![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 22 of 22. This is the beginning of the thread.
Posted by linkadge on February 19, 2006, at 18:19:26
Is this true ??
From:http://psychservices.psychiatryonline.org/cgi/content/full/52/11/1469
The effect of NSRIs on serotonin and dopamine may be explained by the observation that norepinephrine, acting through alpha1 receptors, can induce release of these transmitters (54). However, in addition, the norepinephrine transporter protein—the reuptake site—also has high affinity for the reuptake of dopamine (56). Thus NSRIs are, in effect, dopamine reuptake inhibitors as well.
Linkadge
Posted by Racer on February 19, 2006, at 20:04:18
In reply to NRIs are infact dopamine uptakin inhibitors ?, posted by linkadge on February 19, 2006, at 18:19:26
Dunno, but isn't NE a DA precursor? That would make me think there's something to it...
Then again, what do I know?
Posted by zeugma on February 19, 2006, at 20:09:38
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by Racer on February 19, 2006, at 20:04:18
The NE transporter has a higher affinity than the dopamine transporter for DA.
This is why drugs like atomoxetine and desipramine are effective for ADHD symptoms.
-z
Posted by Phillipa on February 19, 2006, at 20:32:44
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by zeugma on February 19, 2006, at 20:09:38
Tell me more. Fondly, Phillipa
Posted by SLS on February 19, 2006, at 23:30:21
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by zeugma on February 19, 2006, at 20:09:38
> The NE transporter has a higher affinity than the dopamine transporter for DA.
>
> This is why drugs like atomoxetine and desipramine are effective for ADHD symptoms.
>
> -z
It has been a long time since I looked at the literature on this subject, but we are not talking about synaptic dopamine here. It is the dopamine that "leaks" into the interstitial fluids that bathe the soma and axons that are taken up by the NAT. Yes, dopamine does play a role in the regulation (perhaps neuromodulation is a better word) of tone of NE neurons in the frontal cortex. Here, dopamine is acting in slow motion compared to the rapid transduction of signals within the synapse. NRIs are thus not really DA reuptake inhibitors at the synapse of NE or DA neurons.
- Scott
Posted by zeugma on February 20, 2006, at 6:15:08
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by SLS on February 19, 2006, at 23:30:21
I meant that DA is a higher-affinity substrate for the NE transporter than the DA transporter. This means that in some regions of the brain, DA synaptic clearance is more affected by NE transporter blockade than DA transporter blockade, namely those regions where the NE transporter density is greater than the DA transporter density.
unless i'm wrong in how i read this article, which is extremely understandable because my brain feels like it has slowed to a crawl.J Neurosci. 2002 Jan 15;22(2):389-95.
Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines.Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT.
Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
Selective blockers of the norepinephrine transporter (NET) inhibit dopamine uptake in the prefrontal cortex. This suggests that dopamine in this region is normally cleared by the somewhat promiscuous NET. We have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of 3H-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice. At transporter-specific concentrations, nisoxetine and GBR12909 failed to block dopamine uptake into frontal cortex synaptosomes from NET knock-out mice. The efficacy of cocaine at the highest dose (1 mm) was normal in DAT knock-out mice but reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine uptake by 20% in caudate and nucleus accumbens synaptosomes from wild-type and DAT knock-out mice but had no effect in those from NET knock-out mice. Cocaine failed to block dopamine uptake into caudate or nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and GBR12909 each inhibited dopamine uptake into caudate synaptosomes from NET knock-out mice, but cocaine effectiveness was reduced in the case of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in caudate and nucleus accumbens depends primarily on the DAT, dopamine uptake in frontal cortex depends primarily on the NET. These data underscore the fact that which transporter clears dopamine from a given region depends on both the affinities and the local densities of the transporters.
-z
Posted by linkadge on February 20, 2006, at 8:32:39
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » SLS, posted by zeugma on February 20, 2006, at 6:15:08
The above said something interesting. It said that the levels of DA in the neucleus accumbens are mainly controlled by DAT. I am guessing this is why NRI's do not posess the abuse potential that DRI's do?
