Showing papers on "Serotonin published in 2004"

Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice

Abstract: Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

Tryptophan hydroxylase-2 controls brain serotonin synthesis.

Abstract: Dysregulation of brain serotonin contributes to many psychiatric disorders. Tryptophan hydroxylase-2 (Tph2), rather than Tph1, is preferentially expressed in the brain. We report a functional (C1473G) single-nucleotide polymorphism in mouse Tph2 that results in the substitution of Pro447 with Arg447 and leads to decreased serotonin levels in PC12 cells. Moreover, in BALB/cJ and DBA/2 mice that are homozygous for the 1473G allele, brain serotonin tissue content and synthesis are reduced in comparison to C57Bl/6 and 129X1/SvJ mice that are homozygous for the 1473C allele. Our data provide direct evidence for a fundamental role of Tph2 in brain serotonin synthesis.

Central monoamines and their role in major depression

Abstract: The role of the monoamines serotonin and noradrenaline in mental illnesses including depression is well recognized. All antidepressant drugs in clinical use increase acutely the availability of these monoamines at the synapse either by inhibiting their neuronal reuptake, inhibiting their intraneuronal metabolism, or increasing their release by blocking the alpha(2) auto- and heteroreceptors on the monoaminergic neuron. This acute increase in the amount of the monoamines at the synapse has been found to induce long-term adaptive changes in the monoamine systems that end up in the desensitization of the inhibitory auto- and heteroreceptors including the presynaptic alpha(2) and 5-HT(1B) receptors and the somatodendritic 5-HT(1A) receptors located in certain brain regions. The desensitization of these inhibitory receptors would result in higher central monoaminergic activity that coincides with the appearance of the therapeutic response. These adaptive changes responsible for the therapeutic effect depend on the availability of the specific monoamine at the synapse, as depletion of the monoamines will either reverse the antidepressant effect or causes a relapse in the state of drug-free depressed patient previously treated with antidepressant drugs. Furthermore, blocking the somatodendritic 5-HT(1A) or nerve terminal alpha(2) receptors proved to increase the response rate in the treatment of major and treatment-resistant depression, providing further support to the assumption that the antidepressant effect results from the long-term adaptive changes in the monoamine auto- and heteroregulatory receptors. On the other hand, the chronic treatment with antidepressants resulted in D(2) receptors supersensitivity in the nucleus accumbens. This supersensitivity might play a role in the mechanisms underlying antidepressant induced mood switch and rapid cycling.

The therapeutic role of 5-HT1A and 5-HT2A receptors in depression.

Abstract: The selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs, because they are well tolerated and have no severe side effects. They rapidly block serotonin (5-HT) reuptake, yet the onset of their therapeutic action requires weeks of treatment. This delay is the result of presynaptic and postsynaptic adaptive mechanisms secondary to reuptake inhibition. The prevention of a negative feedback mechanism operating at the 5-HT autoreceptor level enhances the neurochemical and clinical effects of SSRIs. The blockade of 5-HT2A receptors also seems to improve the clinical effects of SSRIs. These receptors are located postsynaptically to 5-HT axons, mainly in the neocortex. Pyramidal neurons in the prefrontal cortex are particularly enriched in 5-HT2A receptors. Their blockade may affect the function of prefrontal–subcortical circuits, an effect that probably underlies the beneficial effects of the addition of atypical antipsychotic drugs, which are 5-HT2A receptor antagonists, to SSRIs in treatment-resistant patients.

Serotonin transporter: gene, genetic disorders, and pharmacogenetics.

