Rethinking the role of serotonin receptor signaling in improving autism symptoms: Prucalopride for a sub-group?

For many years, serotonin has been discussed in autism as though the important question were simply whether serotonin is too high or too low. I wonder whether that is asking the wrong question.

Perhaps the more useful question is: What are the individual serotonin receptors doing? And, more importantly: Is a particular receptor signalling too much or too little in a particular person?

This distinction could be important because different serotonin receptors have very different functions and signalling pathways. Some can be stimulated by agonist drugs, while others can be blocked by antagonists. Even more interestingly, the same receptor might conceivably require opposite treatment directions in different people.

A recent email from a long-time reader prompted me to look at this question much more closely.

 

A remarkable observation from a reader

One of our long-time readers wrote to me about her adult autistic son. He has suffered from severe rages for years. BCAA and Niagen had helped to some extent, and Pantogam helped significantly for a few months, but nothing had provided a lasting solution.

More recently, his gastrointestinal motility deteriorated. The mother wondered whether this physical problem might itself be contributing to his increasingly dark mood. Then something unexpected happened. The doctor gave him a few tablets of prucalopride as a trial.

The result was remarkable. His motility improved almost immediately and, at the same time, his mood became dramatically better. His mother noticed his smile returning and described him as sometimes almost giddy.

When the prucalopride ran out, they switched to Cape Aloe, a herbal laxative. That was not successful. His doctor subsequently prescribed prucalopride again, and again there was a dramatic improvement—not only in GI but also in his mood.

There are obvious limitations to a single observation. But the pattern here is a real off-drug/on-drug rechallenge, not a one-off anecdote: prucalopride on, improvement; prucalopride replaced by Cape Aloe, no improvement; prucalopride restarted, improvement again. That is a meaningfully stronger than a single before-and-after report, even though we still do not know whether the mood improvement was caused directly by prucalopride, by the relief of gastrointestinal dysfunction, or by both.

But there is something about this report that makes it particularly interesting: Prucalopride is a selective 5-HT4 receptor agonist. That means our reader may have provided us with an observation involving a very specific serotonin receptor rather than simply “serotonin.”

 

Not the first mention on this blog

Looking back through years of reader comments, this is not actually the first time prucalopride has come up here. Several readers have independently mentioned it as a helpful prokinetic going back to 2018, when a reader recommended it alongside low-dose erythromycin for a son's motility issues. In 2020, another commenter shared a paper on prucalopride's neuroprotective effects on human enteric neurons. And a reader named Leen described, across two separate updates in 2021 and 2023, resolving years of chronic fatigue, concentration problems, autonomic symptoms and mood swings using a regimen that included prucalopride—explicitly describing it as "a serotonin agonist that works in the gut."

None of these comments were prompted by a question about prucalopride specifically, and none reported the same dramatic rage improvement our most recent correspondent described. But taken together, they mean this is not really an n of 1. It is at least four independent readers, over five years, converging on the same drug and the same broad mechanism—GI motility plus a serotonin-mediated effect on mood or energy—without any of them prompting each other. That kind of unprompted convergence is exactly the sort of signal this blog exists to notice.

 

Prucalopride is now available as a much cheaper generic drug

One practical point is worth mentioning. Prucalopride was originally marketed as a very expensive branded drug, and it was the high cost that prompted the approach to me. However, generic prucalopride is now available in the United States and is dramatically cheaper than the original brand-name product.

This is particularly important because the older generation of 5-HT4 agonists had significant safety problems. They are not good alternatives to Prucalopride for its potential effects inside the brain. Prucalopride was developed as a much more selective 5-HT4 agonist, with a substantially improved safety profile compared with some of the older drugs in this class.

It means that if 5-HT4 turns out to be an interesting biological target, there is already an existing, affordable and relatively selective drug capable of activating it.

 

5-HT4: a receptor connecting the gut and brain

5-HT4 receptors are found extensively in the GI tract, where their activation promotes intestinal motility. But they are also found in the brain. 5-HT4 signalling is involved in neurotransmitter release and has been studied in relation to learning, memory, depression and other CNS functions.