Linkadge
Posted by SLS on February 20, 2006, at 9:34:00
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » SLS, posted by zeugma on February 20, 2006, at 6:15:08
I think we are getting our cortical wires crossed.
:-)
The point I was trying to make is that the dopamine found in the cortical areas we are talking about is not released into the synapses of NE neurons, but is mainly found just diffusing passively within the interstitial fluids (extracellularly), having been released by DA neurons elsewhere. It looks for any dopamine receptors it can find. This distant non-synaptic neurotransmission is sometimes called volume neurotransmission. It turns out that the NET is the only uptake pump in some areas able to clear this rogue dopamine. The rest is probably metabolized by catechol-o-methyltransferase (COMPT). Nevertheless, this diffused dopamine does affect the activity of these cortical areas and plays a role in regulating attention and working memory.
I guess the bottom line is that NE uptake inhibitors help to regulate the "tone" of dopaminergic neurons by sweeping up their mess for them. If the brooms break, the tone of DA neurons increases, leading them to become more easily stimulated by the messages they are meant to propogate.
Up until now, we have been talking mainly about the *reuptake* of synaptic neurotransmitters for reuse when we consider its inhibition by drugs. In this case, however, it is the *uptake* and mostly destructive clearance of heterogenous neurotransmitter that is at issue.
To complicate the issue, not all of the DA taken up by NE terminals is deactivated. Some of it still manages to make its way into protective storage vesicles to be released with the next NE action potential.
- Scott
Posted by zeugma on February 20, 2006, at 9:36:09
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by linkadge on February 20, 2006, at 8:32:39
NRI's don't possess abuse liability in studies. Elevation of DA levels in the prefrontal cortex is not considered reinforcing in contrast to elevations in the accumbens. This was a major selling point for atomoxetine.
-z
Posted by SLS on February 20, 2006, at 10:17:50
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by zeugma on February 20, 2006, at 9:36:09
> NRI's don't possess abuse liability in studies. Elevation of DA levels in the prefrontal cortex is not considered reinforcing in contrast to elevations in the accumbens. This was a major selling point for atomoxetine.
>
> -z
It's pretty neat when something on paper actually works out in real life.
- Scott
Posted by SLS on February 20, 2006, at 12:48:41
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » zeugma, posted by SLS on February 20, 2006, at 9:34:00
> I guess the bottom line is that NE uptake inhibitors help to regulate the "tone" of dopaminergic neurons by sweeping up their mess for them.
I said that wrong.
I meant to say that the NE uptake transporter pumps located on noradrenergic neurons act as brooms to sweep up the mess left by the release of dopamine from dopaminergic neurons; a mess for which the dopaminergic neurons are ill equiped to handle for themselves.
> If the brooms break [drug-induced NE uptake transporter inhibition], the tone of DA neurons increases, leading them to become more easily stimulated by the messages they are meant to propogate.
Sorry.
Steven Stahl, MD, has a good handle on this stuff.
- Scott
Posted by zeugma on February 20, 2006, at 13:02:52
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » zeugma, posted by SLS on February 20, 2006, at 9:34:00
> I think we are getting our cortical wires crossed.
>
> :-)
>my cortical wires have fused :-) nonetheless I will try to follow your discussion (there is so much to learn, and so little I know)
> The point I was trying to make is that the dopamine found in the cortical areas we are talking about is not released into the synapses of NE neurons, but is mainly found just diffusing passively within the interstitial fluids (extracellularly), having been released by DA neurons elsewhere. It looks for any dopamine receptors it can find. This distant non-synaptic neurotransmission is sometimes called volume neurotransmission. It turns out that the NET is the only uptake pump in some areas able to clear this rogue dopamine. The rest is probably metabolized by catechol-o-methyltransferase (COMPT). Nevertheless, this diffused dopamine does affect the activity of these cortical areas and plays a role in regulating attention and working memory.>>
COMT pleomorphisms have been associated with ADHD, with response to modafinil, and with cognitive impairment in schizophrenia. All of this is presumably due to alterations in the volume transmission of dopamine in an area poor in DA transporters.
