4c: The Serotonin Hypothesis of Psychosis and Schizophrenia

Overview of the Serotonin Hypothesis of Psychosis

• The third emerging hypothesis concerning psychosis and schizophrenia involves serotonin ($5\text{-HT}$) and its activity.

• The serotonin theory of psychosis proposes that hyperactivity, or a significant imbalance of serotonin—specifically at the serotonin $5\text{-HT}_{2A}$ receptors—is a direct cause of psychosis.

• Disruption of serotonin functioning that results in positive symptoms of psychosis can be attributed hypothetically to:

  • Neurodevelopmental abnormalities in schizophrenia.

  • Neurodegeneration in diseases such as Parkinson's Disease (hallucinations).

  • Excessive activity or imbalance within serotonin pathways.

Serotonin Synthesis and Metabolism

• Synthesis Pathway:

  • The process begins with the amino acid tryptophan, which is transported into the brain from the plasma.

  • Tryptophan acts as the precursor for serotonin synthesis through two enzymatic steps:

    1. Tryptophan Hydroxylase: This enzyme converts tryptophan into $5\text{-hydroxytryptophan}$ ($5\text{-HTP}$).

    2. Aromatic Amino Acid Decarboxylase (also known as $5\text{-HTP decarboxylase}$): This enzyme converts $5\text{-HTP}$ into serotonin ($5\text{-HT}$).

• Storage and Transport:

  • Once synthesized, serotonin is taken up into synaptic vesicles by the Vesicular Monoamine Transporter 2 ($VMAT2$).

  • The presynaptic Serotonin Transporter Pump ($SERT$) terminates serotonin actions by pumping neurotransmitters back into the nerve from the synaptic cleft.

  • After reuptake, serotonin is again taken up by $VMAT2$ and returned to vesicles for future neurotransmission.

• Degradation:

  • Serotonin action is terminated when it is destroyed by the enzyme Monoamine Oxidase ($MAO$), converting it into an inactive metabolite.

  • Serotonin neurons specifically contain $MAO-B$, which has a low affinity for serotonin. Consequently, serotonin is primarily broken down by this enzyme only when intracellular concentrations are exceptionally high.

• Genetic Considerations:

  • Unlike dopamine neurons (some of which lack dopamine transporters), all known serotonin neurons contain serotonin transporters ($SERT$).

  • There are functional polymorphisms in the genes coding for $SERT$, which are a major point of research interest. These polymorphisms can alter the amount of serotonin in the synapse and may predict:

    • The likelihood of a patient responding to treatment.

    • The probability of a patient experiencing side effects from drugs that block the serotonin transporter.

Serotonin Receptors and Neuronal Distribution

• Receptor Diversity:

  • There are approximately $14$ known serotonin receptor subtypes (more than a dozen).

  • At least half of these receptors are known to have clinical relevance, while others are still being researched.

• Receptor Localization:

  • All serotonin receptors are located postsynaptically.

  • Only a few specific receptors are located on the serotonin neuron itself (presynaptically).

• Presynaptic Receptors (Autoreceptors):

  • Serotonin neurons differ from norepinephrine and dopamine neurons because dopamine and norepinephrine neurons have receptors on their dendrites, soma, and terminals. Serotonin neurons have specific distributions for their three presynaptic receptors:

  • Somatodendritic Autoreceptors: Located on the cell body and dendrites.

    1. $5\text{-HT}_{1A}$: When serotonin is released somatodendritically and binds here, it causes a shutdown of serotonin impulse flow, reducing or blocking the release of serotonin into the synaptic space.

    2. $5\text{-HT}_{2B}$: Binding at this site causes an increase in serotonin impulse flow, increasing electricity and the subsequent release of serotonin into the synaptic space.

  • Axon Terminal Autoreceptor:

    1. $5\text{-HT}_{1B/D}$: Located on the axon terminal, this receptor acts as a "gatekeeper." It detects the presence of serotonin in the synaptic space. Once a buildup occurs and binds to the receptor, it shuts down further serotonin release.

Postsynaptic Actions and Cross-Neurotransmitter Regulation

• Downstream Circuitry: Every serotonin receptor subtype can regulate virtually every other neurotransmitter network through downstream circuitry.

• Opposition of Function: $5\text{-HT}_{1A}$ and $5\text{-HT}_{2B}$ work in direct opposition to one another in terms of regulating impulse flow.

• Network Modulation: Serotonin modulates other networks directly and indirectly, including:

  • Norepinephrine in the Locus Coeruleus.

  • Dopamine in the Ventral Tegmental Area ($VTA$).

  • Histamine in the Tuberomammillary Nucleus.

  • Acetylcholine ($ACh$) in the Basal Forebrain.

