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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 20 of 20. This is the beginning of the thread.
Posted by anita on January 16, 2000, at 23:03:50
Does Buspar increase or decrease dopamine, generally speaking? I've seen it labelled as one or the other in Medline -- which is it? If a study says it's a dopamine antagonist, yet goes on to say it increases dopamine in various areas of the brain, does that mean it is an antagonist at dopamine autoreceptors, and thus acts like an agonist?
Thanks,
anita
Posted by jd on January 17, 2000, at 18:21:04
In reply to Buspar: dopamine agonist or antagonist? (Eliz?), posted by anita on January 16, 2000, at 23:03:50
I believe I've read that buspar is a mild antagonist at the D2 receptor, which is why there was a tad of concern at the outset whether it might cause antipsychotic-like side effects. (I don't think there's much concern about this any more.) Your hypothesis sounds reasonable to me: it's known that meds that specifically antagonize the D2 autoreceptor can increase dopamine levels and function like antidepressants. I've don't recall ever hearing buspar called an agonist or partial agonist at dopamine receptors, though it is generally referred to as a partial agonist at serotonin 1A receptors, I believe.
best,
jd> Does Buspar increase or decrease dopamine, generally speaking? I've seen it labelled as one or the other in Medline -- which is it? If a study says it's a dopamine antagonist, yet goes on to say it increases dopamine in various areas of the brain, does that mean it is an antagonist at dopamine autoreceptors, and thus acts like an agonist?
>
> Thanks,
> anita
Posted by Scott L. Schofield on January 19, 2000, at 22:09:29
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by jd on January 17, 2000, at 18:21:04
> I've don't recall ever hearing buspar called an agonist or partial agonist at dopamine receptors, though it is generally referred to as a partial agonist at serotonin 1A receptors, I believe.
I still can't figure out what is meant by "partial agonist". Any clues?
- Scott
Posted by jd on January 19, 2000, at 23:26:20
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by Scott L. Schofield on January 19, 2000, at 22:09:29
I've always been pretty confused too... My basic sense is that a partial agonist stimulates a given set of receptors, but can never do so to the extent of a full agonist. Thus, if there's lots of agonist around, a partial agonist can sometimes end up working more like an antagonist (by competing with the more powerful agonist).
Neurobiology students feel free to chime in... I'm out of my depth. :-)
-jd
>
> I still can't figure out what is meant by "partial agonist". Any clues?
>
>
> - Scott
Posted by JohnL on January 20, 2000, at 1:24:37
In reply to Buspar: dopamine agonist or antagonist? (Eliz?), posted by anita on January 16, 2000, at 23:03:50
> Does Buspar increase or decrease dopamine, generally speaking? I've seen it labelled as one or the other in Medline -- which is it? If a study says it's a dopamine antagonist, yet goes on to say it increases dopamine in various areas of the brain, does that mean it is an antagonist at dopamine autoreceptors, and thus acts like an agonist?
>
> Thanks,
> anitaGood question Anita. And I hope someone can address this in layman terms you and I can understand. These theories have always evaded me regardless of how hard I try to understand.
In literature I have seen it stated that Buspar "binds to" D2 dopamine receptors. The net effect of that is a mystery to me. I don't know what it means. Does it increase dopamine transmission? Decrease? Raise dopamine levels? Lower?
I have no clue. I hope someone can enlighten us. JohnL
Posted by Elizabeth on January 20, 2000, at 9:19:12
In reply to Re: what the heck is a partial agonist?, posted by jd on January 19, 2000, at 23:26:20
My understanding is that a partial agonist is a drug that activates a receptor to less than the maximum extent. I don't know how to express this quantitatively, though. (Where's Adam when we need him! :-) I think that the partial agonists can behave as antagonists at high concentrations.
Buspar is a partial agonist at 5-HT1a receptors and, I believe, a full antagonist at D2 receptors.
Posted by michael on January 20, 2000, at 16:16:47
In reply to Re: what the heck is a partial agonist?, posted by Elizabeth on January 20, 2000, at 9:19:12
> My understanding is that a partial agonist is a drug that activates a receptor to less than the maximum extent. I don't know how to express this quantitatively, though. (Where's Adam when we need him! :-) I think that the partial agonists can behave as antagonists at high concentrations.