One theory is that NE uptake inhibitors, by prolonging the action of DA in the synapse, thereby increase the odds of its stimulating a DA receptor (mostly D1 and D4 receptors). It is the D4 receptor that has been the most highly associated with ADHD (in terms of allelic expression), except for the dopamine transporter itself (strong expression of the DA transporter is conjectured to reduce D4 stimulation in an area naturally low in DA transporters- my own conjecture- i.e. the DA transporter extends into areas normally cleared by the NE transporter, providing yet another mechanism for clearing extracellular DA, and thus reduces D4 stimulation by volume transmission of DA through the extracellular space- I was using 'synapse' perhaps wrongly as a synonym for this space). Overexpression of DA transporters, along with underexpression of D4 receptors, would conceivably cause additive effects and result in some of the more severe phenotypes of ADHD.
It is also worth noting that the dopamine beta hydroxylase enzyme, which converts DA into NE within the NE neuron (and thus after the NE transporter has sucked the DA into the neuron) has also been associated with ADHD, which would provide another reason NE transporter blockade is desirable in ADHD. One theory, based on an animal model, holds that ADHD is a hypernoradrenergic, hypodopaminergic state.
>
> I guess the bottom line is that NE uptake inhibitors help to regulate the "tone" of dopaminergic neurons by sweeping up their mess for them. If the brooms break, the tone of DA neurons increases, leading them to become more easily stimulated by the messages they are meant to propogate.>>I think that NE uptake inhibitors have been investigated for the relief of 'negative symptoms' in schizophrenia, by stimulating the D4 receptors on the PFC, while not causing heightened stimulation of the D2 receptors in the accumbens that are responsible for the 'positive' symptoms.
In terms of ADHD, atomoxetine is considered more potent than placebo but weaker than methylphenidate or amphetamine. But it can be effective in those who have poorer responses to methylphenidate, at least, because overexpression of the DA transporter has been associated with MPH nonresponse (makes sense). In any case I have found atomoxetine to be the most 'stimulant-like' of the drugs I have taken.
>
>
> To complicate the issue, not all of the DA taken up by NE terminals is deactivated. Some of it still manages to make its way into protective storage vesicles to be released with the next NE action potential.>>this is why the NE transporter has been called 'promiscuous.' it makes all of our lives more complicated
:-)
thank you for stimulating my thought (such that it can be)
-z
>
>
> - Scott
Posted by zeugma on February 20, 2006, at 13:14:22
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by SLS on February 20, 2006, at 12:48:41
> > I guess the bottom line is that NE uptake inhibitors help to regulate the "tone" of dopaminergic neurons by sweeping up their mess for them.
>
> I said that wrong.
>
> I meant to say that the NE uptake transporter pumps located on noradrenergic neurons act as brooms to sweep up the mess left by the release of dopamine from dopaminergic neurons; a mess for which the dopaminergic neurons are ill equiped to handle for themselves..>assuming all is well with the dopaminergic neurons, that is.
Presumably we mess around with NE uptake because there's a dysregulation in the system, but not necessarily with the broom that we toss out the window (inactivate). I don't think any study has convincingly linked the broom (NE transporters) with either depression or ADHD, and yet the drugs that act on this mechanism are effective for both disorders. Perhaps because the DA neurons in the prefrontal cortex are not sufficiently responsive to the pool of dopamine that is floating around (tonic DA), and hence require a less efficient cleaning system in order to compensate.
>
> >
>>
> Steven Stahl, MD, has a good handle on this stuff.>>where did he buy his broom? my hands are splintered from all this :-)
-z
>
>
> -
>
Posted by SLS on February 20, 2006, at 13:29:35
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » SLS, posted by zeugma on February 20, 2006, at 13:02:52
Hi Z.
You said a mouthful!
> COMT pleomorphisms have been associated with ADHD, with response to modafinil, and with cognitive impairment in schizophrenia.
Would these represent an overactivity of the enzyme?
> Overexpression of DA transporters, along with underexpression of D4 receptors, would conceivably cause additive effects and result in some of the more severe phenotypes of ADHD.
