listened serotonin receptors peterson

Serotonin Receptors

Introduction

Instructor: Cristina Peterson, PhD, Adjunct Assistant Professor, U of M College of Pharmacy
Course: PHAR 6541 Block 4

Learning Objectives

Understand and identify serotonin receptors
Understand properties of serotonin neurons
Identify serotonin projection systems
Understand serotonin targeting in antipsychotic pharmacotherapy
Understand the effects of lithium

Significance of Serotonin

Serotonin signaling mediates:
  - Appetite
  - Sleep
  - Memory
  - Pain
  - Sexual activity
  - Cardiovascular function
  - Hormone secretion
  - Temperature regulation
Serotonin dysfunction contributes to:
  - Anxiety
  - Depression
  - Panic disorders
  - Obsessive-compulsive disorder (OCD)
  - Schizophrenia
  - Social phobia
  - Suicide
  - Violent aggressive behavior
  - Migraine
  - Hypertension
  - Eating disorders
  - Irritable bowel syndrome

Outline of Key Topics

Serotonin Receptors
Serotonin Neurons
Serotonin Projection Systems
Serotonin Disorders and Therapeutics
Lithium

Serotonin Receptors

Overview of Serotonin Receptors

At least fourteen serotonin (5-HT) receptor subtypes identified.
Grouped based on genetic sequences and second messenger systems:
  - Five (5) different 5-HT1 receptors:
    - 5-HT1A
    - 5-HT1B
    - 5-HT1D
    - 5-HT1E
    - 5-HT1F
  - Three (3) 5-HT2 receptors:
    - 5-HT2A
    - 5-HT2B
    - 5-HT2C
  - Additional receptors:
    - 5-HT3
    - 5-HT4
    - 5-HT5A
    - 5-HT5B (not expressed in humans)
    - 5-HT6
    - 5-HT7
All 5-HT receptors are metabotropic except for 5-HT3, which is an excitatory ionotropic receptor.

G Protein-Coupled Receptors (GPCRs)

GPCR Structure:
- Seven membrane-spanning segments.
- Amino (N) terminal is extracellular; carboxyl (C) terminal is intracellular.
G-Proteins:
- Composed of three subunits: α, β, and γ; the βγ subunit anchors the protein in the membrane.
- Classified functionally into several classes, known as Gαs and Gαi.

Specific Serotonin Receptors

5-HT1A

Type: Inhibitory GPCR
Coupled to inhibitory G-proteins (Gi/o).
Functions:
  - Inhibitory effect on neurotransmission when bound by an agonist.
  - Inhibits cAMP production.
  - Activates K+ channel opening leading to increased channel conductance.

5-HT2A

Type: Stimulatory GPCR
Coupled to Gq proteins.
Functions:
- Increases intracellular Ca2+.
- Stimulates protein kinase C (PKC) via the phosphoinositide system (PLC/PIP2).

5-HT2C

Type: Stimulatory GPCR
Coupled to Gq proteins.
Functions:
- Increases intracellular Ca2+.
- Stimulates PKC via the phosphoinositide system (PLC/PIP2).

5-HT3

Type: Excitatory Ligand-Gated Ion Channel.
Functions:
- Red arrow indicates stimulation of the receptors leading to excitatory responses.

Summary of 5-HT Receptors

Receptor Type	Distribution	Effector Mechanism
5-HT1A	Hippocampus, amygdala, septum, entorhinal cortex, hypothalamus, raphe nuclei	Inhibition of adenylyl cyclase, opening of K+ channels
5-HT2A	Cerebral cortex, claustrum, olfactory tubercle, striatum, nucleus accumbens	Stimulation of phosphoinositide-specific phospholipase C
5-HT2C	Choroid plexus, globus pallidus, spinal cord	Stimulation of phosphoinositide-specific phospholipase C
5-HT3	Hippocampus, entorhinal cortex, various cranial nerves	Ligand-gated cation channel

Serotonin Neurons

Synthesis

Key Compounds in Synthesis:
  - 5HT: 5-hydroxytryptamine
  - 5HTP: 5-hydroxytryptophan
  - TRY-OH: Tryptophan Hydroxylase
  - AAADC: Aromatic Amino Acid Decarboxylase
  - VMAT2: Vesicular Monoamine Transporter 2

Degradation

Mechanism:
- Serotonin is terminated through reuptake by the serotonin transporter (SERT) or destruction by monoamine oxidase (MAO-B).
- MAO-A or B destroys serotonin (5-HT) at high concentrations.

Model of a Synapse

Components include:
  - Tryptophan
  - Tryptophan hydroxylase
  - 5-Hydroxy-Tryptophan
  - Vesicular monoamine transporter
  - 5-Hydroxy-Tryptamine (5-HT)
  - Aromatic amino acid decarboxylase
  - Synaptic cleft and postsynaptic neuron interactions.

Receptor Distribution

5-HT system components are localized pre- and postsynaptically to 5-HT neurons and on glial cells, influencing a range of CNS disorders such as anxiety, depression, addiction, learning and memory, and obesity.