>
> Buspar is a partial agonist at 5-HT1a receptors and, I believe, a full antagonist at D2 receptors.Could someone rephrase the last sentance above, without using the words agonins & antagonist? What's the net effect on the serotonin & dopamine levels/availability?
michael
Posted by Adam on January 20, 2000, at 18:33:18
In reply to Re: what the heck is a partial agonist?, posted by michael on January 20, 2000, at 16:16:47
> > My understanding is that a partial agonist is a drug that activates a receptor to less than the maximum extent. I don't know how to express this quantitatively, though. (Where's Adam when we need him! :-) I think that the partial agonists can behave as antagonists at high concentrations.
> >
> > Buspar is a partial agonist at 5-HT1a receptors and, I believe, a full antagonist at D2 receptors.
>
> Could someone rephrase the last sentance above, without using the words agonins & antagonist? What's the net effect on the serotonin & dopamine levels/availability?
>
> michaelFirst, it's difficult for me to discuss this without using terms like "agonist" and "antagonist" so I'll try to define those terms:
Agonist: A substance that binds/has affinity for a receptor (such as the serotonin 1A or "5-HT1A" receptor) that stimulates a response mediated by that receptor. It might just mimic the action of the natural ligand (i. e. serotonin binding its receptor) or have other effects not caused by the natural ligand (like LSD binding the serotonin receptor, perhaps?)
Antagonist: Essentially the opposite of the agonist. It binds/has affinity for the receptor and blocks responses mediated by that receptor. A dopamine D1 antagonist, for instance, would bind the D1 receptor and prevent or inhibit neurotransmission mediated by this receptor via binding of the natural ligand (dopamine). The ability of such a substance to antagonise such signalling is related to its binding affinity, i. e. its kinetics of binding must be more favorable than the agonist (be it the natural ligand or maybe a drug) to block signalling.
(There are so-called "indirect" agonists and antagonists, but we won't go there.)
My understanding of buspirone's behavior at the 5-HT1A receptor is as follows: It is a presynaptic 5-HT1A ("somatodendritic autoreceptors") full agonist and a partial agonist at postsynaptic 5-HT1A receptors. It was once thought that buspirone just looked like a "partial" agonist at postsynaptic receptors because there was a large reserve of the presynaptic autoreceptors (need for constant sensitivity despite receptor turnover following ligand binding, perhaps), while such was not the case for the postsynaptic cells. This would make the presynaptic-receptor-mediated response appear more sensitive, at least initially, before presynaptic desensitization takes place. However, later on, postsynaptic 5-HT1A full agonists were synthesized, so there goes that theory, apparently. (I can't find the paper now that proposed this, darnit, but I'll look). Thing is, I haven't heard of any other explanation for this behavior, and can't for the life of me understand why the same receptor on one cell (mere micrometers away from another cell, to boot) would have different binding affinities. I could propose all kinds of possible explanations (minor stearic inhibition of buspirone binding due to receptor cofactors found only on postynaptic cells, differential post-translational processing, alternative splicing of 5-HT1A messenger RNA (though this would be an obvious and easy thing to check out, and there's nothing in the literature)), but I'd be pulling things out of my butt, essentially.
To be honest, I really don't know what causes the difference, and I'm not aware of any definitive research on the question.
Posted by michael on January 20, 2000, at 19:12:26
In reply to Re: what the heck is a partial agonist?, posted by Adam on January 20, 2000, at 18:33:18
> > > My understanding is that a partial agonist is a drug that activates a receptor to less than the maximum extent. I don't know how to express this quantitatively, though. (Where's Adam when we need him! :-) I think that the partial agonists can behave as antagonists at high concentrations.
> > >
> > > Buspar is a partial agonist at 5-HT1a receptors and, I believe, a full antagonist at D2 receptors.
> >
> > Could someone rephrase the last sentance above, without using the words agonins & antagonist? What's the net effect on the serotonin & dopamine levels/availability?
> >
> > michael
>
> First, it's difficult for me to discuss this without using terms like "agonist" and "antagonist" so I'll try to define those terms:
>
> Agonist: A substance that binds/has affinity for a receptor (such as the serotonin 1A or "5-HT1A" receptor) that stimulates a response mediated by that receptor. It might just mimic the action of the natural ligand (i. e. serotonin binding its receptor) or have other effects not caused by the natural ligand (like LSD binding the serotonin receptor, perhaps?)