> One theory, based on an animal model, holds that ADHD is a hypernoradrenergic, hypodopaminergic state.
That sort of makes sense to me. It's an interesting idea.
> I think that NE uptake inhibitors have been investigated for the relief of 'negative symptoms' in schizophrenia, by stimulating the D4 receptors on the PFC, while not causing heightened stimulation of the D2 receptors in the accumbens that are responsible for the 'positive' symptoms.
My symptoms overlap greatly with the deficit syndrome seen in schizophrenia. That, and the severity of my cognitive impairments, point to the PFC as a site of dysfunction. I am beginning to more seriously consider rTMS as a modality by which to increase the activity of the left DLPFC.
> In terms of ADHD, atomoxetine is considered more potent than placebo but weaker than methylphenidate or amphetamine.
Statistically speaking, of course, in terms of numbers of "responders" - not in the quality of response.
> But it can be effective in those who have poorer responses to methylphenidate, at least, because overexpression of the DA transporter has been associated with MPH nonresponse (makes sense). In any case I have found atomoxetine to be the most 'stimulant-like' of the drugs I have taken.
Have you ever looked into a drug called mazindol? It is a very potent ligand for the DAT. However, I don't know the extent to which it actually acts as a DA reuptake inhibitor. There has been some debate about this. It might actually act more through NE. It is an approved antiobesity drug still used as a biological probe to assay DAT binding.
What are your thoughts on sibutramine?
- Scott
Posted by linkadge on February 20, 2006, at 13:42:01
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by zeugma on February 20, 2006, at 13:14:22
Bipolars and people with other mood disorders oftentimes have less dense prefronal cortexes.
There is a certain area of the subgenual prefronal cortex that shows some significant problems. Dr Manjii's work with lithium and valproate has shown that lithium and valproate can reverse this shrinkadge but that Antidepressants do not.
"I don't think any study has convincingly linked the broom (NE transporters) with either depression or ADHD, and yet the drugs that act on this mechanism are effective for both disorders."
Neither has any study convincingly linked SERT to depression!
Enhancing catecholamine activity may compensate for reduced prefronal cortex volumes and subsequent reduced regional blood flow. Or something like that :)
Linkadge
Posted by zeugma on February 20, 2006, at 14:48:06
In reply to Re: NRIs are infact dopamine uptakin inhibitors ?, posted by SLS on February 20, 2006, at 13:29:35
Hi Scott.
>
> > COMT pleomorphisms have been associated with ADHD, with response to modafinil, and with cognitive impairment in schizophrenia.
>
> Would these represent an overactivity of the enzyme?The less active COMT enzymes are associated with better response to atypical AP's a nd less severe cognitive impairment in schizophrenia. In ADHD it is paradoxically associated with poorer executive function.
>
> >
> > I think that NE uptake inhibitors have been investigated for the relief of 'negative symptoms' in schizophrenia, by stimulating the D4 receptors on the PFC, while not causing heightened stimulation of the D2 receptors in the accumbens that are responsible for the 'positive' symptoms.
>
> My symptoms overlap greatly with the deficit syndrome seen in schizophrenia. That, and the severity of my cognitive impairments, point to the PFC as a site of dysfunction. I am beginning to more seriously consider rTMS as a modality by which to increase the activity of the left DLPFC.
>I don't know much about rTMS (is that what linkadge was doing?) I have long believed, based no doubt on a crude understanding of brain morphology, that my own symptoms are related to DLPFC dysregulation. In particular, I think it's activated when it's supposed to shut off (during REM) and underactivated when it's supposed to be working (causing a trance-like state during wake). What is the mechanism conjectured responsible for rTMS' stimulation of the DLPFC?
> > In terms of ADHD, atomoxetine is considered more potent than placebo but weaker than methylphenidate or amphetamine.
