![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 9 to 33 of 39. Go back in thread:
Posted by rvanson on October 25, 2007, at 22:15:12
In reply to Dopamine agonists...why aren't more people using?, posted by King of Nothing on October 25, 2007, at 13:38:51
Because they are not specifically indicated for depression by the FDA yet.
Lots of Pdocs will prescribe them "off-label" but many wont do so.
My .02 cents.
> You would think that if dopamine is responsible for energy, motivation and the ability to experience pleasure, more people would be benefiting from such drugs as mirapex and requip. Doesn't this seem to make sense to anybody but me? Yet i have heard of many people using the above mentioned drugs without success..what's up with that?
Posted by amigan on October 26, 2007, at 5:20:59
In reply to Re: Dopamine agonists...why aren't more people usi, posted by djmmm on October 25, 2007, at 20:44:04
> Dopamine isn't necessarily responsible for energy and motivation, those traits have more to do with norepinephrine. Dopamine agonists tend to make people sleepy, hypertensive and nauseated.
You know.. I was about to open a new thread about this. Why dopamine agonists causes sedation? Dopamine suppose to be a stimulating neurotransmitter, thus its agonists should cause stimulation instead! (I don't doubt it, of course)
Could someone with knowledge in psychopharmacy help me to understand this?
Posted by psychobot5000 on October 26, 2007, at 14:18:50
In reply to Re: Dopamine agonists cause sedation. But why?? » djmmm, posted by amigan on October 26, 2007, at 5:20:59
Why dopamine agonists causes sedation? Dopamine suppose to be a stimulating neurotransmitter, thus its agonists should cause stimulation instead! (I don't doubt it, of course)
> Could someone with knowledge in psychopharmacy help me to understand this?I don't know all that much, but, that said, many neurotransmitters, dopamine included, have many targets in your nervous system. It may be that the D2 and D3 receptors these agonists hit merely have nothing to do with energy and etc.
Besides the reasons , i.e. lack of an FDA indication, expensiveness, that people have offered already, I have read that many people who take dopamine agonists find the side-effects excessive. This was certainly the case for me, as requip made me very tired, among a host of other annoying effects.
I would also suggest that saying that these ideas about dopamine being responsible for pleasure, energy, etc, are at best an inaccurate simplification of the way the brain works, and, some researchers believe, an error.
Posted by linkadge on October 26, 2007, at 15:04:53
In reply to Re: Dopamine agonists cause sedation. But why??, posted by psychobot5000 on October 26, 2007, at 14:18:50
Dopamine isn't necessarily a stimulating neurotransmitter. As mentioned previously, much of the actions that we associate with dopamine should really be associated with norepinephrine.
Most people think of certain drugs, ie caffiene, nicotine, amphetamines, ritalin, cocaine etc in terms of dopamine, when much of the energizing effect is probably due to norepinephrine.
We don't really have any pure dopamine reuptake inhibitors. Wellbutrin is as much stronger noradrenerigc effect than dopaminergic effect.
There are some investigational selective dopamine reuptake inhibitors which don't cause much psychomotor activation, but instead can produce drowsiness in human test subjects,
Opiates are an example of drugs that have dopaminergic mechanisms but no noradreneric mechanisms. They can cause euphoria, and pleasure without necesarily producing stimulation.
In certain areas of the brain, and at cetain receptors, dopamine causes inhibiton. The use of dopamine agonists in RLS, and Parkinsons is to produce inhibition. The use of stimulants in ADD can also produce inhibiton.
It also depends on the receptor type too. I think the d1 and d2 receptors produce opposing effects on activation/inhibition.
Linkadge
Posted by King of Nothing on October 26, 2007, at 16:07:56
In reply to Re: Dopamine agonists cause sedation. But why??, posted by linkadge on October 26, 2007, at 15:04:53
So what exactly does norepinephrine do? And what are the best meds to get it? Remeron? Effexor?
