role of serotonin in anxiety and depression

Swati jaiswal, m.pharm ii sem Department of pharmaceutics , it-bhu:

Swati jaiswal, m.pharm ii sem D epartment of pharmaceutics , it-bhu Role of serotonin in anxiety and depression 1

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2 INTRODUCTION TO SEROTONIN Widely distributed amine (animals + plants)‏.In humans, present in GI enterochromaffin cells (90%), platelets and brain. Synthesized from tryptophan (in diet) in two steps. Tryptophan is actively taken up into neurons, converted by tryptophan hydroxylase to 5-hydroxytryptophan, and then decarboxylated by a non-specific amino acid decarboxylase to 5-HT. Availability of tryptophan and the activity of tryptophan hydroxylase are thought to be the main factors that regulate 5-HT synthesis 5-HT is degraded almost entirely by monoamine oxidase, which converts it to 5-hydroxyindole acetaldehyde, most of which is dehydrogenated to form 5-hydroxyindole acetic acid, which is excreted in the urine.

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Biosynthesis of serotonin or 5-hydroxy tryptamine

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The cell bodies are grouped in the pons and upper medulla, are often referred to as raphe nuclei . The rostrally situated nuclei project, via the medial forebrain bundle, to many parts of the cortex, hippocampus, basal ganglia, limbic system and hypothalamus . The caudally situated cells project to the cerebellum, medulla and spinal cord . 4

Receptors of 5HT:

Receptors of 5HT There are seven types (5-HT 1-7 ), with further subtypes of 5-HT 1 (A-F) and 5-HT 2 (A-C). All are G-protein-coupled receptors, except 5-HT 3 , which is a ligand-gated cation channel. 5-HT 1 receptors occur mainly in CNS (all subtypes) and some blood vessels (5-HT 1D subtype). 5-HT 1A receptors are expressed as auto receptors by the 5-HT neurons in the raphe nuclei, and their auto inhibitory effect tends to limit the rate of firing of these cells. They are also widely distributed in the limbic system, and are believed to be the main target of drugs used to treat anxiety and depression . 5-HT 1B and 5-HT 1D receptors are found mainly as presynaptic inhibitory receptors in the basal ganglia. Agonists acting on peripheral 5-HT 1D receptors are used to treat migrane . 5

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5-HT 2 receptors (mostly 5-HT 2A in the brain) exert an excitatory postsynaptic effect, and are abundant in the cortex and limbic system. 5-HT 3 receptors are found chiefly in the area postrema (a region of the medulla involved in vomiting) and other parts of the brain stem, extending to the dorsal horn of the spinal cord. specific antagonists (e.g. ondansetron ) are used to treat nausea and vomiting. They may also have anxiolytic affects, but this is less clear. 5-HT 4 receptors are important in the gastrointestinal tract and are also expressed in the brain, particularly in the striatum. They exert a presynaptic facilitatory effect, particularly on ACh release, thus enhancing cognitive performance. 6

Functional aspects of serotonin:

Functional aspects of serotonin certain physiological and behavioural functions relate particularly to 5-HT pathways ,namely:- hallucinations and behavioural changes sleep, wakefulness and mood feeding behaviour control of sensory transmission (especially pain pathways) Body temperature 7

Anxiety:

Anxiety The root meaning of the word anxiety is 'to vex or trouble‘, in either the absence or presence of psychological stress, anxiety can create feelings of fear, worry, uneasiness and dread. Anxiety is considered to be a normal reaction to stress. It may help a person to deal with a difficult situation by prompting one to cope with it. When anxiety becomes excessive, it may fall under the classification of an anxiety disorder . 8 The intensity and reasoning behind anxiety determines whether it is considered a normal or abnormal reaction .

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Physical effects of anxiety :- heart palpitations, muscle weakness and tension, fatigue, nausea, chest pain, shortness of breath, stomach aches, or headaches. The body prepares to deal with a threat, blood pressure and heart rate are increased, sweating is increased, blood flow to the major muscle groups is increased, and immune and digestive system functions are inhibited (the fight or flight response). External signs of anxiety may include pale skin, sweating, trembling, and pupillary dilation. Emotional effects :- They include "feelings of apprehension or dread, trouble concentrating, feeling tense or jumpy, anticipating the worst, irritability, restlessness watching (and waiting) for signs (and occurrences) of danger, and, feeling like your mind's gone blank" as well as "nightmares/bad dreams, obsessions about sensations, a trapped in your mind feeling, and feeling like everything is scary. Cognitive effects :- thoughts about suspected dangers, such as fear of dying. "You may...fear that the chest pains [a physical symptom of anxiety] are a deadly heart attack 9

Depression :

