Is Serotonin a Cause of Depression?
It’s pretty accepted in the literature that low serotonin can contribute to depression. But it’s not likely necessary or sufficient.
The best current evidence suggests that the 5HT1A receptor (and therefore serotonin as well) plays a role in depression.
Just to bring down one study:
In the prefrontal cortex (DLPFC) and hippocampus, there is a significant decrease in 5-HT1A receptor production in people with major depression and a significant decrease in 5-HT2A receptor production in people with Bipolar .
5-HT1A Receptor: Autoreceptors vs Postsynaptic Receptors
You can get easily confused about a specific point regarding these receptors, so I will clarify this first.
5HT1A receptors are often found on the same neuron that is releasing serotonin (called autoreceptors). The reason the serotonin releasing neuron has the receptor is that it acts as a negative feedback system. When there’s too much serotonin in the gap between neurons, the releasing neuron needs to know so that it can stop releasing more serotonin.
5HT1A receptors are also found on the serotonin receiving neuron (called postsynaptic receptors), where serotonin acts as the key and the 5HT1A receptor acts as the lock. These postsynaptic receptors and their activation cause a chain of events that lead to all the good stuff that serotonin does.
In order to increase serotonin function, we want less activation of the receptors on the releasing neuron (auto-receptors) and more activation on the receiving neuron (postsynaptic receptors).
To overly simplify it… Auto receptors=BAD, Postsynaptic receptors=GOOD.
The goal then is to make the autoreceptors that inhibit serotonin secretion to become less sensitive to serotonin and we want to activate or make more sensitive the postsynaptic receptors.
This mechanism has been shown to be the major mediator in the therapeutic benefits of most mainstream antidepressant supplements and pharmaceuticals, including serotonin precursors like L-tryptophan and 5-HTP, SSRIs, SNRIs, MAOIs, tricyclic antidepressants (TCAs) and tetracyclic antidepressants (TeCAs) .
The Difference Between SSRIs and MDMA
If SSRIs and MDMA (a pure form of ecstasy) both causes increased levels of serotonin, why do you feel very different on MDMA and SSRIs?
This is because, in low doses, the 5HT1A receptor activators actually tend to decrease serotonin release (by also binding to the autoreceptors) and decrease activation of postsynaptic 5-HT1A receptors… and they further decrease serotonin release but increase postsynaptic 5-HT1A receptor activity at higher doses by directly stimulating the receptors in place of serotonin.
The autoreceptors must first become less sensitive (by chronic SSRI stimulation) before the concentration of serotonin in the synapse can increase significantly.
This is theorized to be a major factor in the therapeutic lag that is seen with SSRIs.
Though the responsiveness of the autoreceptors is somewhat reduced with chronic treatment, they still remain effective at constraining large increases in serotonin concentrations.
MDMA, on the other hand, is what’s called an “SRA” or a serotonin releasing agent.
MDMA directly acts on the release mechanisms of serotonin neurons and forces the release to occur regardless of autoreceptor-mediated inhibition.
The downside to that is you’d have to tightly control the dosage or else you’ll be getting too much serotonin because your neurons are not regulating serotonin levels well anymore.
Again, in contrast to SRAs like MDMA, SSRIs actually decrease serotonin levels initially and require several weeks of chronic dosing before serotonin concentrations reach their maximal elevation and full clinical benefits for conditions such as depression and anxiety.
There are drugs in the pipeline to increase serotonin levels more quickly than SSRIs….
Sometimes, 5-HT1A autoreceptors are located on neurons that are meant to inhibit mainly dopamine or glutamate instead of serotonin. So SSRIs can work differently than SRAs, which don’t activate the autoreceptors and involve other neurotransmitters .
Summary of Effects of 5HT1A Activation
The following are some effects of 5-HT1A activation :
- Stimulates vagus nerve
- Reduces fatigue. People with CFS were found to have fewer 5HT1A receptors .
- Increases sociability – partly from oxytocin and endorphins maybe
- Increases sex drive and arousal
- Improves some kinds of learning – improves cognitive functions associated with the prefrontal cortex, possibly via inducing prefrontal cortex dopamine and acetylcholine release.
- Increases dopamine – in the medial prefrontal cortex, striatum, and hippocampus, which could be beneficial for Schizophrenia and Parkinson’s.
- Decreases aggression
- Decreases food intake
- Decreases blood pressure and heart rate via by stimulating the vagus nerve (rostral ventrolateral medulla).
- Decreases impulsivity
- Decreases nausea
- Decreases body temperature/Cools you… Vasodilation of the blood vessels in the skin increases heat loss…
- Decreases pain perception  and substance P (cause of pain, inflammatory) – mediated by 5-HT1A receptors in the dorsal raphe nucleus… Experiments in rodents suggest that 5-HT1A activation (specifically in the brainstem’s raphe nuclei) causes a perception of relatively less pain with a mild pain stimulus, but relatively more pain when exposed to a more intense pain-stimulus. These animal studies are supported by genetic studies . 5HT1A receptors combine with mu-opioid receptors to cause a numbing of pain, and activating the 5HT1A receptor should cause pain relief . There is a substantial connection between depressive disorders and chronic pain and serotonin dysregulation is one such mechanism likely to be shared by both disorders . (Think fibromyalgia…)
- Decreases drug-seeking
- Reverses opioid-induced respiratory depression.