• Nature of Interaction: Serotonin can be excitatory or inhibitory depending on:

  • The receptor subtype involved ($5\text{-HT}_x$).

  • Whether the postsynaptic neuron releases an excitatory transmitter (Glutamate) or an inhibitory transmitter ($GABA$).

Therapeutic Implications of Specific Receptors

$5\text{-HT}_{1A}$ Postsynaptic Receptors

5-HT₁A Postsynaptic Receptors (Simplified)

Key Point:
5-HT₁A receptors are always inhibitory. They tell the neuron they are attached to to slow down or stop firing.

However, the overall effect depends on which neuron is being inhibited:

• If a 5-HT₁A receptor inhibits an excitatory neuron → less activity overall.

• If a 5-HT₁A receptor inhibits an inhibitory GABA neuron → the “brake” is removed, so activity increases (disinhibition).

Think of it as:

Inhibiting an inhibitor = more activity.

Effect on the Nigrostriatal Pathway (Movement)

1. 5-HT₁A receptors inhibit glutamate neurons.

2. Less glutamate stimulates fewer GABA interneurons.

3. GABA neurons become less active.

4. The dopamine neuron is released from inhibition (disinhibited).

5. Dopamine levels increase in the motor striatum.

Result:

✅ More dopamine in the movement pathway
✅ Helps reduce EPS (tremor, rigidity, parkinsonism) caused by D₂-blocking antipsychotics

Effect on the Mesocortical Pathway (Negative & Cognitive Symptoms)

1. 5-HT₁A receptors inhibit glutamate neurons projecting to the VTA.

2. Less glutamate activates fewer GABA interneurons.

3. GABA inhibition decreases.

4. Mesocortical dopamine neurons become more active.

5. Dopamine increases in the prefrontal cortex.

Result:

✅ More dopamine in the prefrontal cortex
✅ May improve:

• Negative symptoms (apathy, lack of motivation)

• Cognitive symptoms (poor concentration, memory problems)

• Affective symptoms (depression, emotional blunting)

Easy Test Tip

5-HT₁A agonism → ↑ dopamine where you want it

• Nigrostriatal pathway → ↓ EPS/motor side effects

• Mesocortical pathway → ↑ cognition, mood, and negative symptoms

Memory Trick:
“1A adds dopamine.”
By inhibiting GABA “brakes,” 5-HT₁A activation allows dopamine neurons to fire more.

$5\text{-HT}_{1B}$ Heteroreceptors

• Heteroreceptor Definition: A receptor for a neurotransmitter other than the one the neuron uses (e.g., a serotonin receptor on a norepinephrine neuron).

• When acting as heteroreceptors on non-serotonin presynaptic terminals (e.g., $NE$ or $DA$ neurons), $5\text{-HT}_{1B}$ receptors inhibit the release of that neuron’s "home" neurotransmitter.

The Role of $5\text{-HT}_{2A}$ in Psychosis and Dopamine Regulation

• $5\text{-HT}_{2A}$ receptors are postsynaptic and excitatory. They regulate three distinct populations of descending glutamate neurons that innervate dopamine pathways:

  1. Mesolimbic/Mesostriatal Pathway: Receptors on glutamate neurons that directly innervate this pathway. Excessive activity leads to increased downstream dopamine release and positive symptoms of psychosis.

  2. Nigrostriatal Pathway: Receptors on glutamate neurons that indirectly innervate this pathway via $GABA$ interneurons in the Substantia Nigra. Excessive stimulation here reduces dopamine release in the motor striatum, leading to drug-induced Parkinsonism.

  3. Mesocortical Pathway: Receptors on glutamate neurons that indirectly innervate the pathway via $GABA$ interneurons in the $VTA$. Excessive stimulation reduces dopamine in the prefrontal cortex, leading to cognitive dysfunction, negative symptoms, and emotional symptoms.

Prolactin Regulation and Other Serotonin Receptors

• Prolactin Secretion: Pituitary lactotrophs secrete prolactin and contain both $D_2$ and $5\text{-HT}_{2A}$ receptors.

  • Dopamine inhibits prolactin via $D_2$ stimulation.

  • Serotonin promotes prolactin release via $5\text{-HT}_{2A}$ stimulation.

  • If $D_2$ is blocked, prolactin rises. However, if both $D_2$ and $5\text{-HT}_{2A}$ are blocked, the inhibition of $5\text{-HT}_{2A}$ prevents serotonin from stimulating release, mitigating (making less severe) hyperprolactinemia.

• $5\text{-HT}_{2C}$ Receptors: Generally excitatory, but largely located on inhibitory $GABA$ interneurons. Therefore, exciting the inhibitor increases $GABA$ action, leading to a net inhibitory effect on downstream neurotransmitter release.