>
> Statistically speaking, of course, in terms of numbers of "responders" - not in the quality of response.That point is often lost on people who think Strattera is 'weaker' than the other ADHD meds. of course, drug companies take this into account when developing drugs. This means that those who would respond to an unconventional modality- not that Strattera, e.g., is a particularily unconventional drug- are left waiting for the next magic bullet to pass them by :-(
>
> >
>
> Have you ever looked into a drug called mazindol? It is a very potent ligand for the DAT. However, I don't know the extent to which it actually acts as a DA reuptake inhibitor. There has been some debate about this. It might actually act more through NE. It is an approved antiobesity drug still used as a biological probe to assay DAT binding.
>
Mazindol is also used in Europe to treat narcolepsy. It is similar to nomifensine? (which was also looked at for ADHD). Did you find that nomifensine had a positive effect on cognition?> What are your thoughts on sibutramine?
>
Ken Gillman, who operates a site called http://psychotropical.com/, speaks highly of this as an AD, at least when I used to visit his site.Have you ever tried it?
I wonder if D4 ligands have been looked at in depression.
-z
>
> - Scott
Posted by zeugma on February 20, 2006, at 15:31:34
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » SLS, posted by zeugma on February 20, 2006, at 14:48:06
given that we have been discussing the promiscuity of transporters for substrates: the D4 receptor is quite promiscuous as well:
1: Eur J Pharmacol. 2006 Feb 15;531(1-3):20-4. Epub 2006 Jan 19.
[(35)S]GTPgammaS binding at the human dopamine D4 receptor variants hD4.2, hD4.4 and hD4.7 following stimulation by dopamine, epinephrine and norepinephrine.Czermak C, Lehofer M, Liebmann PM, Traynor J.
Department of General Psychiatry I, Sigmund Freud Clinics Graz, Wagner Jauregg Platz 1, 8053 Graz, Austria; Institute of Pathophysiology, Medical University of Graz, Heinrichstr. 31a, 8010 Graz, Austria.
Aim of the present study was to investigate possible differences between the human dopamine D4 receptor 48 bp polymorphism variants hD4.2, hD.4. and hD4.7 in agonist stimulated [(35)S]GTPgammaS binding, to investigate dopamine D4 receptor sodium sensitivity and to further characterize norepinephrine and epinephrine agonism at this receptor. G-protein activation at the receptor variants hD4.2, hD4.4 and hD4.7 expressed in CHO-K1 cells, following stimulation by dopamine, norepinephrine and epinephrine, was investigated using the [(35)S]GTPgammaS assay at experimental conditions of 10 and 100 mM sodium, respectively. Dopamine displayed a 2 fold higher potency of stimulating [(35)S]GTPgammaS binding at the hD4.2, compared to the hD4.4 and hD4.7 at 10 mM sodium. A significant difference in sodium sensitivity of basal [(35)S]GTPgammaS binding was found, with the hD4.7 being 1.7 fold more sensitive than the hD4.4 and 2.5 fold more sensitive than the hD4.2. Norepinephrine and epinephrine both produced concentration-dependent increases in [(35)S]GTPgammaS binding at all three receptor variants, and epinephrine showed only 2 fold less potency than dopamine. The present results are in certain line with previous reports of functional 2-3 fold differences between the dopamine D4 receptor variants. Agonism of norepinephrine and epinephrine at the dopamine D4 receptor may indicate an important way of cross-reactivity among the different monoamine neurotransmitter systems.
It's interesting that the 7-repeat polymorphism of the D4 receptor is the one most associated with ADHD symptomology, and also with methylphenidate resistance (1.7 mg/kg is required to bring about satisfactory improvement in symptoms with this polymorphism), consonant with my experience, in which over 1 mg/kg destroyed my appetite and made me severely anxious, but did not produce the improvement that a standard dose of atomoxetine did.
I've felt for a long time that I am more responsive to adrenergic than dopaminergic meds.
-z
Posted by linkadge on February 20, 2006, at 16:13:04
In reply to this is interesting, posted by zeugma on February 20, 2006, at 15:31:34
rTMS has been used with some sucess in individuals who are intollerant of medications used in ADD.
It has a number of unique biochemical effects, some of which are shared by ECT.
It illicits a strong responce in certain areas associated with the regulation of circadian rythem.