Posted by linkadge on October 26, 2007, at 17:42:12
In reply to Norepinephrine information please., posted by King of Nothing on October 26, 2007, at 16:07:56
Norepinephrine is involved in anxiety preception, pain preception, mood, energy levels, vigilance, cognative flexability, attention, alertness etc.
Drugs like wellbutrin, remeron, effexor, cymbalta, straterra affect it to varying amounts.
Stratterra, or older drugs like desipramine/nortryptaline are probably the best ways to get an idea of what norepinephrine does, and whether or not modifying it might influence your condition.
Linkadge
Posted by Brody on October 27, 2007, at 14:02:44
In reply to Dopamine agonists...why aren't more people using?, posted by King of Nothing on October 25, 2007, at 13:38:51
> You would think that if dopamine is responsible for energy, motivation and the ability to experience pleasure........>
>This is long and probably way more than you want to read, but you can scroll about half way down the page to the bold heading for "The Dopamine Connection".
From the folks at "Good Drug Guide":
It's a very comprehensive document.
My chronic TRD is atypical, and norepinephrine affecting meds have been my only pathway to remission. My first success was with the TCA desipramine, (one of those suggested by linkage below.) A 10-14 day trial should be sufficient. My only side effect was dry mouth.
Posted by linkadge on October 27, 2007, at 15:48:28
In reply to Re: Dopamine agonists...why aren't more people usi » King of Nothing, posted by Brody on October 27, 2007, at 14:02:44
I read somewhere too that in certain parts of the brain, the norepinephrine transporter can also metabolize dopamine. So an norepineprine reuptake inhibitor is to some extent a dopamine reuptake inhiibtor too.
Posted by Brody on October 27, 2007, at 16:35:31
In reply to Re: Dopamine agonists...why aren't more people usi, posted by linkadge on October 27, 2007, at 15:48:28
Yes.... I've read that, too. I'm sorry, I thought that was covered in the link I inserted, but I guess not.
Here are two references from PubMed docs:
".........the antidepressants that bind selectively the norepinephrine transporter might produce their therapeutic effect by raising the extracellular concentration of dopamine besides that of norepinephrine......"
and,
"Selective norepinephrine reuptake inhibitors exploit the fact that dopamine transporters are absent in prefrontal cortex, so dopamine has to hitchhike a ride on the norepinephrine transporter in order to be inactivated. Thus, blocking norepinephrine transporters leads to an increase in both dopamine and norepinephrine levels in prefrontal cortex..........."Janet
Posted by amigan on October 27, 2007, at 20:19:09
In reply to Re: Dopamine agonists cause sedation. But why??, posted by linkadge on October 26, 2007, at 15:04:53
> Dopamine isn't necessarily a stimulating neurotransmitter. As mentioned previously, much of the actions that we associate with dopamine should really be associated with norepinephrine.
Ok.
> Most people think of certain drugs, ie caffiene, nicotine, amphetamines, ritalin, cocaine etc in terms of dopamine, when much of the energizing effect is probably due to norepinephrine.I see.
> We don't really have any pure dopamine reuptake inhibitors. Wellbutrin is as much stronger noradrenerigc effect than dopaminergic effect.We use to have one. Amineptine. And iirc, it was a mild stimulant.
> There are some investigational selective dopamine reuptake inhibitors which don't cause much psychomotor activation, but instead can produce drowsiness in human test subjects,
I'm not sure if this is 100% true. See Amineptine.
> Opiates are an example of drugs that have dopaminergic mechanisms but no noradreneric mechanisms. They can cause euphoria, and pleasure without necesarily producing stimulation.Opiates are not a good example imho... I think they cause sedation by activating the opioid receptors.
Imagine a drug that have strong antihistaminic properties and weak noradrenergic. That drug would have been a sedative despite its action on the NE. Perhaps nortriptyline is a good example to this.
> In certain areas of the brain, and at cetain receptors, dopamine causes inhibiton. The use of dopamine agonists in RLS, and Parkinsons is to produce inhibition. The use of stimulants in ADD can also produce inhibiton.