Importantly, 5-HT4 is coupled to Gs (stimulatory G protein), which stimulates adenylyl cyclase and increases intracellular cAMP. The pathway can be represented simply as:

5-HT4 → Gs → adenylyl cyclase → ↑ cAMP

This immediately caught my attention because cAMP is already a recurring theme in the EpiphanyASD research. There may therefore be a connection between three things that might initially appear unrelated: 5-HT4 signalling → cAMP signalling → GI function and brain function.

Human studies have shown that prucalopride can affect brain function and cognition. While prucalopride was designed primarily for peripheral gastrointestinal motility, functional neuroimaging and cognitive studies confirm that it crosses the blood-brain barrier to exert central effects even at standard clinical doses. Existing human studies do not establish prucalopride as an antidepressant or as a treatment for autism, but they do support the idea that 5-HT4 stimulation is capable of producing functional effects in the human brain. That makes our reader’s observation biologically interesting.

 

What about the gut?

5-HT4 is a major regulator of intestinal motility. This means that the improvement could potentially be explained in several different ways:

• Hypothesis 1: The gut improved the brain. Motility had deteriorated. Chronic constipation, discomfort and visceral distress can clearly affect quality of life, sleep and mood. Prucalopride restored motility; his mood improved because he felt physically better.
• Hypothesis 2: Direct CNS effects. Prucalopride activated 5-HT4 receptors in the brain, altering cAMP signalling, neurotransmitter release, neuronal activity or other aspects of brain function. The mood improvement therefore occurred partly independently of the GI improvement.
• Hypothesis 3: Both. This may be the most likely possibility. A single receptor system could affect both sides of the gut-brain axis simultaneously (5-HT4 → intestinal motility and 5-HT4 → CNS signalling). Improving the gut could improve mood and behaviour, while direct CNS effects could potentially contribute further.

There is also an important practical point: Prucalopride is designed to stimulate intestinal motility; it is not simply a passive normalizer of bowel function. Therefore, someone with normal baseline GI function might experience excessive stimulation or loose stools, whereas a person with severe slow transit may experience restoration toward normal function. That makes the baseline phenotype critical.

 

There is already a human autism connection to HTR4

A human genomic study found lower methylation of the HTR4 promoter in children with ASD compared with controls, with the inverse relationship between methylation and age reaching significance specifically in the male ASD cases.

Association of human serotonin receptor 4 promoter methylation with autism spectrum disorder

This is not proof that autistic people have abnormal brain 5-HT4 signalling—the study used peripheral blood rather than brain tissue, was relatively small and requires replication—but it provides a direct human autism association involving the gene encoding the receptor. One caveat worth stating plainly: lower promoter methylation generally predicts higher, not lower, gene expression. Taken at face value, this study points toward more 5-HT4 signalling in ASD, not less—which does not obviously predict that an agonist like prucalopride should help. I don't think that undermines the observation; it is a good illustration of the point made later in this post, that the same receptor could plausibly need opposite treatment directions in different people, and a peripheral blood methylation signal cannot by itself tell us which direction a given individual needs.

So we now have three separate observations:

1.     autism → HTR4 epigenetic association

2.     prucalopride → selective 5-HT4 activation

3.     one autistic adult → striking improvement in motility and mood

 

A remarkable connection: Dup15q syndrome

The story becomes even more interesting when we look at specific genetic neurodevelopmental syndromes. Dup15q syndrome is strongly associated with developmental disability, autism and epilepsy. Recent experimental work in a Dup15q mouse model found gastrointestinal dysmotility and a constipation-like phenotype. The researchers tested prucalopride and found not only improvement in GI transit, but also lower fecal corticosterone (a stress marker) and longer social contact duration in the treated mice. In other words, in this model, restoring 5-HT4-driven gut motility was associated with less stress and more social behaviour—the animal-model version of exactly the gut-to-mood connection our reader described.

This does not show that prucalopride improves autism symptoms or mood in people with Dup15q, but it raises an intriguing hypothesis: Could some autistic people with significant GI dysmotility represent a particularly interesting 5-HT4-responsive phenotype? That is certainly worth investigating.

