Nicotinic Receptors, Anxiety, and PTSD - an A.I. generated discussion

-- Dr. O'Leary explores how an artificial intelligence tool summarizes recent data on the use of nicotinic receptor modulators for the treatment of anxiety and PTSD.  Please send any comments to feedback@psydactic.com.

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References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.

Transcript

Resources fed to A.I. model:

Arvin, Matthew C., Xiao-Tao Jin, Yijin Yan, Yong Wang, Matthew D. Ramsey, Veronica J. Kim, Nicole A. Beckley, Brittany A. Henry, and Ryan M. Drenan. 2019. “Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 39 (22): 4268–81.

“Bionomics Initiates AFFIRM-1, a Phase 3 Clinical Trial with BNC210 for Social Anxiety Disorder - BioSpace.” n.d.

Hampsey, Elliot, Adam Perkins, and Allan H. Young. 2023. “BNC210: An Investigational Α7-Nicotinic Acetylcholine Receptor Modulator for the Treatment of Anxiety Disorders.” Expert Opinion on Investigational Drugs 32 (4): 277–82.

Jin, Xiao-Tao, and Ryan M. Drenan. 2022. “Functional Α7 Nicotinic Acetylcholine Receptors in GABAergic Neurons of the Interpeduncular Nucleus.” Neuropharmacology 208 (108987): 108987.

Mineur, Yann S., Alexa R. Soares, Ian M. Etherington, Zuhair I. Abdulla, and Marina R. Picciotto. 2023. “Pathophysiology of nAChRs: Limbic Circuits and Related Disorders.” Pharmacological Research: The Official Journal of the Italian Pharmacological Society 191 (106745): 106745.

Morel, C., S. P. Fernandez, F. Pantouli, F. J. Meye, F. Marti, S. Tolu, S. Parnaudeau, et al. 2018. “Nicotinic Receptors Mediate Stress-Nicotine Detrimental Interplay via Dopamine Cells’ Activity.” Molecular Psychiatry 23 (7): 1597–1605.

O’Connor, Susan M., Brad E. Sleebs, Ian P. Street, Bernard L. Flynn, Jonathan B. Baell, Carolyn Coles, Nurul Quazi, et al. 2024. “BNC210, a Negative Allosteric Modulator of the Alpha 7 Nicotinic Acetylcholine Receptor, Demonstrates Anxiolytic- and Antidepressant-like Effects in Rodents.” Neuropharmacology 246 (109836): 109836.

Papapetropoulos, Spyros, Elizabeth Doolin, Michael Odontiadis, Dharam Paul, Mark Jaros, Paul Rolan, Charles Taylor, and Murray B. Stein. 2025. “A Phase 2, Placebo-Controlled Study to Evaluate the Efficacy and Safety of BNC210, an Alpha-7 Nicotinic Receptor Negative Allosteric Modulator, for Acute, as-Needed Treatment of Social Anxiety Disorder (SAD) - The PREVAIL Study.” Psychiatry Research 346 (116387): 116387.

Perkins, Adam, Fiona Patrick, Toby Wise, Nicholas Meyer, Ndaba Mazibuko, Alice E. Oates, Anne H. M. van der Bijl, et al. 2021. “Cholinergic Modulation of Disorder-Relevant Human Defensive Behaviour in Generalised Anxiety Disorder.” Translational Psychiatry 11 (1): 13.

Picciotto, M., D. Brunzell, and B. Caldarone. 2002. “E¡ect of Nicotine and Nicotinic Receptors on Anxiety and Depression.”

Picciotto, Marina R., Alan S. Lewis, Gerrit I. van Schalkwyk, and Yann S. Mineur. 2015. “Mood and Anxiety Regulation by Nicotinic Acetylcholine Receptors: A Potential Pathway to Modulate Aggression and Related Behavioral States.” Neuropharmacology 96 (Pt B): 235–43.

Terry, Alvin V., Jr, Keri Jones, and Daniel Bertrand. 2023. “Nicotinic Acetylcholine Receptors in Neurological and Psychiatric Diseases.” Pharmacological Research: The Official Journal of the Italian Pharmacological Society 191 (106764): 106764.

Wise, Toby, Fiona Patrick, Nicholas Meyer, Ndaba Mazibuko, Alice E. Oates, Anne H. M. van der Bijl, Philippe Danjou, et al. 2020. “Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder.” Biological Psychiatry 87 (10): 908–15.