>
> It also depends on the receptor type too. I think the d1 and d2 receptors produce opposing effects on activation/inhibition.Interesting.
Posted by linkadge on October 27, 2007, at 20:47:33
In reply to Re: Dopamine agonists...why aren't more people usi » linkadge, posted by Brody on October 27, 2007, at 16:35:31
Sorry, I should have read the link. Thats interesting about DAT in the frontal cortex. I know that MAO-B is rich in that area too, so I would imagine dopamine metabolism there is affected by NET,MAO-B, and perhaps COMT.
Linkadge
Posted by linkadge on October 27, 2007, at 21:04:00
In reply to Re: Dopamine agonists cause sedation. But why?? » linkadge, posted by amigan on October 27, 2007, at 20:19:09
>We use to have one. Amineptine. And iirc, it was >a mild stimulant.
Yes, but hard to say. I don't know how selective it was. It was abusable but I didn't know it was a strong stimulant.
>I'm not sure if this is 100% true. See >Amineptine.
Well, I was refering to drugs that are still in stages of development. I will try to look for some of the abstracts. There is the issue too of co-release. Oftentimes release of dopamine initiates the release of norepinephrine, and vice versa. So even a pure DRI, might have an indirect noradrenergic effect. Nevertheless, I think a dopamine agonist may circumvent this issue.
>Imagine a drug that have strong antihistaminic >properties and weak noradrenergic. That drug >would have been a sedative despite its action on >the NE. Perhaps nortriptyline is a good example >to this.Yes, but the noradrenergic effects of nortryptaline are still pronounced. It will still get the ticker going. Sedative and stimulant effects don't always totally or directly cancel.
Its really too simplistic to look at it in these ways though, I know. Dopamine does not do one thing.
Linkadge
Posted by cactus on October 28, 2007, at 20:13:27
In reply to Re: Dopamine agonists cause sedation. But why??, posted by linkadge on October 27, 2007, at 21:04:00
I don't know why they cause sedation but when I first started ropinirole I had to go to bed as soon as it kicked in.
Posted by psychobot5000 on October 30, 2007, at 21:39:50
In reply to Re: Dopamine agonists cause sedation. But why?? » linkadge, posted by cactus on October 28, 2007, at 20:13:27
> I don't know why they cause sedation but when I first started ropinirole I had to go to bed as soon as it kicked in.
Worth noting that, though ropinirole sedated me, I did find amineptine stimulating.
dexamphetamine actually makes me a little drowsy, but methylphenidate does the opposite.
Strange.
Posted by tecknohed on October 31, 2007, at 4:54:21
In reply to Norepinephrine information please., posted by King of Nothing on October 26, 2007, at 16:07:56
> So what exactly does norepinephrine do?
Its 'get up and go'!
Posted by Astounder on October 31, 2007, at 14:02:28
In reply to Re: Dopamine agonists cause sedation. But why?? » linkadge, posted by cactus on October 28, 2007, at 20:13:27
Two things to say about differentiating the effects of dopamine agonists from L-DOPA & psychostimulants:
1.) Unlike DA, DA agonists always have a higher affinity for D2Sh than D2Lh. D2Lh is the postsynaptic receptor that mediates the reinforcing, mood elevating, psychomotor activating, wakefulness promoting, and psychotomimetic effects of the psychostimulants we all know and love. D2Sh is the inhibitory presynaptic autoreceptor; activation of this inhibits exocytotic release of dopamine from the axon terminal into the synaptic cleft.