Abstract: The highly evolutionarily conserved serotonin transporter (SERT) regulates the entire serotoninergic system and its receptors via modulation of extracellular fluid serotonin concentrations. Differences in SERT expression and function produced by three SERT genes and their variants show associations with multiple human disorders. Screens of DNA from patients with autism, ADHD, bipolar disorder, and Tourette's syndrome have detected signals in the chromosome 17q region where SERT is located. Parallel investigations of SERT knockout mice have uncovered multiple phenotypes that identify SERT as a candidate gene for additional human disorders ranging from irritable bowel syndrome to obesity. Replicated studies have demonstrated that the SERT 5'-flanking region polymorphism SS genotype is associated with poorer therapeutic responses and more frequent serious side effects during treatment with antidepressant SERT antagonists, namely, the serotonin reuptake inhibitors (SRIs).

Co-expression and In Vivo Interaction of Serotonin1A and Serotonin2A Receptors in Pyramidal Neurons of Prefrontal Cortex

Abstract: The prefrontal cortex plays a key role in the control of higher brain functions and is involved in the pathophysiology and treatment of schizophrenia Here we report that ∼60% of the neurons in rat and mouse prefrontal cortex express 5-HT1A and/or 5-HT2A receptor mRNAs, which are highly co-localized (∼80%) The electrical stimulation of the dorsal and median raphe nuclei elicited 5-HT1A-mediated inhibitions and 5-HT2A-mediated excitations in identified pyramidal neurons recorded extracellularly in rat medial prefrontal cortex (mPFC) Opposite responses in the same pyramidal neuron could be evoked by stimulating the raphe nuclei at different coordinates, suggesting a precise connectivity between 5-HT neuronal subgroups and 5-HT1A and 5-HT2A receptors in pyramidal neurons Microdialysis experiments showed that the increase in local 5-HT release evoked by the activation of 5-HT2A receptors in mPFC by DOI (5-HT2A/2C receptor agonist) was reversed by co-perfusion of 5-HT1A agonists This inhibitory effect was antagonized by WAY-100635 and the prior inactivation of 5-HT1A receptors in rats and was absent in mice lacking 5-HT1A receptors These observations help to clarify the interactions between the mPFC and the raphe nuclei, two key areas in psychiatric illnesses and improve our understanding of the action of atypical antipsychotics, acting through these 5-HT receptors

The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression.

Abstract: The mechanisms by which administration of interferon-alpha induces neuropsychiatric side effects, such as depressive symptoms and changes in cognitive function, are not clear as yet. Direct influence on serotonergic neurotransmission may contribute to these side effects. In addition, the enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan into kynurenine, may play an important role, first, because IDO activation leads to reduced levels of tryptophan, the precursor of serotonin (5-HT), and thus to reduced central 5-HT synthesis. Second, kynurenine metabolites such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brain function. 3-OH-KYN is able to produce oxidative stress by increasing the production of reactive oxygen species (ROS), and QUIN may produce overstimulation of hippocampal N-methyl-D-aspartate (NMDA) receptors, which leads to apoptosis and hippocampal atrophy. Both ROS overproduction and hippocampal atrophy caused by NMDA overstimulation have been associated with depression.

Interaction Between Serotonin Transporter Gene Variation and Rearing Condition in Alcohol Preference and Consumption in Female Primates

Abstract: Background Serotonin neurotransmission and limbic-hypothalamic-pituitary-adrenal (LHPA) axis hormones are thought to be involved in the reinforcement of alcohol intake and contribute to the risk for alcoholism. In humans and macaques, a promoter polymorphism that decreases transcription of the serotonin transporter gene is associated with anxiety and altered LHPA-axis responses to stress, and in female macaques, exposure to early-life stress alters LHPA-axis activation in response to alcohol. We wanted to determine whether serotonin transporter gene promoter variation (rh-5HTTLPR) and rearing condition would interact to influence alcohol preference in female rhesus macaques. Because of the involvement of stress and LHPA-axis activity in symptoms of withdrawal and relapse, we also wanted to determine whether serotonin transporter gene variation and rearing condition would influence changes in the patterns of alcohol consumption across a 6-week alcohol consumption paradigm. Methods Female macaques were reared with their mothers in social groups (n = 18) or in peer-only groups (n = 14). As young adults, they were given access to an aspartame-sweetened 8.4% alcohol solution and vehicle for 1 hour per day, and volumes of consumption of alcoholic and nonalcoholic solutions were recorded. Serotonin transporter genotype ( l/l and l/s ) was determined using polymerase chain reaction followed by gel electrophoresis. Results We found interactions between rearing condition and serotonin transporter genotype, such that l/s peer-reared females demonstrated higher levels of ethanol preference. We also found an effect of rearing condition on the percentage change in alcohol consumed during the 6 weeks as well as a phase by rearing interaction, such that peer-reared animals progressively increased their levels of consumption across the course of the study. This was especially evident for peer-reared females with the l/s rh5-HTTLPR genotype. Conclusion These data suggest a potential interaction between serotonin transporter gene variation and early experience in vulnerability to alcoholism.

