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Dr. Bob is Robert Hsiung, MD,
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Posted by undopaminergic on February 5, 2023, at 16:15:47
In reply to Re: Are Neuroleptics brain specific anticholinergics? » Lamdage22, posted by SLS on February 5, 2023, at 11:17:10
> Hi.
>
>
> I agree with UD.
>
> I wonder, though, if the BBB barrier prevents some substances from exiting the brain that it had previously allowed to enter it. If this occurs, then I imagine the concentration of a drug in the brain becomes higher than that in the rest of the body. Could be.
>I can't clarify your question about the BBB possibly retaining substances. However, another mechanism for accumulation of a substance in the brain is if the substance is lipophilic, in which case the concentrations will be higher in the brain (and other fatty tissues) than the bloodstream.
-undopaminergic
Posted by SLS on February 5, 2023, at 19:43:04
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 5, 2023, at 14:14:31
> Next question: Do MAOI increase histamine?
Like dopamine (DA), norepinephrine (NE), and serotonin (5-HT), the histamine molecule is a biogenic amine. Monoamine oxides type A (MAO-A) leaves histamine virtually untouched. MAO-B metabolizes (breaks-down) histamine, but to a very small degree. MAO exists *inside* the neuron, but not outside the neuron. Histamine is metabolized *outside* the neuron by an enzyme called diamine oxidase (DAO). Another enzyme located outside the neuron is catechol-O-methyltransferase (COMT). As with the MAO enzyme located inside the neuron, it metabolizes DA, NE, and 5-HT outside the neuron, but to a much smaller degree.I don't know very much about how histamine functions in the body.
- Scott
Posted by SLS on February 6, 2023, at 8:03:02
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 5, 2023, at 19:43:04
Hi.
In re: The Blood-Brain Barrier and anticholinergic drugs.
Anticholinergic drugs enter the brain at different rates.
Trospium (Sanctura) is an anticholinergic (muscarinic) drug used to treat overactive bladder, a peripheral function. However, it seems to be blocked from entering the brain almost entirely by the BBB. It can't even be detected in the cerebrospinal fluid (CSF). Trospium effectively treats a broad array of maladies like overactive bladder. It accomplishes this by reducing the tone of the muscles involved. Anticholinergics work by blocking the (muscranic) acetylcholine receptors that normally innervate muscles to contract. These are peripheral effects. However, when an anticholinergic drug makes its way into the brain / CNS, central side-effects can occur:
1. Short-term: Produces impairments in cognition and memory, confusion, impaired concentration, restlessness, agitation, and delirium.
2. Long-term: Increases risk for developing irreversible dementia.
Hopefully, the risk of contracting dementia when using trospium long-term will be much lower than for other anticholinergic drugs.
https://pubmed.ncbi.nlm.nih.gov/22390261/
- Scott
Posted by undopaminergic on February 6, 2023, at 12:45:07
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 5, 2023, at 19:43:04
> > Next question: Do MAOI increase histamine?
>
>
> Like dopamine (DA), norepinephrine (NE), and serotonin (5-HT), the histamine molecule is a biogenic amine. Monoamine oxides type A (MAO-A) leaves histamine virtually untouched. MAO-B metabolizes (breaks-down) histamine, but to a very small degree. MAO exists *inside* the neuron, but not outside the neuron. Histamine is metabolized *outside* the neuron by an enzyme called diamine oxidase (DAO). Another enzyme located outside the neuron is catechol-O-methyltransferase (COMT). As with the MAO enzyme located inside the neuron, it metabolizes DA, NE, and 5-HT outside the neuron, but to a much smaller degree.
>As the name implies, COMT breaks down catecholamines, but not serotonin.
> I don't know very much about how histamine functions in the body.
>I don't know much about histamine either, but I've read it is the neurotransmitter whose activity is most correlated with wakefulness (and inversely correlated with the lack of wakefulness). This is perhaps not so surprising given the sedative effects of antihistamine drugs.
-undopaminergic
Posted by undopaminergic on February 6, 2023, at 12:58:00
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 6, 2023, at 8:03:02
> Hi.
>
> In re: The Blood-Brain Barrier and anticholinergic drugs.
>
> Anticholinergic drugs enter the brain at different rates.