Psychostimulants get around this autoreceptor because they mimic excessive burst firing; that is, they so quickly cause accumulation of DA in the synaptic cleft that when even the presynaptic receptors are saturated and inhibiting further release from the axon, there's more than enough extracellular DA to activate postsynaptic receptors on the dendrite and initiate the action potential. Methamphetamine reverses the DA transporter, depleting axonal DA and spilling it into the synapse; because neurotransmission now no longer reliant on exocytosis of DA from the terminal, autoreceptor activation does nothing. Cocaine and methylphenidate block the reuptake of the catecholamines; here autoreceptors do nothing because the DA in the cleft will stay there to stimulate postsynaptic receptors until they're catabolized by glial cells--which will take quite a while, as the reuptake inhibitors will also block the high-affinity DA and NE transporters on these glial cells, leaving only the low-affinity uptake2. Nicotine's activation of Ca2+-permeable nAChRs on dopaminergic neurons can directly induce burst firing, even during resting potential. Additionally, NE potentiates DA firing in both the short term, but activating alpha2 heteroreceptors on serotonergic neurons that tonically inhibit DA firing, by competing with DA's uptake into glial cells, and in the long term by increasing extrasynaptic DA levels through blocking uptake2 through its metabolite through way of COMT, normetanephrine.
DA agonists cannot overcome these feedback mechanisms like psychostimulants can, because they are unable to mimic or stimulate burst firing; even tonally they are less efficacious than endogenous DA, due to their higher affinity for the autoreceptor than the postsynaptic receptor.
2.) More importantly, there are peripheral DA receptors. These receptors are not normally activated by DA, because most DA is trapped inside the BBB, while peripheral DA is voraciously metabolized by MAO and COMT in glial cells and platelets. Psychostimulants do not activate these receptors because they are not direct agonists. Even L-DOPA's activation of these receptors can limited by co-administration of carbidopa.
On the sympathetic ganglia, peripheral D2 receptors are inhibitory heteroreceptors. Activation results in vasodilation by preventing release of norepinephrine; the resulting orthostatic hypotension causes the feeling of profound drowsiness and weakness. Agonism of D2 receptors in the CTZ causes nausea and vomiting. There are other peripheral D2 and D3 receptors, but their effects are not well understood.
Finally, many DA agonists are also agonists at the presynaptic alpha2 adrenoceptor and antagonists at the postsynaptic alpha1 adrenoceptor giving them additional indirect and direct anti-noradrenergic/sympatholytic actions, respectively.
Posted by linkadge on October 31, 2007, at 22:36:42
In reply to Re: Dopamine agonists cause sedation. But why??, posted by Astounder on October 31, 2007, at 14:02:28
>.) Unlike DA, DA agonists always have a higher >affinity for D2Sh than D2Lh. D2Lh is the >postsynaptic receptor that mediates the >reinforcing, mood elevating, psychomotor >activating, wakefulness promoting, and >psychotomimetic effects of the psychostimulants >we all know and love. D2Sh is the inhibitory >presynaptic autoreceptor; activation of this >inhibits exocytotic release of dopamine from the >axon terminal into the synaptic cleft.
But does it make sense that the theraputic effect of a dopamine agonist would correspond with an overal decrease in post synaptic receptor stimulation?
If they do have higher affinity for presynaptic autoreceptors and the sedation does correspond to a decrease in dopamine release, then why would one get improvement in Parkinson's symptoms right after dosing? Wouldn't one expect the net decrease in post synaptic dopamine receptor function to correspond to worsening Parkinsonian symptoms?
So I guess what I am saying is why do parkinsons symptoms remit at the same time as an increase in sedation? You obviously are getting a net increase in dopaminergic neurotransmission at this point or else or else parkinsons symptoms wouldn't decrease, yet you are experiencing somnolence at the same time.
Also, one would expect the autoreceptors would desensize leading to a net increase in dopamine release overtime. Does the sedation improve over time (I don't know I have never taken it)
Linkadge
Posted by Astounder on November 1, 2007, at 11:30:46
In reply to Re: Dopamine agonists cause sedation. But why??, posted by linkadge on October 31, 2007, at 22:36:42
> >.) Unlike DA, DA agonists always have a higher >affinity for D2Sh than D2Lh. D2Lh is the >postsynaptic receptor that mediates the >reinforcing, mood elevating, psychomotor >activating, wakefulness promoting, and >psychotomimetic effects of the psychostimulants >we all know and love. D2Sh is the inhibitory >presynaptic autoreceptor; activation of this >inhibits exocytotic release of dopamine from the >axon terminal into the synaptic cleft.
