacosta, S. & Anisman, H. (1997). Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: a regional microdialysis study. Brain Res, Vol.761, No.2, (Jul 4 1997), pp. 225-235. Meynen, G., Unmehopa, U.A., van Heerikhuize, J.J., Hofman, M.A., Swaab, D.F. & Hoogendijk, W.J. (2006). Increased arginine vasopressin mRNA expression in the Psychiatric Disorders – Trends and Developments 256 human hypothalamus in depression: A preliminary report. Biol Psychiatry, Vol.60, No.8, (Oct 15 2006), pp. 892-895. Middeldorp, C.M., de Geus, E.J., Willemsen, G., Hottenga, J.J., Slagboom, P.E. & Boomsma, D.I. (2010). The serotonin transporter gene length polymorphism (5-HTTLPR) and life events: no evidence for an interaction effect on neuroticism and anxious depressive symptoms. Twin Res Hum Genet, Vol.13, No.6, (Dec 2010), pp. 544-549. Mill, J. & Petronis, A. (2007). Molecular studies of major depressive disorder: the epigenetic perspective. Mol Psychiatry, Vol.12, No.9, (Sep 2007), pp. 799-814. Millan, M.J. (2011). MicroRNA in the regulation and expression of serotonergic transmission in the brain and other tissues. Curr Opin Pharmacol, Vol.11, No.1, (Feb 2011), pp. 11-22. Moller, D.E. (2000). Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab, Vol.11, No.6, (Aug 2000), pp. 212-217. Morikawa, O., Sakai, N., Obara, H. & Saito, N. (1998). Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter.
eBook - ePub- Loralie J. Langman, Amitava Dasgupta, Loralie J. Langman, Amitava Dasgupta(Authors)
- 2012(Publication Date)
- Wiley-Blackwell(Publisher)
Chapter 9 Pharmacogenetics of Psychoactive Drugs Jorge L. Sepulveda, MD, PhD Philadelphia VA Medical Center and University of Pennsylvania Introduction The human brain is the most complex biological system known, with an estimated 100 billion (10 11) neurons connected by 10 14 (adult) to 10 15 (young child) synapses. Further complexity is achieved by the use of more than 100 different neurotransmitters, many of which interact with several different receptors with multiple anatomic locations and signaling pathways. In contrast with this complexity, a relatively small number of targets have been explored for therapy of mental illness, most commonly involving the serotonin-, dopamine-, norepinephrine-, or gamma-aminobutyric acid (GABA)-dependent pathways. While remarkable effectiveness has been achieved in several conditions, such as in schizophrenia or major depression, allowing a large number of affected individuals to lead nearly normal lives, there is wide variability in the effectiveness and tolerability of most psychotropic drugs. Given the complexity of brain biochemistry and signaling pathways, it is not surprising that broad-spectrum pharmacological interventions (e.g., generalized inhibition of serotonin reuptake at the synapses) are not universally effective and often have undesirable effects. Newer generation psychotropic drugs tend to have narrower targets and more specific actions, with fewer side effects. As an example, newer antidepressants targeting serotonin uptake lack the anticholinergic effects mediated by inhibition of muscarinic acetylcholine receptors in brain and intestine by older tricyclic antidepressants. However, even for newer drugs, predictability of therapeutic effectiveness and tolerability remains difficult
eBook - PDF- Keith S. Dobson, David J. A Dozois(Authors)
- 2011(Publication Date)
- Academic Press(Publisher)
Neurochemical and Transmitter Models of Depression 67 GENETIC ENGINEERING AND BEHAVIORAL IMPAIRMENTS To a c onsi d erable extent, neuro c he m i c al a cc ounts of d epression suggest that stressful events are m ost likely to lea d to pathology in the presen c e of parti c u-lar geneti c ba c kgroun d s. As su c h, ani m al m o d els have in c reasingly fo c use d on the effe c ts of stressors on behavioral outputs given the d eletion (kno c kout) or insertion (transgeni c ) of genes that have been i m pli c ate d as vulnerability fa c -tors for d epression. It has been shown, for instan c e, that m i c e d efi c ient of the 5-HT transporter (5-HTT) exhibite d anxiety an d d epression in several behavioral para d ig m s (Lira et al ., 2003). Moreover, these effe c ts c oul d be antagonize d by repeate d anti d epressant (fluoxetine) treat m ent (Hol m es et al ., 2002) as well as by the 5-HT 1A antagonist, WAY 100635, suggesting the involve m ent of 5-HT 1A re c eptors in these out c o m es (Hol m es et al ., 2003). These fin d ings are so m ewhat para d oxi c al, as it m ight have been expe c te d that d eletion of the transporter woul d in c rease 5-HT availability, an d hen c e d i m inish d epressive sy m pto m s. There are several potential explanations for this out c o m e, in c lu d ing the possibility that kno c king out the gene for 5-HTT fro m birth m ay have pro m ote d c o m pensatory c hanges involving other syste m s. In fa c t, treat m ent over 2 weeks by short inter-fering RNA (siRNA) m e d iate d kno c k d own of 5-HTT within the raphe nu c leus was asso c iate d with attenuate d i mm obility in a for c e d swi m test, just as the anti-d epressant, c italopra m , provoke d this out c o m e (Thakker et al ., 2005). It is of parti c ular interest that although 5-HTT kno c kout m i c e d isplaye d hypoa c tivity, there was no evi d en c e of anhe d onia (a key feature of d epression) ( K alueff et al ., 2006).
- Dennis Ougrin, Tobias Zundel, Audrey V Ng(Authors)
- 2009(Publication Date)
- CRC Press(Publisher)
7 As with those from twins studies, these findings indicate that the familial aggregation of suicidal behaviour is, in part, explained by genetic factors. Molecular genetics of suicidal behaviour More recently, evidence from adoption, twin and family studies has informed molecular studies, which have looked for specific genes implicated in the aetiology of suicidal behaviour. Candidate-based association studies have been the most commonly used approach thus far. In this approach, genes are selected on the basis that they affect biological systems that have been implicated in clinical or neurobiological studies and the extent to which they are associated with the phenotype in question is assessed. Serotonergic system The serotonergic system is the most extensively investigated neurotransmitter system in relation to suicidal behaviour. This is largely because of its role in processes central to suicidal behaviour, such as impulse control and emotional processing. Neurobiological studies have also indicated reduced central serotonergic activity in those with a history of suicidal behaviour. There is evidence of reduced cerebrospinal fluid levels of the serotonergic metabolite 5-hydroxyindole acetic acid (5-HIAA) in individuals who have attempted suicide. 8 Endocrine challenge tests of the central serotonergic system using serotonergic agonists show a blunted prolactin response in depressed patients who have attempted suicide compared with depressed patients with no such history and healthy control subjects. 9 There is also evidence of altered THE GENETICS OF SUICIDAL BEHAVIOUR 39 binding and density of serotonin receptors in the prefrontal cortex and hippocampus of suicide victims. 10 Serotonegic genes involved in synthesis, transmission, transport and breakdown of serotonin have been investigated using association studies. Serotonin transporter The serotonin transporter is responsible for the re-uptake of released serotonin from the synaptic cleft.
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