Transcript:

Welcome to PsyDactic. Today is Sunday, February 23rd, 2025, and I'm your host, Dr. O’Leary, a psychiatrist and fellow in child and adolescent psychiatry in the US National Capital Region. This is a podcast about psychiatry and neuroscience, and I produce it to help me learn, and I hope it does the same for you. More and more, I've been exploring the potential of a I as a tool to help find, consolidate, and summarize a vast amount of information in this world. I mean, the amount of knowledge being generated every day is increasing, and it's far more than any human mind is capable of penetrating. I can't read an article and drive to work at the same time, or read an article and make dinner at the same time. I could have an AI just read journal articles to me, but journal articles are not really written to be read aloud. What I really need is an AI that can read 20 articles about a topic and then give me a 10 to 20 minute accurate audio summary of the content that I can listen to while I wash the dishes. That's exactly what I'm presenting to you today. I want to start including more AI generated episode content and I'm toying with the idea of creating multiple podcast feeds that focus on different topics. For example, a psychopharmarmacology feed, a psychotherapy feed, a neurobiology feed. But what I need first is some feedback from you. So, let me know what you think about this AI generated content. Was it helpful? Do you feel turned off by the idea of learning from AI? Did you notice any mistakes? For example, I noticed some in this episode. One of the AI hosts mispronounces alpha 7 nicotinic receptors by referring to them as A receptors or I receptors. When you hear this, think alpha 7 instead. For your feedback, please go toactic.com and fill out a form there. Or you can email me directly to feedback.com. That's psyd ctic.com. I'm also interested if anyone has any suggestions on the names that I should give these AI hosts. You can provide that feedback as well. So, here it is. My first fully AI generated podcast episode.

Welcome to our deep dives. We've got some really cool research to get into today.

Yeah, definitely.

All about nicotinic receptors and how they might actually help us treat some pretty serious conditions like anxiety and PTSD.

Yeah, for Sure. It's a fascinating area with a lot of potential.

So, uh, we're going to be focusing on one drug in particular today called BNC210.

Okay.

And we're going to be exploring how it kind of interacts with these receptors in the brain, right?

So, first things first, what is BNC210 and why are we even talking about it?

So, BNC210 is this drug that's getting a lot of attention and it's called a negative alossteric modulator of the A7 nicotinic acetylcholine receptor.

Wow, that's a mouthful.

Basically, what it means is it fine-tunes the activity of this specific receptor in the brain. It doesn't completely block it, which is important.

Why is that?

Well, think of it like a dimmer switch versus just like an onoff switch.

Okay.

Completely shutting down a receptor can cause a lot of problems, a lot of side effects.

Yeah, that makes sense. So, it's like a more subtle approach.

Exactly.

But why this particular receptor? What's so special about it?

So, the A7 nicotinic acetylcholine receptor, I

just want to hop in and say notice how she called it the A7 nicotinic receptor when it's the alpha 7 nicotinic receptor. Now, back to the AI. It plays a huge role in how we respond to stress.

Okay.

And also to threats. It's a big part of what we call the brain's fear response.

I see.

And when people have anxiety or PTSD, this receptor can actually become overactive.

So basically, their fear response is kind of on overdrive.

Yeah, you could say that.

So then BNC210 comes in and helps calm things down.

That's the idea. And there's research that shows this is actually happening.

Oh, really?

In a phase 2 study, they gave people with generalized anxiety disorder a single dose of BNC2. 10

just one dose.

Just one dose and it was 300 milligrams.

Okay.

And what they found was that it actually reduced activity in the amydala. The amydala is like the alarm system in your brain. It's always scanning for anything dangerous.

Oh, okay.

And then triggers the fear response when it thinks there's a threat.

I see. So an overactive amydala basically equals lots of anxiety

pretty much. And they often see increased amydala activity in people with anxiety disorders.

So the fact that BNC210 seems to be calming it down That's a good sign.

Definitely a good sign.

It seems like this could be a really effective way to actually treat anxiety then.

Yeah. And what's really interesting is that the effects of BNC210 were actually similar to the effects of Laurazipam.

Lauras Pam. That's a common anti-anxiety medication. Right.

It is exactly

as far as I understand it. The correct pronunciation is laurazzipam also known as Adavan.

But BNC210 potentially has fewer side effects.

Okay. So it could be a faster acting and safer treatment.

Potentially. Yes. That's pretty exciting stuff.

It is.

Let's kind of zoom out a little bit, though. Sure.

I think it would be helpful for our listeners to get a little bit more of a basic understanding of what nicotinic receptors actually are.

Right. To put it simply, they're like little doorways on brain cells. And when certain molecules come along, like acetyloline or even nicotine, they open up.

