Serotonin: The Neurotransmitter

CHAPTER 15: Serotonin

Outline

Serotonin, The Neurotransmitter

  • The indolealkylamine 5-hydroxytryptamine (5-HT; serotonin) was initially identified because of its effects on smooth muscle.

  • The structure of serotonin (5-HT) is hydrophilic and does not readily pass the blood-brain barrier.

  • Discovery history:

    • Mid-19th century: A vasoconstricting factor in serum was identified.

    • 1948: Rapport, Green, and Page isolated the factor and identified it as serotonin.

    • Independently, Esparmer characterized a substance (enteramine) in the gastrointestinal tract that was later identified as serotonin.

    • 1953: Detection of serotonin in brain extracts by Twarog and Page, indicating local synthesis in the brain.

  • Function:

    • 5-HT is implicated in psychiatric disorders like schizophrenia and depression.

    • Psychotherapeutic drugs target serotonergic neurons to treat various mood disorders.

Understanding the Neuroanatomical Organization of Serotonergic Neurons

  • Neuronal cell bodies for serotonin are concentrated in the raphe nuclei (brainstem), with axonal projections widespread across the central nervous system (CNS).

  • 1964: Dahlstrom and Fuxe used histofluorescence to identify nine groups of serotonin-containing cell bodies, mostly in raphe nuclei.

  • Most neurons in the dorsal raphe nucleus are nonserotonergic, with only 40-50% being serotonergic.

  • Techniques to study serotonergic innervation led to better anatomical understanding, including:

    • Immunohistochemistry for serotonin and tryptophan hydroxylase.

    • Axonal transport studies for mapping projections.

Synthesis and Storage of 5-HT

  • L-tryptophan is the precursor for synthesizing 5-HT.

  • The synthesis pathway of serotonin detailed in Figure 15-5:

    1. Tryptophan transport into the brain is facilitated, influenced by dietary sources.

    2. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) via tryptophan hydroxylase.

    3. 5-HTP is then metabolized to 5-HT by aromatic L-amino acid decarboxylase (AADC).

  • Enzymatic rates depend on substrate concentrations:

    • The Km of tryptophan hydroxylase is approximately 30-60 mM.

  • The rate-limiting step in serotonin synthesis is the hydroxylation of tryptophan, primarily impacted by tryptophan hydroxylase activity.

  • AADC functions similarly across serotonergic and catecholaminergic neurons.

Acute Synthesis Regulation

  • Serotonin synthesis can be modulated by neuronal activity, suggesting plasticity in the serotonergic system.

  • Increased synthesis is noted during electrical stimulation, linked to calcium dependence.

  • Long-term changes involve the synthesis of tryptophan hydroxylase protein, particularly after neuronal destruction (>60%).

Serotonin Release Mechanisms

  • 5-HT is primarily stored in vesicles and released via exocytotic mechanisms.

  • The release process involves the vesicular transporter and 5-HT transporters such as SERT.

  • Drugs like MDMA and fenfluramine disrupt typical release mechanisms, causing changes in serotonin concentrations.

Termination of Serotonin Activity

  • The synaptic effects of serotonin are primarily terminated by reuptake via SERT.

  • SERT is characterized as a high-affinity, low-capacity transporter, requiring sodium for function.

  • Activation of SERT is affected by membrane potential changes, and presynaptic receptor activation can enhance or inhibit transport activity.

Catabolism and Deactivation of 5-HT

  • The primary catabolic pathway for 5-HT is oxidative deamination by monoamine oxidase (MAO).

  • MAO exists in two forms: Type A and Type B, differing in substrate specificity.

  • 5-HT is primarily metabolized by type A MAO in vivo, while serotonergic neurons predominantly express type B MAO to avoid interference by its substrates.

Functional Implications of Serotonin

  • 5-HT is involved in various behaviors and can modulate neuroendocrine functions, circadian rhythms, and food intake.

  • Neuroendocrine Function:

    • Serotonin influences hormone secretion (e.g., prolactin, ACTH) and is implicated in the body's stress response.

  • Circadian Rhythmicity:

    • Serotonin serves a role in regulating biological clock mechanisms, particularly in the suprachiasmatic nucleus (SCN).

  • Feeding Behavior:

    • 5-HT appears to inhibit feeding behavior, with drugs that enhance serotonergic activity reducing food intake.

Serotonin Receptors

  • Different pharmacological and physiological studies have helped define serotonin receptor subtypes.

  • Receptors are classified based on operational parameters and molecular characteristics.

    • 5-HT Receptor Families:

    1. 5-HT1 Receptor Family:

      • Includes 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E, and 5-HT1F with roles in inhibiting adenylyl cyclase activity.

    2. 5-HT2 Receptor Family:

      • Comprises 5-HT2A, 5-HT2B, and 5-HT2C receptors involved in stimulating phospholipase C pathway.

    3. 5-HT3 Receptors:

      • Ligand-gated ion channels forming cation channels that facilitate neurotransmission.

    4. 5-HT4, 5-HT6, and 5-HT7 receptors:

      • Coupled to stimulation of adenylyl cyclase, increasing cAMP levels.

  • Notable pharmacological agents targeting these receptors facilitate a range of clinical effects and applications in mood disorders.

Gene Polymorphisms and Mental Illness

  • Genetic variations in serotonin receptors, such as the 5-HT1A polymorphism, are associated with predispositions to various psychiatric disorders. Research suggested that the G allele variant of the 5-HT1A receptor gene may result in lower serotonergic activity, correlating with higher depression and anxiety symptoms.

References

  • Comprehensive references detail the study and findings surrounding serotonin's role as a neurotransmitter, its synthesis pathways, receptors, and connections to psychological health.