>
> But does it make sense that the theraputic effect of a dopamine agonist would correspond with an overal decrease in post synaptic receptor stimulation?
>
> If they do have higher affinity for presynaptic autoreceptors and the sedation does correspond to a decrease in dopamine release, then why would one get improvement in Parkinson's symptoms right after dosing? Wouldn't one expect the net decrease in post synaptic dopamine receptor function to correspond to worsening Parkinsonian symptoms?
>
> So I guess what I am saying is why do parkinsons symptoms remit at the same time as an increase in sedation? You obviously are getting a net increase in dopaminergic neurotransmission at this point or else or else parkinsons symptoms wouldn't decrease, yet you are experiencing somnolence at the same time.
>
> Also, one would expect the autoreceptors would desensize leading to a net increase in dopamine release overtime. Does the sedation improve over time (I don't know I have never taken it)
>
>
> Linkadge
>
>
>
>It's not that they're completely ineffective for their purposes, rather I'm trying to explain why they don't cause the rapid reversal of depressive symptoms like amphetamines do. Though the autoreceptors are activated, the dopamine agonist is still able to activate the postsynaptic receptors, even if less DA is entering the cleft than normal. But their lowered potency compared to pure dopamine (by the ratio of affinity to post- and presynaptic receptors) would explain why L-DOPA eventually becomes preferred over DA agonists in the late stages of Parkinson's, despite its greater incidence of side-effects.
Likely, the autoreceptors do desensitize over time, and this is probably responsible for any delayed antidepressant effects, but by this time you may already be desensitizing the postsynaptic receptors as well. For Parkinson's patients, who have hypersensitive striatal DA receptors, the sedating action of DA agonists are going to be overcome by the psychomotor activation that stimulation of the striatum causes. In depressives who don't have hypersensitive striatal DA receptors (at least, that I know of), there is not going to be psychomotor activation to overcome the sedating effects of the DA agonists.
I haven't taken them, so I don't know how much the sedation improves. You should develop at least partial tolerance to sedation resulting from the alpha1 antagonism and alpha2 agonism, like you do with prazosin and clonidine, respectively. I don't know anything about tolerance to the orthostatic effects of peripheral DA receptors.
Honestly, If I'm going for DA, I'd rather activate the DAergic pathways through augmenting the action of DA itself, instead of trying to mimic it with direct agonists: DL-phenylalanine or microdose L-DOPA + carbidopa, MAO-B or full MAO inhibitors, COMT inhibitors, DRIs, NRIs, glial OCT3/uptake2 blockers, 5HT2A & 5HT2C antagonists, alpha2 antagonists, NMDA antagonists, AMPA agonists, nicotine, intermittent doses of neuroleptics to reverse tolerance, pyridoxal-phosphate, reserpine, tetrabenazine, or kappa-opioid pretreatment, and any other things I can't think of.
Posted by amigan on November 1, 2007, at 11:41:36
In reply to Re: Dopamine agonists cause sedation. But why?? » linkadge, posted by Astounder on November 1, 2007, at 11:30:46
Very educating and illuminating posts! Thanks everyone for this.
Posted by amigan on November 2, 2007, at 6:36:00
In reply to Re: Dopamine agonists cause sedation. But why?? » linkadge, posted by Astounder on November 1, 2007, at 11:30:46
> > >.) Unlike DA, DA agonists always have a higher >affinity for D2Sh than D2Lh. D2Lh is the >postsynaptic receptor that mediates the >reinforcing, mood elevating, psychomotor >activating, wakefulness promoting, and >psychotomimetic effects of the psychostimulants >we all know and love. D2Sh is the inhibitory >presynaptic autoreceptor; activation of this >inhibits exocytotic release of dopamine from the >axon terminal into the synaptic cleft.