>
> Trospium (Sanctura) is an anticholinergic (muscarinic) drug used to treat overactive bladder, a peripheral function. However, it seems to be blocked from entering the brain almost entirely by the BBB. It can't even be detected in the cerebrospinal fluid (CSF). Trospium effectively treats a broad array of maladies like overactive bladder. It accomplishes this by reducing the tone of the muscles involved. Anticholinergics work by blocking the (muscranic) acetylcholine receptors that normally innervate muscles to contract. These are peripheral effects. However, when an anticholinergic drug makes its way into the brain / CNS, central side-effects can occur:
>
> 1. Short-term: Produces impairments in cognition and memory, confusion, impaired concentration, restlessness, agitation, and delirium.
>
> 2. Long-term: Increases risk for developing irreversible dementia.
>
> Hopefully, the risk of contracting dementia when using trospium long-term will be much lower than for other anticholinergic drugs.
>
> https://pubmed.ncbi.nlm.nih.gov/22390261/
>
>
> - ScottFor local (such as nasal mucosa) treatment ipratropium and tiotropium are other antimuscarinics that don't cross the blood-brain-barrier. I'm using the former to reduce night-time salivation.
-undopaminergic
Posted by Lamdage22 on February 6, 2023, at 14:15:59
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by undopaminergic on February 6, 2023, at 12:45:07
> I don't know much about histamine either, but I've read it is the neurotransmitter whose activity is most correlated with wakefulness (and inversely correlated with the lack of wakefulness). This is perhaps not so surprising given the sedative effects of antihistamine drugs.
>
> -undopaminergicSome psychiatrists describe psychosis as being 'too awake'.
Posted by Lamdage22 on February 6, 2023, at 14:18:00
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:15:59
Posted by Lamdage22 on February 6, 2023, at 14:50:44
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:18:00
It seems that Histamine is at least involved in Psychosis and Schizophrenia. https://www.hmpgloballearningnetwork.com/site/pcn/article/antihistamine-decreases-schizophrenia-symptoms
Maybe in a subset of patients? Im trying to get further testing in the histamine/mast cell direction asap. Im opting to go to a lab directly. I won't go around begging doctors.
Posted by undopaminergic on February 6, 2023, at 15:10:35
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:50:44
> It seems that Histamine is at least involved in Psychosis and Schizophrenia. https://www.hmpgloballearningnetwork.com/site/pcn/article/antihistamine-decreases-schizophrenia-symptoms
>Note that this study is about a histamine *H2*-receptor antagonist (famotidine). Ordinary antihistamines block the H1-receptor.
Trimipramine and clozapine do block histamine H2, though, in addition to H1.
-undopaminergic
Posted by SLS on February 6, 2023, at 19:11:09
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by undopaminergic on February 6, 2023, at 12:45:07
> > > Next question: Do MAOI increase histamine?
> >
> >
> > Like dopamine (DA), norepinephrine (NE), and serotonin (5-HT), the histamine molecule is a biogenic amine. Monoamine oxides type A (MAO-A) leaves histamine virtually untouched. MAO-B metabolizes (breaks-down) histamine, but to a very small degree. MAO exists *inside* the neuron, but not outside the neuron. Histamine is metabolized *outside* the neuron by an enzyme called diamine oxidase (DAO). Another enzyme located outside the neuron is catechol-O-methyltransferase (COMT). As with the MAO enzyme located inside the neuron, it metabolizes DA, NE, and 5-HT outside the neuron, but to a much smaller degree.
> As the name implies, COMT breaks down catecholamines, but not serotonin.
Good catch. Thanks.
> > I don't know very much about how histamine functions in the body.
> I don't know much about histamine either, but I've read it is the neurotransmitter whose activity is most correlated with wakefulness (and inversely correlated with the lack of wakefulness). This is perhaps not so surprising given the sedative effects of antihistamine drugs.I'm not sure how many pathways / neurotransmitters are involved with sleep. It's more than one, though. Hypocretin (orexin) is important in maintaining wakefulness. Hypocretin was first labeled as being a neuropeptide. Later, it was found in synaptic vesicles, so it is now often considered to be a neurotransmitter. Another substance that reduces wakefulness and promotes sleep is adenosine. Unlike hypocretin, it is not found in presynaptic vesicles, and is therefore considered a neuropeptide. Adenosine is liberated from the cell membrane along the neuron and into the fluid. There are several types of adenosine receptor. The major role of adenosine is to inhibit wakefulness and promote sleep. Caffeine produces its stimulatory behavioral effects by blocking adenosine receptors, and thus prevents adenosine from performing its role to oppose wakefulness.