So, they're kind of like gatekeepers for the brain

in a way. Yes. And they're involved in so many different functions

like what

things like mood, attention, learning memory,

right? and of course our stress response.

So pretty important stuff,

very important.

And we've been talking a lot about this AS7 subtype,

but what about other types of nicotinic receptors?

Yeah, there are actually a whole family of them, each with its own specific job and location in the brain.

So it's not an unsized fits all kind of thing.

Not at all. For example, the I4 former 2 receptor,

she means alpha for beta 2.

That one's involved in the rewarding effects of nicotine.

Ah, so that's the one that gets hijacked in addiction.

Exactly. It plays a big role in how nicotine gets so addictive. That makes sense. So, how does BNC210 fit into all of this this whole world of different receptors and functions?

Well, here's where it gets really interesting. Studies have shown that chronic nicotine exposure, so think like smoking cigarettes regularly,

okay,

can actually increase the number of certain nicotinic receptors in the brain.

Wait, so smoking can physically change your brain?

It can. Yeah. It's a really powerful example of how our environment can actually shape our brain.

Wow. And so, how does that tie back to BNC210? So, while BNC210 is targeting that A7 receptor to reduce anxiety,

right,

it's also possible that it's helping to counteract some of the negative effects of all that nicotine exposure.

So, it's kind of like hitting the reset button on those changes

in a way. Yeah, you could think of it like that. It's helping to rebalance the system.

Fascinating. It seems like there's so much more to learn about how these receptors work.

Absolutely. We're just starting to scratch the surface

and how they're infected by things like nicotine.

Exactly. And all of this research could have a huge impact on how we treat things like anxiety, PTSD, and even addiction.

It sounds like BNC210 could be a real gamecher.

It could be.

But before we get too ahead of ourselves, I think it's important to talk about the brain regions that are involved in all of this.

Yeah, absolutely. We've already talked about the amydala, but some other key players are the hippocampus, which is crucial for memory formation.

Okay.

Especially when it comes to fearful memories, and then there's the prefrontal cortex, that's like the CEO of the brain. It helps us regulate emotions, make decisions, and control impulses.

So, it's like a whole network of brain regions all working together to shape our emotional responses.

Exactly. And those nicotinic receptors are scattered throughout all of these areas

and affecting how they communicate with each other.

Precisely.

This is getting complex.

It is. It's a complex system, but by understanding these intricate pathways, we can develop better, more targeted therapies.

We left off talking about this really promising drug BMC210,

right? We talked about how it targets the A7 nicotinic acetylcholine receptor and how it's shown some really good results in reducing that amydala activity,

right? Which basically means less anxiety.

Yeah, exactly. And we focus mainly on studies with humans,

but there's actually some really fascinating research using rodent models that can give us even more insights.

Oh, really? So, like mice and rats.

Exactly.

I'm always curious how they translate those findings from animals to humans.

Yeah. It's not a perfect one to one, but it can be really helpful.

Okay. So, what kind of things are they doing with these rodents?

Well, one study used something called the mouse defense test battery.

Okay.

It's basically a way to how mice react to different threats,

like a little obstacle course for anxious mice,

kind of. You could think of it like that. They're carefully designed to kind of assess those anxiety levels.

Okay?

And what they found was that both low and high doses of BNC210 actually decrease something they call flight intensity.

Flight int. So like how much the mice try to run away from something scary.

Exactly. It's a measure of their threat avoidance behavior.

So less fleeing, less panic.

Right. And remember what we saw in the human studies with the amydala, right?

Less activity there. So, it seems to be lining up,

right? It suggests that BNC210 is actually having an impact on those fear pathways in the brain.

Exactly. And it seems to be reducing that fear response.

That's really interesting.

Yeah. And there's another detail that's really important.

What's that?

So, they measured something else too called risk assessment intensity.

Risk assessment. So, like how cautiously the mice approach a potential threat.

Exactly. And BNC210 didn't affect that at all.

Oh, so they're not just becoming completely fearless or reckless.

Nope. They're still evaluing the situation. and being careful,

right? They're still thinking things through.

Exactly. Which suggests that BMC210 isn't just like sedating them or messing with their cognitive function,

right? It's not like just knocking them out.

Yeah. It seems to be very specifically targeting those fear and anxiety pathways

without disrupting other important behaviors.

Precisely. Which is huge because that means fewer side effects,

right? Because a lot of those current medications for anxiety, they can make people drowsy.

Exactly. Or foggyheaded.

So if BNC210 can work without those side effects, that's a huge deal.

Yeah. It could be a real gamecher for people who are struggling.