> >
> > But does it make sense that the theraputic effect of a dopamine agonist would correspond with an overal decrease in post synaptic receptor stimulation?
> >
> > If they do have higher affinity for presynaptic autoreceptors and the sedation does correspond to a decrease in dopamine release, then why would one get improvement in Parkinson's symptoms right after dosing? Wouldn't one expect the net decrease in post synaptic dopamine receptor function to correspond to worsening Parkinsonian symptoms?
> >
> > So I guess what I am saying is why do parkinsons symptoms remit at the same time as an increase in sedation? You obviously are getting a net increase in dopaminergic neurotransmission at this point or else or else parkinsons symptoms wouldn't decrease, yet you are experiencing somnolence at the same time.
> >
> > Also, one would expect the autoreceptors would desensize leading to a net increase in dopamine release overtime. Does the sedation improve over time (I don't know I have never taken it)
> >
> >
> > Linkadge
> >
> >
> >
> >
>
> It's not that they're completely ineffective for their purposes, rather I'm trying to explain why they don't cause the rapid reversal of depressive symptoms like amphetamines do. Though the autoreceptors are activated, the dopamine agonist is still able to activate the postsynaptic receptors, even if less DA is entering the cleft than normal. But their lowered potency compared to pure dopamine (by the ratio of affinity to post- and presynaptic receptors) would explain why L-DOPA eventually becomes preferred over DA agonists in the late stages of Parkinson's, despite its greater incidence of side-effects.
>
> Likely, the autoreceptors do desensitize over time, and this is probably responsible for any delayed antidepressant effects, but by this time you may already be desensitizing the postsynaptic receptors as well. For Parkinson's patients, who have hypersensitive striatal DA receptors, the sedating action of DA agonists are going to be overcome by the psychomotor activation that stimulation of the striatum causes. In depressives who don't have hypersensitive striatal DA receptors (at least, that I know of), there is not going to be psychomotor activation to overcome the sedating effects of the DA agonists.
>
> I haven't taken them, so I don't know how much the sedation improves. You should develop at least partial tolerance to sedation resulting from the alpha1 antagonism and alpha2 agonism, like you do with prazosin and clonidine, respectively. I don't know anything about tolerance to the orthostatic effects of peripheral DA receptors.
>
> Honestly, If I'm going for DA, I'd rather activate the DAergic pathways through augmenting the action of DA itself, instead of trying to mimic it with direct agonists: DL-phenylalanine or microdose L-DOPA + carbidopa, MAO-B or full MAO inhibitors, COMT inhibitors, DRIs, NRIs, glial OCT3/uptake2 blockers, 5HT2A & 5HT2C antagonists, alpha2 antagonists, NMDA antagonists, AMPA agonists, nicotine, intermittent doses of neuroleptics to reverse tolerance, pyridoxal-phosphate, reserpine, tetrabenazine, or kappa-opioid pretreatment, and any other things I can't think of.I think you pretty much covered them all. :-P
I can only think of adenosine antagonists like caffeine, but i suspect that it is not very potent.
I see that 5HT2A and 5HT2C antagonists increase dopamine. Does this mean that certain antidepressants like mirtazapine are expected to do the job? Are there any more potent 5HT2A/C antagonists than this drug?
Posted by Astounder on November 2, 2007, at 12:43:49
In reply to Re: Dopamine agonists cause sedation. But why?? » Astounder, posted by amigan on November 2, 2007, at 6:36:00
> I see that 5HT2A and 5HT2C antagonists increase dopamine. Does this mean that certain antidepressants like mirtazapine are expected to do the job? Are there any more potent 5HT2A/C antagonists than this drug?
Mirtazapine, a potent 5-HT2a/c antagonist, immediately and robustly increases DA firing in some areas, like the frontal cortex and the ventral tegmental area, which are involved in executive functioning and reward, respectively.