The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release.

Abstract: The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is stored at peripheral sites in mast cells and released from this peripheral source upon IgE cross-linking. In this study, we investigated the expression of serotoninergic receptors (5-HTR), the signaling pathway, and biological activity of 5-HT on human dendritic cells (DC), showing that immature and mature DC expressed mRNA for different serotoninergic receptors. Thereby, the mRNA of 5-HTR(1B), 5-HTR(1E), 5-HTR(2A), 5-HTR(2B), one splicing variant of the 5-HTR(3), 5-HTR(4), and 5-HTR(7) receptors were detected. Immature DC preferentially expressed mRNA for the heptahelical 5-HTR(1B), 5-HTR(1E), and 5-HTR(2B) receptors, while mature DC mostly expressed 5-HTR(4) and 5-HTR(7). The mRNA expression level of the ligand-gated cation channel 5-HTR(3) and the heptahelical 5-HTR(2A) did not significantly change during maturation. Isotype-selective receptor agonists allowed us to show that 5-HT stimulated 5-HTR(3)-dependent Ca(2+) influx in immature and mature DC. Moreover, we revealed that 5-HTR(1) and 5-HTR(2) receptor stimulation induced intracellular Ca(2+) mobilization via G(i/o) proteins in immature, but not mature, DC. Activation of 5-HTR(4) and 5-HTR(7) induced cAMP elevation in mature DC. Functional studies indicated that activation of 5-HTR(4) and 5-HTR(7) enhanced the release of the cytokines IL-1beta and IL-8, while reducing the secretion of IL-12 and TNF-alpha in mature DC. In summary, our study shows that 5-HT stimulated, in a maturation-dependent manner, different signaling pathways in DC. These data point to a role for 5-HT in regulating the immune response at peripheral sites.

5-HT2 receptors.

Abstract: 5-HT(2) receptors are G-protein coupled receptors that currently comprise three subtypes: 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. The subtypes are related in their molecular structure, amino acid sequence and signaling properties. 5-HT(2A) and 5-HT(2C) receptors have a widespread distribution and function in the central nervous system. 5-HT(2A)and 5-HT(2C) receptor antagonism is a property of certain antipsychotic and antidepressant drugs. 5-HT(2B) receptors have a restricted expression in the central nervous system. They have an important role in embryogenesis and in the periphery. In this article, selected aspects of 5-HT(2) receptor research are reviewed for each subtype under three main headings : (i) genes, protein structure and receptor signaling; (ii) receptor localization with emphasis on the CNS and (iii) compounds. The general discussion reflects on the reasons for the limited success in the clinic of 5-HT(2) receptor subtype selective drugs.

Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women

Abstract: Background and aims: Serotonin (5-hydroxtryptamine, 5-HT) is an important factor in gut function, playing key roles in intestinal peristalsis and secretion, and in sensory signalling in the brain-gut axis. Removal from its sites of action is mediated by a specific protein called the serotonin reuptake transporter (SERT or 5-HTT). …

Serotonin in pain and analgesia: actions in the periphery.