>
> Antagonist: Essentially the opposite of the agonist. It binds/has affinity for the receptor and blocks responses mediated by that receptor. A dopamine D1 antagonist, for instance, would bind the D1 receptor and prevent or inhibit neurotransmission mediated by this receptor via binding of the natural ligand (dopamine). The ability of such a substance to antagonise such signalling is related to its binding affinity, i. e. its kinetics of binding must be more favorable than the agonist (be it the natural ligand or maybe a drug) to block signalling.
>Thanks for the lesson! Is this what you said?
Both Agonists and Antogonists have the ability to bind to a particular type of receptor (HT-1a, D2, etc.)
The difference is in the effect/result of this binding to the receptor?
When a Serotonin Agonist binds to a particular type of receptor, the result is the same as what happens when real serotonin actually binds to that particular type of receptor. It mimics serotonin, and in effect "increases the availability of serotonin"?
Whereas a Serotonin Antagonist would bind to that same particular type of receptor, but would not trigger that event. And in binding to that receptor, reduces the number of receptors available to serotonin for binding, which would in this case, approximate reducing the "availability of serotonin"?
Posted by confused on January 20, 2000, at 20:17:59
In reply to Re: what the heck is a partial agonist?, posted by Elizabeth on January 20, 2000, at 9:19:12
a layman's question: What exactly is an agonist?
What is an antagonist? I have an idea but do not understand completely.thank-you!
> My understanding is that a partial agonist is a drug that activates a receptor to less than the maximum extent. I don't know how to express this quantitatively, though. (Where's Adam when we need him! :-) I think that the partial agonists can behave as antagonists at high concentrations.
>
> Buspar is a partial agonist at 5-HT1a receptors and, I believe, a full antagonist at D2 receptors.
Posted by Scott L. Schofield on January 21, 2000, at 8:53:17
In reply to Re: what the heck is a partial agonist?, posted by Adam on January 20, 2000, at 18:33:18
Hi Adam.
That was a wonderfully infomative explanation. I look forward to reading more of you.> > Could someone rephrase the last sentance above, without using the words agonins & antagonist?
Let me see if I can give this a try.An agonist is a molecule that sticks (binds) to a receptor and stimulates the the receptor to do what it was designed for. It gives the receptor a tickle.
An antagonist molecule blocks the receptor, also by binding to it. Only this time, it does not tickle it. Now that the agonist is prevented from getting to the receptor, nothing gets done. It is an inhibitor.
> > What's the net effect on the serotonin & dopamine levels/availability?I'll leave this one to someone else. I would like to know myself.
- Scott
Posted by Sam on January 21, 2000, at 17:38:24
In reply to Re: what the heck is a partial agonist?, posted by Adam on January 20, 2000, at 18:33:18
Are these presynaptic "autoreceptors" the same as reuptake receptors or a different type of receptor or are reuptake receptors a subtype of these "autoreceptors"?
Posted by Sam on January 21, 2000, at 18:20:35
In reply to Re: what the heck is a partial agonist?, posted by michael on January 20, 2000, at 19:12:26
The "availability" of serotonin or other neurotransmitter is not usually effected much by agonists or antagonists of the postsynaptic receptors. What would determine the "availability" would be the production and storage of the neurotransmitter (in the cell), the reuptake of the neurotransmitter, (absorbtion back into the cell), and the enzymatic degradation of the free neurotransmitter in the synaptic cleft (gap between pre and postsynapse) by MAO or COMT etc.. The neurotransmitter concentration in the synaptic cleft can be increased by antagonism of the reuptake receptors (reuptake antagonist, reuptake inhibitor) which has about the same effect as a postsynaptic agonist. Some drugs can effect several of these mechanisms at once.
Posted by anita on January 22, 2000, at 18:53:41
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by JohnL on January 20, 2000, at 1:24:37
Well, I asked my pdoc about this Buspar & dopamine issue, and he said he would say it was more of a dopamine agonist than antagonist (i.e., it generally increases dopamine transmission).
Still confused tho.
anita
> > Does Buspar increase or decrease dopamine, generally speaking? I've seen it labelled as one or the other in Medline -- which is it? If a study says it's a dopamine antagonist, yet goes on to say it increases dopamine in various areas of the brain, does that mean it is an antagonist at dopamine autoreceptors, and thus acts like an agonist?
> >
> > Thanks,
> > anita
>
> Good question Anita. And I hope someone can address this in layman terms you and I can understand. These theories have always evaded me regardless of how hard I try to understand.