It also shows an interesting pattern of receptor alteration. It desensitizes both 5-ht1a/b autoreceptors. It downregulates beta adrenoreceptors. I also think it has some effects on dopamine autoreceptors.
I have experiemented with all sorts of different parameters and frequencies. 15hz seems to produce the strongest effect on mood.
15 hz also (surprisingly) led to an almost immediate reduction in my headaches.
rTMS (like ECT) in animals, increases the behavioral sensitivity to stimulants.
(this may be due to 5-ht autorceptor downregulation, since mice 5-ht autoreceptor mutant mice also display an increased behavioral responce to stimulants)
Linkadge
Posted by zeugma on February 21, 2006, at 13:50:19
In reply to Re: this is interesting, posted by linkadge on February 20, 2006, at 16:13:04
> rTMS has been used with some sucess in individuals who are intollerant of medications used in ADD. >>
did you find that your attention/focus was improved while undergoing rTMS?
>
> It has a number of unique biochemical effects, some of which are shared by ECT.>>then one would expect it to be especially good for the most severe depressions.
>
> It illicits a strong responce in certain areas associated with the regulation of circadian rythem. >>my circadian rhythms are so disturbed that off medication, they are utter chaos.
>
> It also shows an interesting pattern of receptor alteration. It desensitizes both 5-ht1a/b autoreceptors. It downregulates beta adrenoreceptors. I also think it has some effects on dopamine autoreceptors.>a while ago (maybe thirty years) there was a beta adrenoceptor hypothesis of AD action. there still is one, apparently, in panic disorder: the only AD's (so called) that are not also antipanic agents are trazodone, bupropion, and buspirone (buspirone is considered an AD by many investigators, and i agree) and none of these down regulate beta adrenoceptor receptors. so perhaps rTMS is an antipanic treatment as well?
(although I wonder if AP's are also antipanic agents, and clonazepam is a most powerful antipanic agent)
>
>
>
> 15 hz also (surprisingly) led to an almost immediate reduction in my headaches.
>
yes, that is surprising. given that the hypnagogic hallucinations/ sleep paralysis I experience with distressing frequency on Provigil feel like electrical shocks sometimes, and leave headaches and insomnia in their wake, I would be most reluctant to apply an electrical device to my skull. that is just my own prejudice.
> rTMS (like ECT) in animals, increases the behavioral sensitivity to stimulants.
>
> (this may be due to 5-ht autorceptor downregulation, since mice 5-ht autoreceptor mutant mice also display an increased behavioral responce to stimulants)
>
i've read that too. the dopamine/serotonin relationship is complex.
-z
> Linkadge
>
>
>
>
>
Posted by linkadge on February 21, 2006, at 16:47:53
In reply to Re: this is interesting » linkadge, posted by zeugma on February 21, 2006, at 13:50:19
>did you find that your attention/focus was >improved while undergoing rTMS?
Yes, my concentration improved imedately, but my actually cognition and comprehention improved later. It was like I was using different parts of my brain to process information, and that those areas hadn't been worked in a while.
>then one would expect it to be especially good >for the most severe depressions.
It is kindof variable, even like ECT. There have been those who have failed ECT and responded to rTMS, and vice versa. There will, of course, be people who fail both.
>a while ago (maybe thirty years) there was a >beta adrenoceptor hypothesis of AD action. there >still is one, apparently, in panic disorder: the >only AD's (so called) that are not also >antipanic agents are trazodone, bupropion, and >buspirone (buspirone is considered an AD by many >investigators, and i agree) and none of these >down regulate beta adrenoceptor receptors. so >perhaps rTMS is an antipanic treatment as well?
Yes perhaps. It is really dumb because I think that the beta-adrenorceptor theory was replaced by the theory about 5-ht2 system downregulation only after the advent of the SSRI's.
Beta adrenoreceptor density may not be a result of circulating norepinephrine though, since I have read that NMDA antagonists can downregulate adrenoreceptors.
>(although I wonder if AP's are also antipanic >agents, and clonazepam is a most powerful
>antipanic agent)I personally found no anti-panic effect of the antipsychotics. Some of them made my panic disorder worse. Exercise has anti-panic effects, and it too reduces adrenoreceptor density, among other things.