The most potent 5-HT2a blocking antidepressant is the tricyclic amitripytline (Elavil). It has higher affinity than serotonin itself, which explains why, even though a highly effective serotonin and norepinephrine reuptake inhibitor, it does not cause the serotonin syndrome in combination with a full MAOI (multiple reuptake inhibitors, like Effexor, clomipramine, and imipramine usually seem to cause a worse serotonin syndrome than pure SSRIs). Nefazodone and trazodone are both also 5-HT2a antagonists.
Many of the typical antipsychotics, such as chlorpromazine (Thorazine), and the antihistamine cyproheptadine are highly efficacious at this site, which is why they're used to treat the serotonin syndrome. Low dose (0.5-1 mg) Risperdal (along with its active metabolite) is probably the most selective 5-HT2a antagonist on the market with its with subnanomolar affinity; most other atypicals have a high affinity for this site, including clozapine, olanzipine, sertindole, ziprasidone, aripiprazole.
At 5-HT2c, most of the typical and atypical neuroleptics that have strong 5-HT2a blocking also have strong action here, though you can't go by the binding data alone, since some work as inverse agonists. Again, cyproheptadine and Elavil bind strongly, with Elavil acting as an inverse agonist. The pipeline antidepressant/anti-insomnic drug agomelatine (Valdoxan) is selective for 5-HT2c receptors in addition to M1 & M2 melatonin receptors.
Any drug that results in prolonged stimulation of both the 5-HT1 & 5-HT2 series receptors--SSRIs, SNRIs, MAOIs--is going eventually cause the downregulation of 5-HT2 series receptors. Conversely, blockers of the 5-HT2 receptors also result in their downregulation.
I would stay away from 5-HT2c antagonists honestly, unless you're OCD or anorexic, since they can cause massive weight gain. If you work out though, they can help in bulking up. Drugs with stimulate these receptors are not always anxiogenic: MDMA's psychomotor stimulating & wakefulness promoting effects are partly through 5-HT2a stimulation, and this receptor may play a part in MDMA's release of oxytocin (which is responsible for its anxiolytic, empathogenic, and disinhibiting effects). Stimulation of the 5-HT2c receptor is responsible for the actions of the serotonergic anorectics, like megadose (900 mg/d) 5-HTP, reuptake inhibitors like sibutramine, and releasers like fenfluramine.
Atypical opiates like tramadol, levorphanol, and methadone have functional, naloxone-reversible 5-HT2a/c blocking actions, which explains why they can be used long term to treat OCD & Tourettism. Opposite direct 5-HT2c blockers, opiate abuse has been known to cause weight loss, though withdrawal can cause weight gain. This is probably because opiates substitute for food-induced reward in animal studies.
Posted by Amigan on November 2, 2007, at 13:40:19
In reply to Re: Dopamine agonists cause sedation. But why?? » amigan, posted by Astounder on November 2, 2007, at 12:43:49
Posted by linkadge on November 2, 2007, at 15:08:36
In reply to Re: Dopamine agonists cause sedation. But why?? » amigan, posted by Astounder on November 2, 2007, at 12:43:49
>The most potent 5-HT2a blocking antidepressant >is the tricyclic amitripytline (Elavil). It has >higher affinity than serotonin itself, which >explains why, even though a highly effective >serotonin and norepinephrine reuptake inhibitor, >it does not cause the serotonin syndrome in >combination with a full MAOI
That depends. It is not a strong 5-ht1a antagonist which means that some symptoms of serotonin syndrome can still occur namely hyothermaia.
>Again, cyproheptadine and Elavil bind strongly, >with Elavil acting as an inverse agonist. The >pipeline antidepressant/anti-insomnic drug >agomelatine (Valdoxan) is selective for 5-HT2c >receptors in addition to M1 & M2 melatonin >receptors.
The combination of cyproheptadine and melatonin is very effective for insomnia in myself.
>Conversely, blockers of the 5-HT2 receptors also >result in their downregulation.