• $5\text{-HT}_3$ Receptors: Excitatory.

  • Located in the Chemoreceptor Trigger Zone (brain stem) and $GI$ tract; mediate nausea, vomiting, and $GI$ side effects.

  • In the prefrontal cortex, they are on $GABA$ interneurons; stimulation inhibits $NE$ and $ACh$.

  • Near glutamate neurons, they inhibit the release of serotonin (a roundabout self-regulation).

• $5\text{-HT}_7$ Receptors: Excitatory, but frequently on $GABA$ interneurons, resulting in a net inhibitory effect. In the cortex, they lead to the inhibition of glutamate and serotonin.

Clinical Evidence and Specific Disorders

• Hallucinogenic Substances: $LSD$, mescaline, and psilocybin act by agonizing $5\text{-HT}_{2A}$. This overstimulation induces symptoms similar to schizophrenia (dissociative experiences, visual hallucinations). Antagonists (blockers) of $5\text{-HT}_{2A}$ mitigate these experiences.

• Parkinson's Disease Psychosis:

  • Pathophysiology: Loss of dopamine terminals (motor) and loss of serotonin nerve terminals in the prefrontal and visual cortex.

  • The loss of serotonin leads to a futile upregulation (increased production) of $5\text{-HT}_{2A}$ receptors in the cortex.

  • Excessive receptors create an imbalance in excitatory actions on glutamate dendrites, causing psychosis similar to substance-induced symptoms.

  • $5\text{-HT}_{2A}$ antagonists manage these symptoms without exacerbating motor symptoms.

• Dementia-Related Psychosis:

  • Pathophysiology: No upregulation of $5\text{-HT}_{2A}$. Instead, cortical neurons (including $GABA$ inhibitory neurons) are knocked out by plaques, tangles, Lewy bodies, or stroke damage.

  • Lack of $GABA$ inhibition on surviving glutamate neurons causes excessive $5\text{-HT}_{2A}$-related stimulation of the $VTA$, striatum, and visual cortex, leading to psychosis.

  • Hallucinogens and 5-HT₂A Receptors

    Hallucinogens such as:

    • LSD

    • Psilocybin

    • Mescaline

    work by stimulating (agonizing) 5-HT₂A receptors.

    This excessive 5-HT₂A activation increases cortical glutamate activity and can cause:

    • Visual hallucinations

    • Altered perception

    • Dissociation

    • Psychosis-like symptoms

    5-HT₂A antagonists (blockers) can reduce these effects by preventing excessive receptor activation.

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    Parkinson’s Disease Psychosis

    What happens?

    In Parkinson’s disease, there is:

    • Loss of dopamine neurons in motor pathways

    • Loss of serotonin neurons in the cortex

    As serotonin input decreases, the brain compensates by creating more 5-HT₂A receptors (upregulation) in the cortex.

    Why does psychosis occur?

    The increased number of 5-HT₂A receptors makes cortical neurons overly responsive, resulting in:

    • Visual hallucinations

    • Delusions

    • Psychotic symptoms

    Treatment

    5-HT₂A antagonists (such as Pimavanserin) reduce psychosis without worsening motor symptoms because they do not significantly block dopamine receptors.

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    Dementia-Related Psychosis

    What happens?

    In dementia, psychosis is usually not caused by increased 5-HT₂A receptors.

    Instead, brain damage from:

    • Alzheimer’s plaques and tangles

    • Lewy bodies

    • Vascular injury/stroke

    causes loss of cortical neurons, including inhibitory GABA neurons.

    Why does psychosis occur?

    With fewer GABA neurons:

    • There is less inhibition of glutamate neurons.

    • Glutamate activity becomes excessive.

    • Overactivation of cortical circuits contributes to hallucinations and delusions.

Summary of Findings

• Serotonin regulates its own release (presynaptic) and all other major neurotransmitters (postsynaptic).

• Serotonin hyperactivity/imbalance specifically at $5\text{-HT}_{2A}$ receptors on glutamate neurons in the cerebral cortex is linked to psychosis.

• The interaction of $5\text{-HT}_{2A}$ and $NMDA$ receptor actions hypothetically leads to hyperactive dopamine in downstream mesolimbic pathways, connecting the positive and negative symptoms of schizophrenia.

• Parkinson’s psychosis:

  • ↑ 5-HT₂A receptors (upregulation)

  • Excess sensitivity to serotonin signaling

  Dementia psychosis:

  • Loss of inhibitory GABA control

  • Excess glutamate activity due to neuronal loss

  Both can produce hallucinations and delusions, but through different mechanisms.