Google and PubMed are fun to look through when we are discussing points of interest. I already knew some basics regarding hypocretin, adenosine, and caffeine, but I don't like to leave things that I am uncertain about go unchecked. I start out trying to fact-check what I'm writing, but this usually leads to expanding the scope of the discussion and adding details.
I didn't want to leave you with the impression that I was really that smart. <grin>.
- ScottP.S. I really should have double-checked COMT. <wink>
Posted by SLS on February 6, 2023, at 19:19:45
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:18:00
> https://pubmed.ncbi.nlm.nih.gov/17349864/
Thanks, Lamdage. I had no idea.
I found something that you might find useful:
https://pubmed.ncbi.nlm.nih.gov/20021346/
How does that blood test work?
- Scott
Posted by Lamdage22 on February 7, 2023, at 2:49:50
In reply to Re:Neuroleptics brain specific antihistaminergic? » Lamdage22, posted by SLS on February 6, 2023, at 19:19:45
You mean the test(s) I am contemplating? From what I have gathered thus far: There are urine tests for the following:
Histamin, N-Methylhistamin and Prostaglandin D2 11-β-PGF2α
Blood:
Serum-Tryptase.
Serum-Chromogranin A.
chilled plasma: Prostaglandin D2, und/oder 11-β-PGF2α.
chilled Plasma: Histamin
chilled Plasma: HeparinThese can give you a good idea if your mast cells are overactive. There are mast cell stabilizers, natural and pharmaceutical.
Posted by Lamdage22 on February 7, 2023, at 2:51:19
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 7, 2023, at 2:49:50
My apologies: 11-beta-PGF2alpha
Posted by undopaminergic on February 7, 2023, at 11:15:54
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 6, 2023, at 19:11:09
>
> I'm not sure how many pathways / neurotransmitters are involved with sleep. It's more than one, though.
>Dopamine too. I find it particularly interesting that dopamine neurons involved in wakefulness have been found in a region called the ventral periaqueductal gray (vPAG):
https://pubmed.ncbi.nlm.nih.gov/16399687/
"Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter"> Hypocretin (orexin) is important in maintaining wakefulness. Hypocretin was first labeled as being a neuropeptide. Later, it was found in synaptic vesicles, so it is now often considered to be a neurotransmitter. Another substance that reduces wakefulness and promotes sleep is adenosine. Unlike hypocretin, it is not found in presynaptic vesicles, and is therefore considered a neuropeptide. Adenosine is liberated from the cell membrane along the neuron and into the fluid. There are several types of adenosine receptor. The major role of adenosine is to inhibit wakefulness and promote sleep. Caffeine produces its stimulatory behavioral effects by blocking adenosine receptors, and thus prevents adenosine from performing its role to oppose wakefulness.
>I think maybe what you mean by "neuropeptide" is "neurohormone" or "neuromodulator". A neuropeptide is a substance that (1) has a peptide structure, and that (2) is involved with the nervous system. Orexin does have a peptide structure, but adenosine does not.
-undopaminergic
Posted by undopaminergic on February 7, 2023, at 11:20:30
In reply to Re:Neuroleptics brain specific antihistaminergic? » Lamdage22, posted by SLS on February 6, 2023, at 19:19:45
>
> I found something that you might find useful:
>
> https://pubmed.ncbi.nlm.nih.gov/20021346/
>I'm very interested in trying a histamine H3-receptor antagonist (or inverse agonist), but none are clinically available.
-undopaminergic
Posted by SLS on February 8, 2023, at 6:02:51
In reply to Re:Neuroleptics brain specific antihistaminergic? » SLS, posted by undopaminergic on February 7, 2023, at 11:15:54
Hi, UD.
> I think maybe what you mean by "neuropeptide" is "neurohormone" or "neuromodulator". A neuropeptide is a substance that (1) has a peptide structure, and that (2) is involved with the nervous system. Orexin does have a peptide structure, but adenosine does not.
Another good catch. Thanks.