Serotonin Projection Systems

Overview

Most serotonin neurons have their cell bodies in the midline of the brain stem, specifically in the raphe nuclei, and project to various parts of the CNS.

Caudal Raphe Nucleus

Represents 15% of the population of serotonergic neurons.
Origin: Caudal Raphe Nucleus
Termination: Medulla, Cerebellum, and descends into the spinal cord via anterior and lateral raphespinal tracts.
Physiology: Regulates the release of enkephalins and nociception.

Median Raphe Nucleus

Origin: Median Raphe Nucleus
Termination: Ventral tegmental area (VTA), hypothalamus, cerebral cortex, and hippocampus.
Notable Physiology: Important for long-term memory formation through projections to the hippocampus.

Dorsal Raphe Nucleus

Comprises 85% of 5-HT neurons in the brain.
Origin: Extends from oculomotor nucleus to the middle of the pons.
Termination: Cerebral cortex, substantia nigra, hippocampus, and pons.
Notable Physiology: Involved in a variety of functions including learning, memory, and affect; extensively studied in depression.

Heterogeneous Populations

Serotonin neurons share locations but have distinct functions; therapeutic development emphasizes targeting specific neuronal populations related to disorders.
Altering serotonin levels can lead to serious side effects including cardiorespiratory dysfunction, hyperthermia, and mental health effects.

Serotonin Outside the CNS

In addition to central functions, serotonin influences vascular biology, blood pressure, and hemostasis.
Notably contributes to vasoconstriction or vasodilation, depending on receptor expressions in blood vessel walls.
Approximately 90% of the body's serotonin is produced in the digestive tract.
Peripheral serotonin levels can be linked to disorders such as irritable bowel syndrome and cardiovascular diseases.

Serotonin Disorders and Therapeutics

Serotonin Receptors as Drug Targets

Serotonin receptors serve as therapeutic targets due to their extensive expression and regulation of various physiological functions.

Examples of Pharmacotherapy

Sumatriptan (Imitrex): Used for migraines (5HT1F, 1B, 1D receptors)
SSRIs: Utilized for depression.
MAOIs: Used in depression therapy.
Ondansetron (Zofran): Targets nausea (5HT3 receptor).

Serotonin Hypothesis of Schizophrenia

Schizophrenia involves both environmental and genetic factors.
Key Definitions:
- Psychotic disorder: Characterized by delusions or hallucinations.
- Psychotomimetic: Drugs inducing altered perceptions mimicking psychosis.
Research includes LSD as an agonist at 5HT2 receptors, which acts as a model for schizophrenia psychosis, highlighting receptor abnormalities.

5HT2A Localization and Impact

High density of 5-HT2A receptors found in the cerebral cortex and other brain areas, implicating their role in depression treatment.
Some antidepressants, e.g., trazodone, are antagonists of the 5-HT2A receptor, enhancing sleep quality via prolonged slow-wave sleep.

Antipsychotic Drug Principles

Include blockade of 5-HT2A receptors in treatment protocols for schizophrenia.
First-generation antipsychotics mainly block D2 dopamine receptors but cause serious movement-related adverse effects.
Second-generation antipsychotic drugs (e.g., clozapine, risperidone) block both D2 and 5-HT2A receptors, resulting in lower EPS side effects.
Aripiprazole (Abilify) is noted for its unique pharmacological action, potentially being a third-generation drug.

Extrapyramidal Side Effects (EPS)

EPS arise due to disruptiveness in the Extrapyramidal System, affecting posture and muscle tone.
Symptoms lead to reduced quality of life, potentially causing treatment abandonment and disease relapse.
Observed in various medications, notably those blocking D2 receptors and SSRIs.

Mechanism

EPS associated mainly with D2 receptor antagonism in pathways related to movement regulation.

Lithium Treatment

Overview of Lithium

Key Historical Use:
- Found effective for treating mania and introduced in 1949.
- Considered a first-line treatment for bipolar disorder, aiding in mood stabilization and reducing suicidality risks.

Mechanism of Action

Macro-level: Influences mood and cognition, stabilizing manic and depressive states.
Micro-level: Modulates neurotransmission; specifically:
  - Decreases excitatory neurotransmission via inhibition of dopamine
  - Enhances GABAergic activity
  - Regulates second messenger systems, impacting neuroprotective mechanisms and oxidative defenses.

Summary of Key Takeaways

There exists a wide array of serotonin receptors with disparate signaling mechanisms.
Serotonin is produced in the raphe nucleus with neurons projecting throughout the brain and spinal cord.
A significant portion of serotonin is produced peripherally.
Pharmacological examples such as Aripiprazole illustrate the multifaceted targeting of serotonin in treatment.
Lithium confirms its position as a first-line treatment through a distinct mechanism enhancing inhibitory signal pathways.

Study Suggestions/Highlights

Identify serotonin receptor subtypes and their signaling cascades.
Identify major serotonin projection systems.
Explain the dual targeting of serotonin and dopamine receptors by antipsychotic therapeutics.
Understand lithium’s broad mechanism of action in mood stabilization.

Conclusion

The study of serotonin, its receptors, and related pharmacotherapies underscores its complex role shaping various mental health conditions and treatment strategies.