Probably by indireclty potentiating 5-ht1a
>I would stay away from 5-HT2c antagonists >honestly, unless you're OCD or anorexic, since >they can cause massive weight gain. If you work >out though, they can help in bulking up.
For some people agents with 5-ht2c antagonism can be very effective for reducing agitation and augmenting antidepressant responce. Fluoxetine for example is actually a stronger 5-ht2c antagonist that 5-ht reuptake inhibitor. Unlike other SSRI's, fluoxetine actually increase frontal cortex levels of nor/dopamine.
>Drugs with stimulate these receptors are not >always anxiogenic: MDMA's psychomotor >stimulating & wakefulness promoting effects are >partly through 5-HT2a stimulation, and this >receptor may play a part in MDMA's release of >oxytocin (which is responsible for its >anxiolytic, empathogenic, and disinhibiting >effects).
MDMA is not a selctive 5-ht2a agonist though. Its hard to say whether it is these metabolites are really non anxiogenic, or if other aspects of the drug simply cancel out the anxiogenic effects of 5-ht2a agonist metabilites. Trazodone, for instance, has a metabolite that mcpp which is similar in some respects to MDMA. MCPP is a 5-ht2a agonist, yet trazodone itself is a 5-ht2a antagonist.
Also, MDMA or one of its metabolites acts as a 5-ht2c antagonist which probably enhnaces accumbal release of dopamine.
>Stimulation of the 5-HT2c receptor is >responsible for the actions of the serotonergic >anorectics, like megadose (900 mg/d) 5-HTP, >reuptake inhibitors like sibutramine, and >releasers like fenfluramine.
Yeah and 5-ht2b agonsts are what is responsible for cardiac hypertrophy and valve dammage. Probably why to avoid all SSRI's.
>opiate abuse has been known to cause weight >loss, though withdrawal can cause weight gain.
Or the exact opposite.
>This is probably because opiates substitute for >food-induced reward in animal studies.
Animals will not starve themselves to death if able to continuasly self administer opiates as they will if they are able to continusly self administer cocaine/meth.
Linkadge
Posted by linkadge on November 2, 2007, at 15:11:23
In reply to Re: Dopamine agonists cause sedation. But why?? » amigan, posted by Astounder on November 2, 2007, at 12:43:49
http://www.biopsychiatry.com/gbr12909.htm
The selective dopamine reuptake inhibitor causes dose dependant *sedation* in human volunteers.
I still argue that it is norepinephrine which is mainly responsible for the "stimulating" aspects of stimulants. Yet dopamine is more involved in reward.
Linkadge
Posted by Astounder on November 2, 2007, at 16:27:44
In reply to Re: Dopamine agonists cause sedation. But why??, posted by linkadge on November 2, 2007, at 15:08:36
> That depends. It is not a strong 5-ht1a antagonist which means that some symptoms of serotonin syndrome can still occur namely hyothermaia.
Hypothermia is not a normal symptom of the serotonin syndrome. Do you mean hyperthermia?
Animal studies indicate that hyperthermia from serotonin syndrome is mediated entirely through 5-HT2a receptors:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11164765&ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10867971&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusRitanserin, pipamperone, and risperidone are highly selective for the 5-HT2 series over 5-HT1a, and risperidone is 5-HT2a selective over 5-HT2c.
5-HT1a may be responsible for some of the behavioral symptoms, though.
There are clinical studies in humans proving the safety of a MAOI with Elavil:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6342565&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=7435677&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus> Yeah and 5-ht2b agonsts are what is responsible for cardiac hypertrophy and valve dammage. Probably why to avoid all SSRI's.
SSRIs actually reduce plasma and platelet 5-HT levels with chronic use, though, so they shouldn't cause cardiac fibrosis. Unrelatedly, because 5-HT induces platelet aggregation, SSRIs are thrombolytic in vitro, and there are ongoing studies to determine if SSRIs reduce the risk of infarction and stroke.
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