Depression is the most common of the affective disorders Worldwide, depression is a major cause of disability and premature death. True clinical depression is a mood disorder in which feelings of sadness, loss, anger, or frustration interfere with everyday life for a long period of time. The exact cause of depression is not known. Many researchers believe it is caused by chemical imbalances in the brain, which may be hereditary or caused by events in a person's life. 10 Depression

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11 Depression can change or distort the way people see themselves and their lives, as well as other people around them. People who have depression usually see everything with a more negative attitude, unable to imagine that any problem or situation can be solved in a positive way. Symptoms include: Agitation, restlessness, and irritability Dramatic change in appetite, often with weight gain or loss Extreme difficulty concentrating Fatigue and lack of energy Feelings of hopelessness and helplessness Feelings of worthlessness, self-hate, and inappropriate guilt Inactivity and withdrawal from usual activities, a loss of interest or pleasure in activities that were once enjoyed Thoughts of death or suicide Trouble sleeping or excessive sleeping

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12 TYPES OF DEPRESSION TYPES OF ANXIETY

ROLE OF SEROTONIN IN DEPRESSION:

ROLE OF SEROTONIN IN DEPRESSION 13

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Disorders in serotonergic activity could contribute to many of the symptoms of major depression, for example, mood, appetite, sleep, activity, suicide, and cognitive dysfunction. Interference with 5-HT synthesis or storage may induce depression in some vulnerable individuals. Abnormalities in serotonergic activity in depression could occur at one or more of several levels, for example, diminished availability of L-tryptophan (L-TRP), the precursor of 5-HT, impaired 5-HT synthesis, release, reuptake, or metabolism, or 5-HT postsynaptic receptor abnormalities. Finally, antidepressant drugs may act, in part, by enhancing central serotonergic activity. 14 Evidences to support serotonin hypothesis:-

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Serotonin, Stress, Glucocorticoids, and Corticotropin Releasing Factor Type 1 Receptors :

Serotonin, Stress, Glucocorticoids, and Corticotropin Releasing Factor Type 1 Receptors Serotonergic systems are susceptible to stress and cortisol. Acute stress causes cells in the raphe nuclei to release 5-HT, but long-term stress can deplete these stores. This depletion may be permanent. Stress may affect raphe cells through glucocorticoid receptors, which are present in the serotonergic cells and which affect the amounts and types of proteins produced by these cells. An important protein affected by glucocorticoid treatment is tryptophan hydroxylase, the enzyme that synthesizes 5-HT. 16

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Continued….. Chronic treatment with glucocorticoids reduces by six fold the amount of messenger ribonucleic acid for tryptophan hydroxylase. The projected downstream effects are less tryptophan hydroxylase protein and, thus, less 5-HT—perhaps eventually resulting in the symptoms of depression. Besides these downstream effects, the raphe nuclei also have been reported to contain CRFR-1 receptors. In rats, infusion of CRF into the raphe nucleus causes dose-dependent decreases of 5-HT release into the pleasure-related nucleus accumbens. Pretreatment with a CRFR-1 antagonist abolished this effect 17

The Serotonin Reuptake Transporter and Stress :

The Serotonin Reuptake Transporter and Stress After a raphe cell releases 5-HT , the cell uses the serotonin reuptake transporter (SERT) to recover the 5-HT for the next firing. The SERT protein is the well-known target of SSRIs and SNRIs; these drugs block cellular reuptake of 5-HT so that the neurotransmitter signal is magnified, as 5-HT remains in the synaptic cleft for longer durations. SERT gene(called SLC6A4 - Solute Carrier family 6, member 4) exhibits polymorphism - some long and some short allele. 18

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Long and short alleles differ in the length of the promoter region difference in binding area potential for regulatory proteins variability in SERT expression Gene possibilities: s/s or s/l or l/l neurons with "two longs" take up twice as much serotonin from the synaptic cleft as cells with one or two shorts People with the “s” allele may have an increased risk for depression 19

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21 Depression is not based on a simple gene or a cluster of gene. But on a gene and environment interaction both. In genetic carriers of the short form of the SERT, depression was more likely to occur when more stressful life events had occurred. There was a rough dose-response curve, with stress as the “dose” and depression as the “response.” No such relationship was observed in subjects with the genotype homozygous for the long form of the transporter. Genotype for the short-form transporter alone, however, was not sufficient to predict the onset of depression. The contribution of stress was necessary to observe the relationship.