>yes, that is surprising. given that the >hypnagogic hallucinations/ sleep paralysis I >experience with distressing frequency on >Provigil feel like electrical shocks sometimes, >and leave headaches and insomnia in their wake, >I would be most reluctant to apply an electrical >device to my skull. that is just my own >prejudice.I've regretted doing it, entering bouts of paranoia that I will end up with a brain tumor one day.
Linkadge
Posted by SLS on February 22, 2006, at 6:14:54
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » SLS, posted by zeugma on February 20, 2006, at 14:48:06
> Mazindol is also used in Europe to treat narcolepsy.
That's interesting. Despite it being such a high affinity DAT ligand that may or may not inhibit DA reuptake, it seems that the actions of mazindol result in large increases of NE. How might this fit into a model of narcolepsy?
> It is similar to nomifensine? (which was also looked at for ADHD).
> Did you find that nomifensine had a positive effect on cognition?
I was hoping that it would be. Unfortunately, mazindol might not be the potent DA reuptake inhibitor it was first thought to be. Nomifensine was indeed a DA reuptake inhibitor along with being a potent NE reuptake inhibitor. For some people with TRD, it was a powerful antidepressant with few side effects that has been the only thing that ever worked for them. I can't speak to its potential as an ADD drug. I never saw it used to treat it. However, it cleared-up my cognitive impairments for the time I responded to it. For me, an almost instantaneous improvement in cognitive function always accompanies a true antidepressant response.
> > What are your thoughts on sibutramine?
> Ken Gillman, who operates a site called http://psychotropical.com/, speaks highly of this as an AD, at least when I used to visit his site.Thanks for the link. I'll have to check it out.
> Have you ever tried it?
No, and I doubt I could get my prescription plan to pay for it. They require that you be weighed frequently and remain eligible for an indication of obesity.
> I wonder if D4 ligands have been looked at in depression.
I don't know. The only thing that comes to mind is sulpiride (but not amisulpride), which acts as a ligand to D4. It is an antagonist. Ropinirole seems to ring a bell also, but would be an agonist. If you come up with anything on ropinerole, please post what you find.
- Scott
Posted by zeugma on February 22, 2006, at 21:48:14
In reply to Re: NRIs are infact dopamine uptakin inhibitors ? » zeugma, posted by SLS on February 22, 2006, at 6:14:54
> > Mazindol is also used in Europe to treat narcolepsy.
>
> That's interesting. Despite it being such a high affinity DAT ligand that may or may not inhibit DA reuptake, it seems that the actions of mazindol result in large increases of NE. How might this fit into a model of narcolepsy?>>Norepinephrine is anticataleptic. That is why TCA's were the classical treatment for cataplexy as well as the ancillary symptoms of narcolepsy, sleep apralysis and hypnagogic hallucinations. SSRI's are also anticataleptic- essentially any drug that prolongs REM latency will work. Atomoxetine is now recommended as a preferred treatment for cataplexy.
Whether NE has a role to play in wakefulness is much more controversial. Some have found an alerting effect from reboxetine in narcolepsy. Modafinil probably works through the alpha-1 receptor and the D4 receptor (this latter is just a speculation of mine), because it has been reported to specifically antagonize the EEG effects of clozapine, which is both a powerful alpha-1 antagonist and D4 antagonist; this specific antagonism was not seen to the same degree in the interaction between modafinil and other neuroleptics, most of which antagonize alpha-1 and D4 receptors to a lesser degree.
Apomorphine also displayed an interaction with clozapine, albeit to a lesser degree. Apomorphine is apparently the most selective of the dopamine agonists for D4.
The D4 receptor, besides resembling the NE transporter in its lack of ligand specificity (any catecholamine will do, although the extent to which this is true is dependent on which polymorphrphism is present) also apparently participates in the regulation of glutamate and GABA pathways in a complicated way- perhaps explaining some of modafinil's mysterious actions. I am speculating wildly, of course.
>
> > It is similar to nomifensine? (which was also looked at for ADHD).
>
> > