Emerging Hypothesis on Psychosis and Schizophrenia: The Role of Serotonin

Serotonin Theory of Psychosis

• Proposes hyperactivity or imbalance of serotonin, especially at serotonin 5-HT2A receptors, causes psychosis.
• Disruption may be due to:
  • Neurodevelopmental abnormalities in schizophrenia
  • Neurodegeneration in diseases like Parkinson’s

Serotonin Synthesis and Function

• Begins with tryptophan, an amino acid precursor.
• Two enzymes convert tryptophan into serotonin:
  • Tryptophan hydroxylase converts tryptophan into 5-hydroxytryptophan.
  • Aromatic amino acid decarboxylase converts 5-hydroxytryptophan into serotonin (5-HT).
• Serotonin is transported into synaptic vesicles by vesicular monoamine transporter (VMAT2).
• Broken down by monoamine oxidase when serotonin concentration is high.

Serotonin Receptors

• Over 14 known receptors, with about half having clinical relevance.
• Presynaptic Receptors:
  • 5-HT1A, 5-HT1B, and 5-HT2B regulate serotonin neuron activity.
  • Somatodendritic autoreceptors: 5-HT1A, 5-HT2B.
  • Axon terminal autoreceptor: 5-HT1BD.
• Postsynaptic Receptors:
  • Regulate other neurotransmitters via downstream effects.

Serotonin Regulation

• 5-HT1A Receptors:
  • Inhibit serotonin impulse flow on presynaptic neurons.
  • On postsynaptic neurons, can affect the release of other neurotransmitters like dopamine.
  • Important in antidepressant actions.
• 5-HT2A Receptors:
  • Excitatory, located postsynaptically, affects release of dopamine.
  • Linked to the positive symptoms of psychosis via glutamate neurons.

Postsynaptic Effects

• 5-HT1A Receptors: Inhibit or disinhibit neurotransmitter release based on location.
• 5-HT2A Receptors: Excitatory but can lead to inhibitory effects depending on neuron type.
• 5-HT2C, 5-HT3, 5-HT7 Receptors: Generally excitatory but often located on inhibitory GABA interneurons, thus leading to net inhibitory effects.

Implications in Disorders

• Parkinson's Disease: Loss of serotonin terminals leads to upregulation of 5-HT2A receptors causing psychotic symptoms.
• Dementia-Related Psychosis: Lack of inhibition on glutamate neurons causes excess stimulation leading to psychosis.

Conclusion

• Serotonin regulates not only its release but also impacts other neurotransmitter systems.
• Hyperactivity or imbalance of serotonin, particularly at 5-HT2A receptors, is linked to psychosis and conditions like schizophrenia.
• Understanding serotonin's diverse roles helps in treating psychotic symptoms across various disorders.