Abstract: The purpose of this article is to summarize recent findings on the role of serotonin in pain processing in the peripheral nervous system. Serotonin (5-hydroxtryptamine [5-HT]) is present in central and peripheral serotonergic neurons, it is released from platelets and mast cells after tissue injury, and it exerts algesic and analgesic effects depending on the site of action and the receptor subtype. After nerve injury, the 5-HT content in the lesioned nerve increases. 5-HT receptors of the 5-HT3 and 5-HT2A subtype are present on C-fibers. 5-HT, acting in combination with other inflammatory mediators, may ectopically excite and sensitize afferent nerve fibers, thus contributing to peripheral sensitization and hyperalgesia in inflammation and nerve injury.

Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor.

Abstract: OBJECTIVE: The authors used magnetic resonance spectroscopy (MRS) to assess the effect of acute administration of the selective serotonin reuptake inhibitor (SSRI) citalopram on cortical levels of γ-aminobutyric acid (GABA). METHOD: Ten healthy volunteers received either intravenous citalopram (10 mg) or saline in a randomized, double-blind, crossover design. The occipital GABA/creatine ratio was measured with a proton MR spectral editing technique. RESULTS: In comparison with saline, citalopram produced a mean increase of 35% in relative brain GABA concentration in the occipital cortex. CONCLUSIONS: These findings extend previous work showing that SSRI treatment increases cortical GABA in depressed patients and suggest that this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement.

Differential Expression of 5HT-1A, α1b Adrenergic, CRF-R1, and CRF-R2 Receptor mRNA in Serotonergic, γ-Aminobutyric Acidergic, and Catecholaminergic Cells of the Rat Dorsal Raphe Nucleus