 

5-HT4 is only one serotonin receptor

This is where the story broadens. There are multiple serotonin receptors, and they do not all do the same thing. A simplified map looks like this: 

5-HT1A → Gi/o → ↓cAMP

5-HT2A → Gq → PLC/Ca²⁺/PKC signalling

5-HT4 → Gs → ↑cAMP

5-HT7 → Gs → ↑cAMP

This immediately suggests that “serotonin” is far too crude a description of the system. Two people could theoretically have completely different problems with serotonin signalling even if their overall serotonin concentrations were identical: one person might have excessive signalling through one receptor, while another might have inadequate signalling through another. This raises a possibility particularly relevant to personalized medicine: Perhaps one person needs a receptor agonist while another needs an antagonist.

 

5-HT2A keeps appearing

5-HT2A is probably the serotonin receptor that has appeared most often in discussions of autism and altered perception. There is a substantial literature concerning 5-HT2A in autism, including genetic and receptor-function studies, alongside a remarkable amount of anecdotal material from autistic adults concerning psychedelic drugs such as psilocybin, which strongly activate 5-HT2A.

The EpiphanyASD material includes readers describing unusual responses to psychedelics, including one person with Asperger's who reported an unusually weak psychedelic response and wondered whether altered receptor biology might explain it. While such observations cannot be taken as proof of altered receptor function, they help generate hypotheses.

It is also important that drugs can move receptor signalling in opposite directions. For example, atypical antipsychotics like aripiprazole and risperidone feature potent 5-HT2A antagonist/inverse agonist activity as part of their complex pharmacology. Because these drugs act on multiple systems—particularly dopamine—we cannot attribute benefits solely to 5-HT2A blockade. However, it highlights how heavily clinical practice has tilted toward blocking this receptor, rarely considering whether baseline signaling might be deficient in certain individuals.

 

5-HT7 may be even more interesting

My investigation of 5-HT7 has produced an unexpected pattern. Like 5-HT4, 5-HT7 is a Gs-coupled receptor (5-HT7 → Gs → adenylyl cyclase → ↑cAMP). There is an increasingly interesting neurodevelopmental literature surrounding this receptor. Experimental activation of 5-HT7 has produced effects on synaptic plasticity, dendritic spines, synaptic protein synthesis, long-term potentiation, and learning and memory.

This is particularly interesting because these processes are disturbed in several genetic neurodevelopmental syndromes associated with autism:

• BTBR autism model: A recent study in BTBR mice found reduced 5-HT7 expression in cortical synaptic material. Selective activation of 5-HT7 with the agonist LP-211 restored synaptic protein synthesis and normalized dendritic spine abnormalities.
• Fragile X syndrome: In Fmr1 knockout mice, 5-HT7 activation reversed abnormalities in hippocampal synaptic plasticity via adenylyl-cyclase-dependent mechanisms, improving learning and behavioural outcomes.
• Rett syndrome: Experimental work in MECP2 models suggests 5-HT7 signaling can modify downstream neuronal plasticity despite the presence of the primary genetic abnormality.
• Angelman syndrome: 5-HT7 stimulation improved synaptic protein synthesis, dendritic spine density, long-term potentiation, and cognitive deficits in an Angelman mouse model.
• Pitt-Hopkins syndrome: TCF4 deficiency alters neuronal development and synaptic function. While 5-HT7 has not yet been directly studied in Pitt-Hopkins models, it represents an ideal system to test whether TCF4 disruption alters HTR7 expression, cAMP production, or downstream PKA/CREB signaling.

These distinct genetic disorders converge on synaptic plasticity and intracellular signaling pathways where serotonin receptors act as modifiable downstream regulators.

Note: 5-HT2A and 5-HT7 each appear twice above because the same receptor can plausibly be pushed in either direction depending on the person—that duality is the whole point of this table, not a typo. The 5-HT7 antagonist row is left without a named drug because selective 5-HT7 antagonists (e.g., SB-269970) remain research compounds only, with no clinically approved option yet.