- Inhibition of penile erection
- Takes longer to get to REM sleep
- Impairs certain aspects of memory and learning – due to interference with memory-encoding mechanisms and by inhibiting the release of glutamate and acetylcholine in various areas of the brain.
- In the raphe nucleus, 5HT1A autoreceptor activation causes rats to be less active .
- Causes pupils to get smaller or contract
5HT1A and Hormones
5-HT1A receptor activation induces the secretion of the following hormones :
- Cortisol – one reason why people might have low cortisol isn’t because of adrenal fatigue, but because the 5HT1A receptors aren’t being activated.
- Oxytocin – contributes to the prosocial, anti-aggressive, and anti-anxiety properties
- Growth hormone
- Endorphins (beta) – contributes to an anti-depressant, anti-anxiety, and anti-pain effects
5HT1A and Spirituality
In people, PET scans have found that the more 5-HT1A was sensitive to serotonin in the raphe nuclei, hippocampus, and neocortex, the less they self-reported a tendency to have spiritual experiences .
This would indicate that people who are overly spiritual might be lacking in serotonin or more precisely, they have less activation of the 5HT1A postsynaptic receptors.
5HT1A and The Circadian Rhythm
5HT1A receptors have less of a powerful response, depending on the time of the day. In rats, peak responses were observed in what would be our daytime while the weakest responses were observed in what would be our nighttime .
The 5HT1A receptor might help you set your circadian rhythm as well.
In hamsters, 5HT1A activators induce a significant phase advance (make you wake up earlier) under constant light conditions .
The 5HT1A activators accelerated the rate of entrainment to the hamsters that had a shifted circadian rhythm .
So if you’re traveling across time zones, activating these receptors is a good idea.
Another study found 5HT1A activators had an inhibitory effect on Per1 and Per2 mRNA levels in the SCN (which is induced by light), which occurred only during the hamster’s mid-subjective day, but not during the early subjective day or subjective night .
SNPs in the 5HT1A gene:
What Decreases 5HT1A Autoreceptors or Increases Postsynaptic Receptors
- CBD activates 5HT1A receptors .
- T3 is effective in both augmenting and accelerating the therapeutic response to antidepressant drugs. When given to animals, it reduced the sensitivity of 5-HT1A (and 5HT1B) auto-receptors (and postsynaptic) in the hypothalamus . I do notice an anti-depressant effect when I up my thyroid hormone production with ICES/LLLT.
- Estradiol accelerates the effects of fluoxetine (SSRI) on these receptors, presumably by blunting the increase in 5HT1A autoreceptors from SSRIs in the hypothalamus (PVN) .
- Cortisol. Chronic exposure to cortisol desensitizes 5-HT1A autoreceptors receptors .
- Lithium increases 5HT1A postsynaptic sensitivity, while not changing the autoreceptors and it’s thought that this is in part responsible for its anti-depressant activity .
- St John’s Wort increases the number of postsynaptic 5-HT1A (and 5-HT2A) receptors .
- Ashwagandha decreases 5-HT1A signaling .
- Zinc acts as a blocker of the 5HT1A receptor and prevents the binding of this receptor . However, it also helps block the combining of the 5HT1A receptor and another receptor (galanin 1), which results in an anti-depressive effect .
- Fish Oil …When animals were fed diets low in Omega-3’s (ALA), 5-HT1A receptors decreased, causing the SSRI not to work properly .
What Modulates the 5HT1A Receptor
- Exercise (aerobic) increases 5HT1A receptors in the dorsal raphe when they were reduced in an animal stress model .
- Melatonin potentiates the 5-HT1A receptor in the hypothalamus, which results in its cooling effects .
- DHA prevented negative effects of a high-fat diet on the 5-HT1A receptor .
- Magnesium and Calcium (divalent cations) increase the binding of serotonin to the 5HT1A receptors in the cortex (Purkinje cells) . Manganese also helps 5HT1A activators bind better .
- Butyrate increases 5-HT1A receptors in the hypothalamus .
- Rhodiola increases the number of 5HT1A receptors .
- Curcumin 
- Ginger is a partial activator of 5HT1A 
- Bitter orange essential oil 
- CBD (partial) [32, 33]
- Kudzu root/Puerarin 
- Hesperidin 
- Yohimbine 
- Ginkgo 
- Buspirone 
- Shrooms/Psilocybin 
- MDMA or the pure version of ecstasy increases feelings of love, empathy, and connection to others by stimulating oxytocin activity primarily via activation of the 5-HT1A receptors .
- Quetiapine 
- Amphetamines 
- LSD 
- DMT 
Chronic intake of SSRIs induces less sensitivity of the auto- and post-synaptic 5-HT1A receptors in the hypothalamus, so it’s both good and bad, but better than not for some people .
Chronic Transcranial Magnetic Stimulation (rTMS) reduces the sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus, and the study says that “this may be significant in relation to the therapeutic mechanism of rTMS” .
Berberine decreases the serotonergic system by activation of 5-HT1A autoreceptors and inhibition of postsynaptic 5-HT1A and 5-HT2 receptors. Since serotonin is mainly an excitatory neurotransmitter, this effect decreased anxiety in animals .
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