- Scott
Posted by SLS on February 9, 2023, at 5:43:27
In reply to Re:Neuroleptics brain specific antihistaminergic? » SLS, posted by undopaminergic on February 7, 2023, at 11:20:30
> >
> > I found something that you might find useful:
> >
> > https://pubmed.ncbi.nlm.nih.gov/20021346/
> >
>
> I'm very interested in trying a histamine H3-receptor antagonist (or inverse agonist), but none are clinically available.
>
> -undopaminergic
>Do you know whether or not any H3 antagonists are in the pipeline for FDA approval?
- Scott
Posted by undopaminergic on February 9, 2023, at 10:10:52
In reply to Re:Neuroleptics brain specific antihistaminergic? » undopaminergic, posted by SLS on February 9, 2023, at 5:43:27
> > >
> > > I found something that you might find useful:
> > >
> > > https://pubmed.ncbi.nlm.nih.gov/20021346/
> > >
> >
> > I'm very interested in trying a histamine H3-receptor antagonist (or inverse agonist), but none are clinically available.
> >
> > -undopaminergic
> >
>
> Do you know whether or not any H3 antagonists are in the pipeline for FDA approval?
>No, I don't know. But I was wrong: betahistine is mostly a histamine H3-receptor antagonist, and it is clinically available in Europe, including my location, but it was withdrawn from the market in the US.
-undopaminergic
Posted by Lamdage22 on February 9, 2023, at 11:21:51
In reply to Re:Neuroleptics brain specific antihistaminergic? » SLS, posted by undopaminergic on February 9, 2023, at 10:10:52
Yep, that rings a bell. Are you still experiencing psychotic symptoms?
Was hospital of any help? Are you out again?
Posted by Jay2112 on February 9, 2023, at 19:10:51
In reply to Re:Neuroleptics brain specific antihistaminergic? » SLS, posted by undopaminergic on February 9, 2023, at 10:10:52
> > > >
> > > > I found something that you might find useful:
> > > >
> > > > https://pubmed.ncbi.nlm.nih.gov/20021346/
> > > >
> > >
> > > I'm very interested in trying a histamine H3-receptor antagonist (or inverse agonist), but none are clinically available.
> > >
> > > -undopaminergic
> > >
> >
> > Do you know whether or not any H3 antagonists are in the pipeline for FDA approval?
> >
>
> No, I don't know. But I was wrong: betahistine is mostly a histamine H3-receptor antagonist, and it is clinically available in Europe, including my location, but it was withdrawn from the market in the US.
>
> -undopaminergic
>I took betahistine for almost 3 months (I am in Canada). It seemed to make me very depressed. I was taking it for inner-ear problems.
Jay
Posted by undopaminergic on February 12, 2023, at 11:55:22
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 9, 2023, at 11:21:51
> Yep, that rings a bell. Are you still experiencing psychotic symptoms?
>No, and I haven't had a full psychosis since the end of 2009 (resembling paranoid schizophrenia).
> Was hospital of any help?
Not much. Especially when considering that I would have sought outpatient treatment without it.
> Are you out again?
No.
-undopaminergic
Posted by undopaminergic on February 12, 2023, at 12:00:25
In reply to Re:Neuroleptics brain specific antihistaminergic? » undopaminergic, posted by Jay2112 on February 9, 2023, at 19:10:51
> > > > >
> > > > > I found something that you might find useful:
> > > > >
> > > > > https://pubmed.ncbi.nlm.nih.gov/20021346/
> > > > >
> > > >
> > > > I'm very interested in trying a histamine H3-receptor antagonist (or inverse agonist), but none are clinically available.
> > > >
> > > > -undopaminergic
> > > >
> > >
> > > Do you know whether or not any H3 antagonists are in the pipeline for FDA approval?
> > >
> >
> > No, I don't know. But I was wrong: betahistine is mostly a histamine H3-receptor antagonist, and it is clinically available in Europe, including my location, but it was withdrawn from the market in the US.
> >
> > -undopaminergic
> >
>
> I took betahistine for almost 3 months (I am in Canada). It seemed to make me very depressed. I was taking it for inner-ear problems.
>
> JayH3 antagonists increase histaminergic neurotransmission, and should have stimulant-like effects. Maybe you have endogenously high histamine? Do you benefit from regular (H1) antihistamines?