 

Beyond "High" vs. "Low" Serotonin: A Precision Framework

Measuring overall serotonin levels is far too crude. Two individuals can share identical serotonin concentrations yet have entirely different receptor expression levels, binding sensitivities, or downstream intracellular responses.

This distinction explains why conventional clinical trials often yield inconclusive results. Imagine ten autistic people given a drug that blocks a specific serotonin receptor: if five improve because they have excessive baseline signaling and five deteriorate because they have deficient signaling, the net result in the trial is zero. The intervention is labeled ineffective, missing the critical underlying signal: different biological subgroups require opposite treatment directions.

Moving toward precision pharmacology requires mapping five specific parameters rather than searching for a single "autism neurotransmitter":

• Phenotype: (e.g., severe slow-transit GI dysmotility combined with mood dysregulation)
• Candidate Target Receptor: (e.g., 5-HT4 or 5-HT7)
• Pathway Mechanism: (e.g., Gs coupling → adenylyl cyclase → ↑cAMP)
• Directional Need: (Excessive vs. deficient baseline signaling)
• Targeted Intervention: (Selective agonist vs. selective antagonist)

 

Mapping Natural Experiments

Our reader’s report is not a proven treatment for autism, but it is a powerful hypothesis-generating observation. It connects severe GI dysmotility and severe mood disturbance directly to selective 5-HT4 activation via prucalopride—a mechanism supported by human HTR4 promoter methylation studies and preclinical Dup15q models.

Many readers have shared intriguing observations involving targeted pharmaceuticals, supplements, and 5-HT2A agonists like psilocybin. When examined systematically—preserving the individual context, baseline phenotype, specific agent, dose, duration, and direction of outcome—these natural experiments can help identify potential biomarkers or clinical features that predict whether a person needs signaling at a specific receptor pushed up or pulled down.

The future of serotonin-based interventions in autism will not be about simply raising or lowering global serotonin, but about matching the right receptor signaling direction to the right person.

Note: This post was enriched using the AI copilot to apply the EpiphanyASD knowledgebase and identify relevant reader observations (some of which I had forgotten about).

https://www.epiphanyasd.com/p/ai-copilot.html

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

Today we have a complex dysfunction, but we have a plausible understanding of the detailed biological underpinnings and several therapeutic options. It is relevant to people with autism who have impaired sensory gating (they find noises like a clock ticking annoying), and perhaps those who struggle with complex thought. It is very likely to be disturbed in some people with ADHD and many with schizophrenia.

Trouble in the Pre-Frontal Cortex

For a recap on sensory gating, here is an earlier post:-

Sensory Gating in Autism, Particularly Asperger's

Today’s dysfunction relates to HCN channels located on those tiny dendritic spines in a part of the brain called the pre-frontal cortex. These are a type of voltage gated potassium channel found in your brain and heart, there are 4 types, it looks to me that HCN2 is the key one today.

The pre-frontal cortex (PFC) is seen as the part of the brain most affected by mental illness (schizophrenia, bipolar, ADHD etc.), although medicine’s current understanding looks rather medieval to me.

These HCN channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network (created by numerous interacting neurons) is effectively disconnected.

By keeping these channels closed, it is thought that you can improve working memory and reducing distractibility. Now you might think distractibility is an odd word, and it is not a word I expected to encounter, what it really means is impaired sensory gating. This is a core feature of Asperger’s, ADHD and schizophrenia.

One of the key risk genes for schizophrenia, DISC1, also affects HCN channels and this may account for some of the cognitive deficit found in schizophrenia. High level thinking is particularly affected.  It is thought that loss of DISC1 function in the PFC would likely prevent proper PDE4 function, leading to a dysregulated build-up of cAMP in dendritic spines resulting in excessive opening of HCN channels

Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction

I did wonder how nicotine fits in, since in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker. For a change, everything seems to fit nicely together. There are different ways to block HCN channels, some of which are indirect. One common ADHD drug, Guanfacine, keeps these channels closed, but in a surprising way.

Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic  receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.

Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

This would explain why stress makes people’s sensory gating problems get worse. So someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. In Monty, aged 14 with ASD, the only time he exhibits significantly impaired sensory gating, is when he has stopped all his Polypill therapies for several days. I think stress/anxiety is what has changed and this opens those HCN channels. Then even the sound of someone eating food next to him makes him angry.

Excessive opening of HCN channels might underlie many lapses in higher cognitive function.

While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.

The University of Maastricht holds patents on the use of Roflumilast, a PDE4 inhibitor, to improve cognition; most interestingly, this takes effect at one fifth of the COPD dosage, for which it is an approved drug. At high doses PDE4 inhibitors have annoying side effects, but at low doses they tend to be trouble-free.

One effect of a PDE4 inhibitor is that it reduces cAMP. So a PDE4 inhibitor acts indirectly like an HCN blocker.

Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.

So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today. This is something that should indeed be investigated across different types of cognitive dysfunction.

There are numerous dysfunctions that can impair cognition and they can occur in different diagnosis. For example impaired autophagy is a key feature of Huntington’s, impaired remyelination defines multiple sclerosis, low levels of nerve growth factor are a key feature of Rett syndrome. Less severe dysfunctions of these processes occur in entirely different conditions.

It is thought that people with Alzheimer’s might benefit from PDE4 inhibition. If it was me, I would try it in all types of dementia or cognitive loss of any kind.

PDE4 Inhibitors

There have been many mentions of PDE4 inhibitors elsewhere in this blog. They are broadly anti-inflammatory and anti-oxidant, but currently only widely used to treat asthma in Japan and COPD in Western countries. COPD is a kind of very severe asthma.

Traditionally a PDE4 inhibitor is thought of as drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). That all sound complicated, just think of it as increasing cAMP.

Now cAMP is a messenger in many biological processes, one of which relates to PKA (Protein Kinase A). In autism we know that PKA, PKB and PKC are often disturbed. These PKs are very important because they have the ability to literally change the function of thousands of proteins in your body. This is similar to how epigenetic tags can switch on or switch off a particular gene. PKs, via a different mechanism we will look at in another post, change the function of proteins, so it is very important that you have the correct level of PKA, PKB and PKC.

We saw in a recent post that the Pitt Hopkins gene TCF4 is regulated by PKA and that under-expression of TCF4 is also a feature of some ID and schizophrenia. So more PKA, please.

The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A 

You can use a PDE4 inhibitor to increase cAMP, which then increases PKA.

Other effects of PDE4 inhibitors

Today’s post is about sensory gating and the effect here of PDE4 inhibitors is via the effect of cAMP on those HCN channels in your tiny dendritic spines.

There are numerous other effects of PDE4 that may also be therapeutic. One interesting effect is that inhibition of PDE4 can mimic calorie restriction by activating AMPK/SIRT1 pathway.

Calorie restriction has just been shown in a large trial to be able to reverse type 2 diabetes, if initiated with a few years of the disease developing.

Humans have evolved based to periods of feast and famine. Periods of fasting may be therapeutic for many modern conditions.

Not surprisingly one side effect of PDE4 inhibitors is weight loss. Many psychiatric drugs cause troubling weight gain.

Acute administration of Roflumilast enhances sensory gating in healthy young humans in a randomized trial. 

Abstract

 

INTRODUCTION:

Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.

METHODS:

The current study investigated the effects of the PDE4 inhibitor Roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).

RESULTS:

Results show that Roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means Roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.

CONCLUSION:

The PDE4 inhibitor Roflumilast has a favourable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.

Treating Cognitive Impairment with Roflumilast, Maastricht University

Background Information

Selective phosphodiesterase (PDE) inhibition has been considered as a very promising target for cognition enhancement.

Roflumilast is a PDE4 inhibitor that has been developed by Takeda for Chronic Obstructive Pulmonary Disease (COPD). In recent year, Maastricht University has been collaborating with Takeda to develop Roflumilast for cognitive impairments

In 2015 Takeda sold COPD indication of Roflumilast to AstraZeneca, and ownership of IP for treatment of cognitive impairment returned to Maastricht University.