Abstract: The dorsal raphe nucleus (DR) contains the highest concentration of serotonin neurons in the brain and has extensive ascending projections that innervate most forebrain structures (Steinbusch, 1981). These projection neurons have been shown to regulate a wide variety of physiological responses and behaviors, including sleep–wake states, feeding, nociception, neuroendocrine responses, and motor activities (Jacobs and Azmitia, 1992). In addition, increasing evidence has implicated serotonin in affective conditions, such as depression and anxiety (Kahn et al., 1988; Graeff et al., 1996). However, the DR is not a homogeneous structure, and serotonin neurons have been classified into subpopulations according to their electrophysiological properties in behaving animals. For example, the activity of type I neurons that make up the majority of serotonergic neurons is correlated with the degree of behavioral arousal and motor activity (Jacobs and Fornal, 1999). In contrast, the firing rate of the small group of type II serotonergic neurons, found at the caudal interface of the DR and median raphe nucleus, does not correlate with changes in arousal or activity (Rasmussen et al., 1984). Although substantial numbers of DR neurons contain serotonin, many other neurotransmitters are also present, including γ-aminobutyric acid (GABA), dopamine, glutamate, and corticotropin-releasing factor (CRF), and the distribution of cellular neurochemical phenotypes varies across the rostral-caudal extent of the nucleus (Gamrani et al., 1979; Stratford and Wirtshafter, 1990; Jacobs and Azmitia, 1992; Commons et al., 2003). In addition, both afferent and efferent projections exhibit a distinct topographic arrangement (Kohler and Steinbusch, 1982; Van Bockstaele et al., 1993; Peyron et al., 1996, 1998). Together these observations are consistent with the idea that distinct regions of the DR may subserve different functions. Experimental support for this idea has recently been obtained with the animal model of learned helplessness. In this model, animals that experience uncontrollable shock exhibit a behavioral profile different from that of animals that have control over and can escape an equivalent shock, including an interference with subsequent escape behavior (Overmier and Seligman, 1967; Irwin et al., 1980), increased conditioned fear responses (Osborne et al., 1975), and increased anxiety (Short and Maier, 1993). Converging evidence suggests that the expression of learned helplessness following an uncontrollable stressor requires activation of the serotonergic neurons of the DR, specifically, in the caudal half of the nucleus, and interventions that reduce that activation prevent the development and/or expression of learned helplessness behaviors (Maier et al., 1993, 1994, 1995; Maswood et al., 1998; Grahn et al., 1999; Greenwood et al., 2003). Administration of CRF into the caudal, but not rostral, DR impeded escape behavior and increased conditioned fear in a manner similar to uncontrollable stress (Hammack et al., 2002). Furthermore, the behavioral consequences of exposure to uncontrollable shock were prevented by administration of a CRF receptor antagonist into the DR before exposure to the shock (Hammack et al., 2002). Use of more selective agonists and antagonists revealed that these effects were due to activation of the CRF-R2 receptor (Hammack et al., 2003). Consistent with these effects is the observation that CRF increases serotonergic activity in a subpopulation of cells in the caudal DR (Lowry et al., 2000). In contrast, the activity of serotonergic cells in the rostral to mid-DR is reportedly inhibited by CRF (Kirby et al., 2000). Despite the growing evidence for rostral-caudal and dorsal-ventral variations in DR responses, relatively little is known about the relative distribution and colocalization patterns of neurotransmitters and receptors in the DR. The present dual in situ hybridization study was therefore carried out to assess whether there was a rostral-caudal difference in the distribution of mRNA encoding the CRF receptors (types 1 and 2) in the DR and to determine whether they are expressed in serotonergic, GABAergic, or catecholaminergic neurons. In addition, the distribution and colocalization pattern of the α1b adrenergic receptor (α1b ADR) mRNA was determined, because noradrenergic afferents to the DR exert a tonic excitatory effect on serotonergic neurons of the DR through an α1 ADR mechanism (Baraban and Aghajanian, 1980a,b, 1981; Yoshimura et al., 1985), intra-DR administration of a selective α1 ADR antagonist prevents the behavioral consequences of uncontrollable stress exposure (Grahn et al., 2002), and mRNA for the α1b subtype is highly expressed in the rat DR (Day et al., 1997). Finally, the colocalization pattern of serotonin 1A (5HT-1A) receptor mRNA was determined, because this autoreceptor plays a vital role in the direct inhibition of serotonergic activity (Sprouse and Aghajanian, 1987), because its activation can prevent and reverse the enhancement of fear conditioning and interference with escape produced by exposure to inescapable shock (Maier et al., 1995), and because its expression on nonserotonergic neurons has been reported recently (Kirby et al., 2003). The distribution of mRNA encoding these receptors in serotonergic, GABAergic, and catecholaminergic neurons at four rostral-caudal levels, and dorsal, ventral, and lateral divisions of the DR is described. The differential distribution patterns observed provide additional evidence that the DR has a functional topographic organization.

Prefrontal cortical projections to the rat dorsal raphe nucleus: Ultrastructural features and associations with serotonin and γ‐aminobutyric acid neurons

Abstract: Studies of human brain indicate that both the ventromedial prefrontal cortex (PFC) and the dorsal raphe nucleus (DRN) may be dysfunctional in major depressive illness, making it important to understand the functional interactions between these brain regions. Anatomical studies have shown that the PFC projects to the DRN, although the synaptic targets of this excitatory pathway have not yet been identified. Electrophysiological investigations in the rat DRN report that most serotonin neurons are inhibited by electrical stimulation of the PFC, suggesting that this pathway is more likely to synapse onto neighboring γ-aminobutyric acid (GABA) neurons than onto serotonin cells. We tested this hypothesis by electron microscopic examination of DRN sections dually labeled for biotin dextran amine anterogradely transported from the PFC and immunogold-silver labeling for tryptophan hydroxylase (TrH) or for GABA. In the DRN, the majority of PFC axons either synapsed onto unlabeled dendrites or failed to form detectable synapses in single sections. Other PFC axons synapsed onto either TrH- or GABA-immunolabeled processes. Considerably more tissue sampling was necessary to detect PFC synapses onto TrH- than onto GABA-labeled dendrites, suggesting that the latter connections are more common. In other cases, PFC terminals and TrH- or GABA-immunoreactive dendrites either were closely apposed, without forming detectable synapses, or were separated by glial processes. These results provide potential anatomical substrates whereby the PFC can both directly and indirectly regulate the activity of serotonin neurons in the DRN and possibly contribute to the pathophysiology of depression. J. Comp. Neurol. 468:518–529, 2004. © 2003 Wiley-Liss, Inc.