>
> In literature I have seen it stated that Buspar "binds to" D2 dopamine receptors. The net effect of that is a mystery to me. I don't know what it means. Does it increase dopamine transmission? Decrease? Raise dopamine levels? Lower?
>
> I have no clue. I hope someone can enlighten us. JohnL
Posted by jd on January 23, 2000, at 23:52:58
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by anita on January 22, 2000, at 18:53:41
Anita,
Here's perhaps a clue to reducing the confusion-- A dopamine antagonist can still end up increasing dopamine transmission if it specifically antagonizes the dopamine "feedback" receptors called autoreceptors. When these receptors are activated, they in effect tell your system that there's already "enough" dopamine. Antagonize them, and your system is fooled into releasing extra dopamine to compensate. It's a bit like blowing cold air on your thermostat to trick your heater into going on. Can't guarantee that this is an effect of Buspar, but it's a good bet if it's indeed an antagonist (as I believe it to be).
--jd
> Well, I asked my pdoc about this Buspar & dopamine issue, and he said he would say it was more of a dopamine agonist than antagonist (i.e., it generally increases dopamine transmission).
>
> Still confused tho.
>
> anita
>
> > > Does Buspar increase or decrease dopamine, generally speaking? I've seen it labelled as one or the other in Medline -- which is it? If a study says it's a dopamine antagonist, yet goes on to say it increases dopamine in various areas of the brain, does that mean it is an antagonist at dopamine autoreceptors, and thus acts like an agonist?
> > >
> > > Thanks,
> > > anita
> >
> > Good question Anita. And I hope someone can address this in layman terms you and I can understand. These theories have always evaded me regardless of how hard I try to understand.
> >
> > In literature I have seen it stated that Buspar "binds to" D2 dopamine receptors. The net effect of that is a mystery to me. I don't know what it means. Does it increase dopamine transmission? Decrease? Raise dopamine levels? Lower?
> >
> > I have no clue. I hope someone can enlighten us. JohnL
Posted by jamie on January 24, 2000, at 3:19:58
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by jd on January 23, 2000, at 23:52:58
I saw in a research abstract that buspar increases dopamine and NE (by up to 240%) but decreases serotonin (by 50%). Given these effects, it is a mystery how it can augment an AD or treat anxiety. As is often the case, theory vs reality is perplexing.jamie
Posted by Scott L. Schofield on January 24, 2000, at 16:33:28
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by jamie on January 24, 2000, at 3:19:58
> I saw in a research abstract that buspar increases dopamine and NE (by up to 240%) but decreases serotonin (by 50%). Given these effects, it is a mystery how it can augment an AD or treat anxiety. As is often the case, theory vs reality is perplexing.It is important to remember that it is no more than theory as to how any of these drugs work to produce their clinical effects - both good and bad.
- Scott
Posted by anita on January 25, 2000, at 0:51:32
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by jd on January 23, 2000, at 23:52:58
Thanks --- this is what I thought, too. It's very confusing when you read a Medline abstract and it says something is an antagonist, but doesn't say whether it is at presynaptic or postsynaptic receptors. Also confusing is how ppl use the terms autoreceptor and presynaptic receptor interchangeably.
Ayiyi,
anita
> Anita,
> Here's perhaps a clue to reducing the confusion-- A dopamine antagonist can still end up increasing dopamine transmission if it specifically antagonizes the dopamine "feedback" receptors called autoreceptors. When these receptors are activated, they in effect tell your system that there's already "enough" dopamine. Antagonize them, and your system is fooled into releasing extra dopamine to compensate. It's a bit like blowing cold air on your thermostat to trick your heater into going on. Can't guarantee that this is an effect of Buspar, but it's a good bet if it's indeed an antagonist (as I believe it to be).
> --jd
>
>
Posted by Elizabeth on January 25, 2000, at 7:06:20
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by anita on January 25, 2000, at 0:51:32
> Also confusing is how ppl use the terms autoreceptor and presynaptic receptor interchangeably.
They shouldn't; there is also such a thing as a presynaptic heteroreceptor. (However, that may not be relevant depending on the context.)
Posted by Sam on January 28, 2000, at 1:10:12
In reply to Re: Buspar: dopamine agonist or antagonist? (Eliz?), posted by Elizabeth on January 25, 2000, at 7:06:20
So what kinds of presynaptic receptors are there? Would one be the same as a reuptake receptor? My Med. Chem. book doesn't mention "autoreceptors", it is a bit old though.
This is the end of the thread.
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