Compelling clinical results

A single administration of Roflumilast improves episodic memory in mice, and in young and elderly healthy subjects at a non-emetic dose

As shown in the figure, healthy (A) and memory impaired (B) elderly subjects showed better performances in the delayed recall of the Verbal Learning Task after roflumilast

Key Features and Advantages

Opportunities to reposition a clinically-proven safe compound with a well-established pharmacology.

Compelling preclinical and clinical evidences showing that Roflumilast effectively deliver to the brain to produce robust cognitive enhancement.

Pro-cognitive effects at low dose (5 times lower than COPD indication), which allows to circumvent the emetic effects commonly observed with other PDE4 inhibitors

Maastricht University has a strong IP protection extending to at least 2033.

Effect of Roflumilast on cognitive function in schizophrenia

PDE inhibitors in psychiatry--future options for dementia, depression and schizophrenia?

Author information

Abstract

Phosphodiesterases are key enzymes in cellular signalling pathways. They degrade cyclic nucleotides and their inhibition via specific inhibitors offers unique 'receptor-independent' opportunities to modify cellular function. An increasing number of in vitro and animal model studies point to innovative treatment options in neurology and psychiatry. This review critiques a selection of recent studies and developments with a focus on dementia/neuroprotection, depression and schizophrenia. Despite increased interest among the clinical neurosciences, there are still no approved PDE inhibitors for clinical use in neurology or psychiatry. Adverse effects are a major impediment for clinical approval. It is therefore necessary to search for more specific inhibitors at the level of different PDE sub-families and isoforms.

Brain Networks Strengthened By Closing Ion Channels, Research Could Lead To ADHD Treatment

The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.

Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."

Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical  norepinephrine or by medications like guanfacine.

 “Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility,” she said. “This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels.”

Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC cognitive deficits based on the data reported in the Cell paper.

The full Yale paper:

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Guanfacine for the Treatment of Cognitive Disorders: A Century of Discoveries at Yale

The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette’s Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Nicotine blocks the hyperpolarization-activated current Ih and severely impairs the oscillatory behavior of oriens-lacunosum moleculare interneurons.

Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.

Modulation of HCN channels in lateral septum by nicotine

Conclusion

I think many people stand to benefit from the drugs mentioned in today’s post, but for different biological reasons. A person with Pitt Hopkins may benefit from Roflumilast because it will upregulate PKA and then increase expression of their remaining TCF4 gene.

In a person with schizophrenia there are multiple reasons these drugs might help them and it will depend on which genes they have that are misexpressed (TCF4, DISC1 etc.).

In a person with idiopathic Asperger’s and impaired sensory gating it looks like the effect on HCN channels is what is important.

I think low dose Roflumilast has great potential for many. The Japanese drug Ibudilast very likely will provide similar benefits, but at what dosage?

PDE4 inhibitors do have side effects at higher doses in part because there are several different types of PDE4 (PDE4A, PDE4B, PDE4C etc) and different drugs effect different subtypes differently.

Ibudilast is used as a daily drug therapy for asthma in Japan and is being studied as a therapy for Multiple Sclerosis (MS) in the US.

Roflumilast is sold by Astra Zeneca as Daxas/Daliresp but at a high dose of 500mcg to treat flare ups of COPD (Chronic Obstructive Pulmonary Disease) it does cause troubling side effects, but it reduces your chance of dying from COPD.

The cognitive dose used in research is 100mcg. Higher doses had no cognitive/sensory gating benefit.

Further investigation of the ADHD drug Guanfacine should be made, because some of the people who benefit from a PDE4 inhibitor might get a similar effect from Guanfacine. People with Pitt Hopkins would not be in this category. A person with Asperger’s and impaired sensory dating should respond to Guanfacine, a cheap drug.

At the end of the day, choice of therapy will come down to side effects and cost. In the US, Roflumilast is expensive ($330), seven times more expensive than in some other countries; in the UK the price of the same 30 tablets is $50. One pack would be enough for 5 months at the suggested dose.