Serotonergic Regulation of Membrane Potential in Developing Rat Prefrontal Cortex: Coordinated Expression of 5-Hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 Receptors

Abstract: The developing prefrontal cortex receives a dense serotonergic innervation, yet little is known about the actions of serotonin [5-Hydroxytryptamine (5-HT)] in this region during development. Here, we examined the developmental regulation of 5-HT receptors controlling the excitability of pyramidal neurons of this region. Using whole-cell recordings in in vitro brain slices, we identified a dramatic shift in the effects of 5-HT on membrane potential during the postnatal developmental period. In slices derived from young animals [postnatal day (P) 6 to P19], administration of 5-HT elicits a robust depolarization of layer V pyramidal neurons, which gradually shifts to a hyperpolarization commencing during the third postnatal week. This progression is the result of coordinated changes in the function of 5-HT7 and 5-HT2A receptors, which mediate different aspects of the depolarization, and of 5-HT1A receptors, which signal the late developing hyperpolarization. The loss of the 5-HT7 receptor-mediated depolarization and the appearance of the 5-HT1A receptor-mediated hyperpolarization appears to reflect changes in receptor expression. In contrast, the decline in the 5-HT2A receptor depolarization with increasing age was associated with changes in the effectiveness with which these receptors could elicit a membrane depolarization, rather than loss of the receptors per se. Together, these results outline coordinated changes in the serotonergic regulation of cortical excitability at a time of extensive synaptic development and thus suggest a key role for these receptor subtypes in the postnatal development of the prefrontal cortex.

5-HT1 receptors.

Abstract: Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. The genes encoding 5-HT(1) receptors have been cloned in both human and rodents, allowing the demonstration that they all belong to the G-protein-coupled receptor super-family with the characteristic 7 hydrophobic (transmembrane) domain-containing amino acid sequence. All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels. Probes derived from the knowledge of amino acid sequence of the receptor proteins and of nucleotide sequence of their encoding mRNAs allowed the mapping of all the 5-HT(1) receptor types in the central nervous system and other tissues. For the last twenty years, both pharmacological investigations with selective agonists and antagonists and phenotypical characterization of knock-out mice have been especially informative regarding the physiological implications of 5-HT(1) receptor types. This research ends notably with the development of triptans, whose agonist activity at 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptors underlies their remarkable efficacy as antimigraine drugs. Clear-cut evidence of the implication of 5-HT(1) receptors in anxiety- and depression-like behaviours and cognitive performances in rodents should hopefully promote research toward development of novel drugs with therapeutic potential in psychopathological and dementia-related diseases.

The serotonergic system and anxiety.

Abstract: The wide use of serotonin reuptake inhibitors and serotonin receptor agonists in anxiety disorders has suggested a key role for the modulatory neurotransmitter in anxiety. However, serotonin's specific role is still uncertain. This article reviews the literature concerning how and where serotonergic agents modulate anxiety. Varying and sometimes conflicting data from human and animal studies argue for both anxiolytic and anxiogenic roles for serotonin, depending on the specific disorder, structure, or behavioral task studied. However, recent data from molecular genetic studies in the mouse point toward two important roles for the serotonin 1A receptor. In development, serotonin acts through this receptor to promote development of the circuitry necessary for normal anxiety-like behaviors. In adulthood, serotonin reuptake inhibitors act through the same receptor to stimulate neurogenesis and reduce anxiety-like behaviors. These studies highlight that the complex serotonin system likely plays various roles in the regulation of anxiety both during development and in adulthood.