-undopaminergic
Posted by SLS on February 13, 2023, at 21:41:38
In reply to Re:Neuroleptics brain specific antihistaminergic? » Jay2112, posted by undopaminergic on February 12, 2023, at 12:00:25
Hi.
I just read that the H3 receptor is exclusively a presynaptic autorececeptor. Is this your understanding as well?
If H3 receptors operate like DA and NE presynaptic autoreceptors, an agonist of H3 autoreceptors would reduce the presynaptic release of histamine. This would be analogous to the pharmacodynamics of clonidine. Clonidine is selective as an agonist of presynaptic NE alpha-2 autoreceptors. The net effect is to reduce presynaptic NE release. Depression is a very common side effects of clonidine. Mirtazepine is the antithesis of clonidine. It is a selective *antagonist* of presynaptic NE alpha-2 autoreceptors. It increases the release of NE. The net effect of mirtazepine is to act clinically as an antidepressant. However,there are other properties of mirtazepine that must be considered when explaining how it produces its antidepressant effects. I don't know much about how mirtazepine acts at postsynaptic serotonin receptors. Does mirtazepine cause a net increase in DA activity in the prefrontal cortext?
- Scott
Posted by SLS on February 13, 2023, at 21:46:01
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by undopaminergic on February 12, 2023, at 11:55:22
Sorry. I didn't see your previous post.
> Yep, that rings a bell. Are you still experiencing psychotic symptoms?
> >
>
> No, and I haven't had a full psychosis since the end of 2009 (resembling paranoid schizophrenia).
>
> > Was hospital of any help?
>
> Not much. Especially when considering that I would have sought outpatient treatment without it.
>
> > Are you out again?
>
> No.
>
> -undopaminergic
>
Posted by undopaminergic on February 14, 2023, at 11:32:22
In reply to Re:Neuroleptics brain specific antihistaminergic? » undopaminergic, posted by SLS on February 13, 2023, at 21:41:38
> Hi.
Hi.
> I just read that the H3 receptor is exclusively a presynaptic autorececeptor. Is this your understanding as well?
>It's my impression, but don't quote me on it. I think the H3 receptor is found only in the CNS.
> If H3 receptors operate like DA and NE presynaptic autoreceptors, an agonist of H3 autoreceptors would reduce the presynaptic release of histamine. This would be analogous to the pharmacodynamics of clonidine. Clonidine is selective as an agonist of presynaptic NE alpha-2 autoreceptors. The net effect is to reduce presynaptic NE release.
>Yes, but I think clonidine (like guanfacine) also targets some postsynaptic alpha2-adrenoceptors. It also has an effect on imidazoline receptors.
> Depression is a very common side effects of clonidine. Mirtazepine is the antithesis of clonidine. It is a selective *antagonist* of presynaptic NE alpha-2 autoreceptors. It increases the release of NE. The net effect of mirtazepine is to act clinically as an antidepressant. However,there are other properties of mirtazepine that must be considered when explaining how it produces its antidepressant effects. I don't know much about how mirtazepine acts at postsynaptic serotonin receptors.
>If I recall correctly, mirtazpine blocks (postsynaptic) serotonin 5-TH2A and 5-HT2C receptors.
Yohimbine is a more selective alpha2-adrenoceptor antagonist.
I did not react well to mirtazapine, and I'm inclined to blame the alpha2-antagonism. I liked guanfacine much better. Maybe it's because I have ADHD and working memory impairment.
I had a weird experience with mirtazapine. After taking it and eating a protein-rich meal, I felt some kind of cramping that affected mostly the neck. I hypothesised that it happened because the amino acids (specifically tyrosine and phenylalanine) were converted to noradrenaline and released into the synapse in a dishinhibited manner due to the mirtazapine blockade of autoreceptors. But it may be placebo.
> Does mirtazepine cause a net increase in DA activity in the prefrontal cortext?
>The blockade of the serotonin 5-HT2A and -C receptors should work to that effect, but it is unlikely to have a net stimulant effect due to the blockade of histamine H1-receptors. That's why it is usually taken at night. However, I wouldn't be surprised if it does have a stimulant effect on some users.
-undopaminergic
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Dr. Bob is Robert Hsiung, MD,
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