Serotonin (5-HT) drives fear and conditions such as anxiety/PTSD

haidut

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Conversely, blocking 5-HT or lowering its synthesis can probably cure most fear-based conditions such as generalized anxiety disorder (GAD), PTSD, psychotic conditions (e.g. schizophrenia), etc. At least, those are the findings of the study below, which demonstrated that animals completely lacking the 5-HT2C receptor were absolutely fearless and impervious to the development of anxiety and stress-driven pathologies. Interestingly enough, the 5-HT2C receptor is the primary controller of ACTH release, and thus the activation of the HPA axis. In other words, activating 5-HT2C (which serotonin does) activates the stress system, while blocking it stops the stress response. Even more interestingly, many SSRI drugs (and especially Prozac) are antagonists of the 5-HT2C receptor, which probably explains most of their antidepressant effects.

Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac) - PubMed
Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism - PubMed
5-HT2C receptor - Wikipedia

In other words, chronic stress drives conditions such as depression, anxiety and PTSD through the HPA axis, and blocking the HPA system or its master regulator 5-HT has therapeutic effects for those conditions. One of the most widely-available serotonin antagonists is cyproheptadine and it has already been shown to stop the nightmares of people diagnosed with PTSD. Other serotonin antagonists capable of blocking 5-HT2C include metergoline, the tricyclic class of antidepressants, and the OTC chemical Benadryl. Yes, diphenhydramine (commercially sold as Benadryl) is an antagonist on several 5-HT receptors. Word of caution for Benadryl - in doses below 150mg daily it has mostly 5-HT antagonism effects, but in higher doses it starts to act as an SSRI so many/most of its benefits may be negated. Thus, if Benadryl is used I'd stick to doses in the 50mg-100mg daily range, which have already been shown to have therapeutic effects in conditions such as diabetes, so we know the lower doses are effective and there is no need for taking the higher doses that many doctors and pharma companies push for financial reasons (i.e. higher doses = more money spent).

And now, as per the study below, it looks like blocking those pathways can also prevent those conditions. So, once again we have strong evidence that 5-HT is anything by the "happy hormone" and promoting its effects through the administration of SSRI drugs or due to chronic stress (i.e. 5-HT rises during stress) is perhaps the most detrimental approach to "treating" mental health. To make matters worse, since chronic activation of HPA has now been implicated in virtually all chronic/degenerative conditions, promoting serotonin and its effects pharmacologically or environmentally is a guarantee for a public health disaster.

Constitutive 5-HT2C receptor knock-out facilitates fear extinction through altered activity of a dorsal raphe-bed nucleus of the stria terminalis pathway - Translational Psychiatry
Fearlessness Can Be Learned - Neuroscience News

"...Mice lacking a specific serotonin receptor unlearn fear faster than those with the receptor. The findings open the door to the development of new treatments for PTSD and other disorders associated with fear...The neurotransmitter serotonin plays a key role in both the onset and in the unlearning of fear and anxiety. A research team from the Department of General Zoology and Neurobiology headed by Dr. Katharina Spoida and Dr. Sandra Süß in the Collaborative Research Center “Extinction Learning” at Ruhr University Bochum, Germany, has been investigating the underlying mechanisms. The researchers showed that mice lacking a specific serotonin receptor unlearn fear much faster than the wild type. The results of the study provide a viable explanation how drugs that are typically used for the treatment of post-traumatic stress disorder (PTSD) alter our brain activity. The ability to unlearn fear is often impaired in PTSD patients, making it more difficult to carry out therapies."

"...To this end, they examined so-called knock-out mice that lack a certain serotonin receptor—the 5-HT2C receptor—due to genetic modifications. These mice learned in one day to associate a certain sound with a mild but unpleasant electrical stimulus. “As a result of this learning process, on the following day they showed a fear response that was characterized by a motionless pause as soon as the tone was played, which we refer to as ‘freezing,'” explains Katharina Spoida. In the next step, the researchers repeatedly played the tone to the mice without applying the electrical stimulus. “Interestingly, we noticed that knock-out mice learned much faster that the tone does not predict the fear stimulus than mice who lacked this specific genetic modification,” says Katharina Spoida. “Consequently, it looks like the absence of the serotonin receptor provides an advantage for extinction learning.”
 

laleto12

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Great study. Thank you!

I believe this is the root cause of my problems.

Is there any substance that does this but isn't anti-histamine and anti-cholinergic?
 
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DonLore

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Doesn't GABA have a larger role in anxiety, PTSD and fear? What is your opinion on this @haidut ? As benzodiazepines and other GABAergics effectively block anxiety, but also cause strong fear when withdrawing
 

Frankdee20

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Doesn't GABA have a larger role in anxiety, PTSD and fear? What is your opinion on this @haidut ? As benzodiazepines and other GABAergics effectively block anxiety, but also cause strong fear when withdrawing
GABA is an inhibitory transmitter and helps attenuate over activity in the brain. Excess serotonin leads to stress signals, but normally GABA/Glutamate is the polarity. Benzodiazepine withdrawal is simply glutamate rebound and down regulated GABA receptors
 

DonLore

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GABA is an inhibitory transmitter and helps attenuate over activity in the brain. Excess serotonin leads to stress signals, but normally GABA/Glutamate is the polarity. Benzodiazepine withdrawal is simply glutamate rebound and down regulated GABA receptors
Yeah even if serotonin plays a role in anxiety/PTSD, the GABA system is easily the major player, not serotonin. I mean, Gabaergics are the gold standard for stopping any feeling of anxiety or panic, like benzos, phenibut, z-drugs, GHB
 

Frankdee20

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Yeah even if serotonin plays a role in anxiety/PTSD, the GABA system is easily the major player, not serotonin. I mean, Gabaergics are the gold standard for stopping any feeling of anxiety or panic, like benzos, phenibut, z-drugs, GHB
Absolutely
 

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