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5-HT1A receptors and the ballicules that bind them

The serotonin (5-HT) ballicule

ki of serotonin to various 5-HT receptors - 5-HT1A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT7
The receptor binding affinities of serotonin itself. It has low binding affinity for the serotonin transporter (SERT) also, which pumps serotonin back into the presynaptic neuron.

The 5-HT1A serotonin receptor

5-HT1Ӓ serotonin receptor mnemonics

❖ The Ӓ is stylized with an Umlaut, not officially, but to emphasize its importance—think of the dots as the headlights on a school bus. Downstream effects are similar to those mediated by 5-HT2Ă receptors, stylized as Ă representing alien tentacles because antipsychotics—“little green men”—block 5-HT2Ă receptors.

❖ The 5-HT1Ӓ receptor resembles a school bus because it is the buspirone (Buspar)–“Bus spear” –receptor.

❖ 5-HT1Ӓ receptor-binding pegs on ballicules also resemble school buses.

5-HT1A serotonin receptor by Jason Cafer MD
The 5-HT1A serotonin receptor looks like a school BUS because BUSpirone binds it.

The 5-HT1A serotonin receptor

❖ The most widespread serotonin receptor

❖ Binding of serotonin to these receptors inhibits the neuron from firing.

❖ The raphe nucleus in the brainstem is responsible for the release of serotonin to other parts of the brain. 5-HT1Ӓ receptors in the raphe are largely somatodendritic autoreceptors.

Downregulation and desensitization of somatodendritic 5-HT1Ӓ autoreceptors are thought to be critical to the delayed antidepressant effect of serotonin reuptake inhibitors (SRIs).

❖ 5-HT1Ӓ receptors in other brain areas are postsynaptic receptors.

5-HT1A serotonin receptor agonists

5-HT1A serotonin receptor agonist ballicule by Jason Cafer MD
The yellow 5-HT1Ӓ- binding peg on this ballicule has a “+” sign to designate it as an agonist, i.e., activator of the receptor.

❖ Activation of 5-HT1Ӓ receptors on presynaptic serotonin neurons results in decreased serotonin synthesis and release, by negative feedback. Activation of 5-HT1Ӓ receptors on postsynaptic GABAergic neurons increases downstream release of dopamine.

➤ Vasodilation and decreased heart rate (central sympatholytic effect involving the vagus nerve)

➤ Antiemetic effects (anti-serotonergic)

➤ Possible improvement of Parkinson’s disease

(downstream dopaminergic effects)

➤ Increased libido (anti-serotonergic and

downstream dopaminergic effects)

❖ The principal libido enhancing action of flibanserin (Addyi) at postsynaptic 5-HT1Ӓ receptors

5-HT1A serotonin receptor partial agonists

5-HT1A serotonin receptor partial agonist by Jason Cafer MD
The yellow 5-HT1Ӓ receptor-binding peg on this ballicule resembles a school bus. Buspirone–”Bus spear”– is a 5-HT1A partial agonist.

❖ The principal anxiolytic action of buspirone (Buspar) and gepirone (Exxua) at 5-HT1Ӓ receptors (somatodendritic autoreceptors in the raphe nucleus)

❖ Part of the antidepressant action of vilazodone (Viibryd) and vortioxetine (Trintellix), which contain “built-in buspirone” activity

❖ Partial activation of 5-HT1Ӓ receptors results in downstream effects similar to those produced by blocking 5-HT1Ӓ receptors, i.e., dopamine enhancement and glutamate inhibition.

➤ Reduce parkinsonian symptoms caused by D2 antagonists

➤ Improve positive, negative, and cognitive symptoms of schizophrenia

➤ Decrease aggression

➤ Improve sexual functioning

❖ Binding of SGAs to 5-HT1Ӓ receptors:

➤ Strong: brexpiprazole

➤ Mod/strong: aripiprazole, cariprazine, lurasidone

➤ Moderate: asenapine, ziprasidone, iloperidone

➤ Weak: clozapine, quetiapine, risperidone, paliperidone

5-HT1A serotonin receptor antagonists

5-HT1A serotonin receptor antagonist ballicule by Jason Cafer MD
The yellow 5-HT1A-binding peg on this ballicule has no “+” sign, meaning it blocks the receptor, i.e., is an antagonist.

Pindolol (Visken) is a beta blocker that also blocks somatodendritic 5-HT1Ӓ receptors.

❖ It has been postulated that pindolol may enhance the antidepressant effect of SSRIs by blocking the SSRI-induced feedback inhibition of serotonin release.

Serotonin binding to 5-HT1A receptor by Jason Cafer MD
The serotonin ballicule binding to a 5-HT1A receptor
raphe nucleus and serotonin by Jason Cafer MD
Neurons in the raphe nucleus--"Ralphie nucleus"--make and release serotonin, which binds to 5-HT1A receptors on GABA interneurons, which affects dopamine neurotransmission downstream.

Two locations of 5-HT1A receptors

Somatodendritic 5-HT1A presynaptic receptors and postsynaptic locations
Two locations of 5-HT1A receptors

Somatodendritic 5-HT1A serotonin autoreceptors

These are located on presynaptic serotonin neurons.

When serotonin binds these receptors, serotonin release is decreased by a negative feedback mechanism. SRIs, by increasing serotonin availability, have initial effects of decreased firing of the serotonin neuron, which is counterproductive to the antidepressant effect. Over weeks, the delayed SRI effect is downregulation and desensitization of these receptors, which leads to increased firing and antidepressant effects.

At somatodendritic 5-HT1Ӓ autoreceptors on presynaptic serotonin neurons:

Buspirone (Buspar) and gepirone (Exxua) are full agonists

Pindolol (Visken) is an antagonist

Postsynaptic 5-HT1A serotonin receptors

These are located on postsynaptic GABA interneurons.

5HT serotonin and 5-HT1A receptors by Jason Cafer MD
Serotonin released by serotonergic neuron, ready to bind to 5-HT1A receptor on the postsynaptic neuron

Binding of serotonin to these receptors increases dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) neurotransmission in downstream circuits. However, the direct effect of serotonin binding to 5-HT1Ӓ receptors is to inhibit firing of the postsynaptic neuron, which is a GABA interneuron. GABA interneurons have inhibitory effects on DA, NE, and ACh neurons. Negative times negative equals positive–serotonin binding to 5-HT1Ӓ receptors inhibits the inhibitory GABA neurons, causing increased downstream DA, NE, and ACh.

At postsynaptic 5-HT1Ӓ receptors on GABAergic neurons:

Buspirone (Buspar) and gepirone (Exxua) are partial agonists.

➤ enhanced sexual functioning

Flibanserin (Addyi) is a full agonist.

➤ enhanced sexual functioning

A couple of ballicules that bind 5-HT1A receptors

Gepirone and buspirone binding to 5-HT1A receptors by Jason Cafer MD
Buspirone and gepirone are 5-HT1A partial agonists at postsynaptic 5-HT1A serotonin receptors. They function as full agonists at somatodendritic 5-HT1A autoreceptors.

Buspirone is approved for Generalized Anxiety Disorder. Gepirone is approved for Major Depressive Disorder.

Copyright 2023, CaferMed Publishing

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