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Another study found that the short SERT allele is associated with production of significantly higher levels of glucocorticoids. A significant interaction of the short allele and higher glucocorticoid levels was associated with smaller hippocampus volume. This relationship was stronger among short allele carriers than in noncarriers 22

ROLE OF SEROTONIN IN ANXIETY:

Definitive pathophysiologic mechanisms for anxiety have not yet been determined, but anxiety symptoms and the resulting disorders are believed to be due to disrupted modulation of several neurotransmiters (like NE, 5-HT)and neropeptides (CCK, NPY,CRF)within the central nervous system. Most commonly it is believed that an underactivation of the serotoninergic system and an overactivation of the noradrenergic system are involved in anxiety . Disruption of the gamma-aminobutyric acid (GABA) system has also been implicated because of the response of many of the anxiety-spectrum disorders to treatment with benzodiazepines. 23 ROLE OF SEROTONIN IN ANXIETY

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24 The anxiety/fear circuitry of all types of anxiety disorders is centered on the amygdala. Amygdala integrates sensory and cognitive information, and then determines whether a fear response should be triggered (including activation of the HPA axis) Amygdala-centered circuits may be over activated in specific anxiety disorder subtypes. HPA axis is also hyperactive in anxiety patients. Amygdala-centered circuits are often targets of anxiolytic medications. Serotonergic afferents project from the raphe to the amygdala and can dampen activity of the amygdala .

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Injection of an SSRI into the amygdala of animals can reduce anxious behavior, and SSRIs are used for treatment of GAD. Also it is found that agents that enhance serotonin neurotransmission may stimulate hippocampal 5-HT 1A receptors, thus promoting neuroprotection and neurogenesis and exerting an anxiolytic effect . The amygdala also contains circuitry using γ-aminobutyric acid (GABA),which normally reduces the activity of the amygdala. Injection into the amygdala of an indirect GABA agonist, such as the benzodiazepine diazepam, reduces anxious behaviors in animals, and this class of agent is widely used in the treatment of anxiety disorders. 25

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The amygdala not only activates the CRF-containing HPA axis, it also contains CRFR-1 receptors and has CRF-containing projections of its own. In animals, stress increases the concentration of CRF in the amygdala. It is observed that microinjection of CRF into the amygdala generates anxiety-like behaviors. Conversely, anxiety-like behaviors can be reduced by administering a CRF receptor antagonist into the amygdala 26

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The dorsal raphe nucleus receives CRF projections from the amygdala The raphe nuclei apparently contain CRFR-1 receptors. Infusion of low concentrations of CRF into the dorsal raphe nucleus reduces the activity of its serotonergic cells, apparently through action at the CRFR-1 receptor. Thus, a CRFR-1 antagonist could ameliorate anxiety-related dysregulation at the raphe nucleus, upstream of the effects mediated by SSRIs. 27

Evidence supporting hyperactivity of serotonergic system in anxiety:

Evidence supporting hyperactivity of serotonergic system in anxiety The advent of selective agonists and antagonists for 5-HT receptor subtypes has rekindled investigation of the role of 5-HT in anxiety mechanisms. Drugs that tend to increase 5-HT functions are anxiogenic while blockade of serotonergic neurotransmission produced anti-anxiety effects. 28

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It was shown that administration of para-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor, produced anxiolytic effects in animal tests of anxiety. Neurochemical studies on the effects of BZs on brain 5-HT metabolism also support the hypothesis because systemic administration of BZs has been reported to decrease synthesis and release of 5-HT in many regions of rat brain. Lesions of serotonergic pathways, resulting from the injection of neurotoxins 5,6 or 5,7-dihydroxytryptamine (5,7-DHT) have been reported to produce anxiolytic profiles in conflict paradigms. 29

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4. Anxiolytic behavioural effects of 5-HT-1A receptor agonists such as buspirone appear to be produced by the stimulation of presynaptic 5-HT-1A autoreceptors (somatodendritic) that inhibit the synthesis and secretion of serotonin. Alternatively, antagonists of 5-HT-1A, 5-HT-2, or 5-HT-3 receptors may exhibit anxiolytic effects by blocking postsynaptic serotonin receptors. 5. A number of commonly used antidepressants, such as amitriptyline, clomipramine and trazodone are potent antagonists of 5-HT-2A receptors and demonstrate anxiolytic effects in some animal models. 30

Schematic overview of the localization of 5-HT receptors on a hypothetical serotonergic neuron showing possible involvement of various receptor types in mediation of anxiety and depression. :

31 Schematic overview of the localization of 5-HT receptors on a hypothetical serotonergic neuron showing possible involvement of various receptor types in mediation of anxiety and depression.

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6. Early evidence from clinical trials indicated that ritanserin , a slective 5-HT-2 receptor antagonist, may be an effective anxiolytic agent and is being tested in a variety of psychiatric syndromes, including anxiety disorders. 7. It was also reported that cortical 5-HT-2A receptors are down-regulated by the long-term administration to rats a variety of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). 8. It was also found that meta- chlorophenylpiperazine (m-CPP), a metabolite of the antidepressants trazodone and nefazodone , produces axiogenic behaviour mediated by the stimulation of 5-HT-2C receptors. Blockade of 5-HT-2C receptors with selective 5-HT-2C receptor antagonists can prevent anxiogenic effects of m-CPP 32

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33 THANKYOU