Definitely. So, we've been talking a lot about anxiety, but what about PTSD,

right?

How does BNC210 look in terms of treating PTSD?

So, remember how we talked about the hippocampus and how it's involved in memory formation? Yeah.

Well, it's also really important for processing and understanding those scary memories, those traumatic memories,

right?

And in people with PTSD, the hippocampus can actually get disregulated.

What does that mean?

Well, it means it has trouble distinguishing between a real threat and something that's harmless

like a trigger.

Exactly. Like a trigger. And that can lead to all sorts of problems like flashbacks, nightmares, intense anxiety even when they're in a safe situation.

It's like their brain is stuck in danger mode.

Yeah, you could say that. So the question is, how can BNC210 help with that, right?

Well, research suggests that modulating those A7 nicotinic receptors, remember that's what BNC210 does, right?

Could actually play a role in improving something called fear extinction.

Fear extinction. So like unlearning the fear.

Exactly. It's the process of basic basically getting the fear response to calm down over time.

I see. So, even though they've been through something traumatic, their brain can start to realize that it's not dangerous anymore.

Right. It's kind of similar to exposure therapy.

Oh, right. Where they gradually expose themselves to the things they're afraid of.

Exactly. In a safe environment, of course. Right.

Until their anxiety starts to decrease.

So, the idea is that BNC210 could make that process even more effective.

Right. It could help people with PTSD process those traumatic memories and move on.

So, it's not just about masking the symptoms, it's about addressing the root cause.

Exactly. And there's some pre-clinical evidence for this.

Oh, really?

Yeah. Studies with animals have shown that modulating the A7 receptor can actually enhance fear extinction.

So, it's looking promising.

It is, but we need more research, especially in humans, to really understand how well it works.

Right. Of course. So, all of this sounds really amazing, but I have to ask, yeah,

what about long-term effects?

Right.

What happens if someone takes BNC210 for a really long time, like months or even years?

Do we know if it's safe? That's the big question. And honestly, we need more long-term studies to really get a good answer. The initial research is definitely encouraging, but it's still early days. We need to be careful and do things the right way with good scientific investigation

because we know that chronic nicotine exposure can actually change those nicotinic receptors in the brain.

Exactly.

So, we need to figure out how BNC210 affects that whole balance in the long run.

And in the final part of our deep dive, we're going to talk about the bigger picture. What does all of this research mean and what could future hold for treatments based on these nicotinic receptors.

What's the big takeaway here for our listener?

I think the big takeaway is that we're starting to see a real shift in how we think about and treat mental health conditions.

Okay.

You know, for years the focus has been on targeting these really broad neurotransmitter system,

right? Like serotonin and dopamine.

Yeah, exactly. The usual suspects.

So, it's kind of like using a sledgehammer when what you really need is a scalpel.

That's a great analogy. But now with this research on nicotenic receptors, we're getting a lot more specific,

right? We're honing in on those specific subtypes and the circuits they're involved in.

So instead of this oneizefits-all approach, we can start to tailor treatments to the individual.

Precisely. It's all about hitting the right target with the right tool.

And that's what BNC210 is doing. Right.

Exactly. It's not just shutting down the whole system. It's fine-tuning that I7 receptor.

And that means fewer side effects.

Hopefully. Yes.

And this kind of targeted approach could have implications for so many other al health conditions too.

Absolutely. Not just anxiety and PTSD. We're talking about depression, addiction, even cognitive disorders.

Wow. The possibilities are really endless.

It's a very exciting time to be in this field.

It sounds like we're on the verge of some major breakthroughs.

I think so.

But of course, there's still a lot we don't know,

right?

So, what are some of the big questions that still need to be answered?

Well, one of the biggest ones is what happens in the long term,

right?

You know, what are the effects of modulating these receptors over a long period? of time, months, years.

We need to make sure it's safe.

Absolutely. We need to understand the potential risks and benefits

because like we talked about before, chronic nicotine exposure can really change the brain.

It can.

So, we need to be very careful and make sure we're not messing with that delicate balance.

Exactly. The brain is incredibly complex.

You know, it's not like we can just go in and tinker with one thing without affecting something else.

It's all interconnected. We have to be very careful. Every new discovery opens up a whole new world of possibilities.

It's been a real pleasure talking to you today. Guys,

thank you so much for sharing your expertise with us,

of course. Happy to do it.

And if you want to learn more, we'll be sure to include some links to the studies we talked about in the show notes.

Definitely check them out.

And that's it for this episode of The Deep Dive.

Thanks for listening, everyone.

Keep those brains buzzing and we'll catch you next time.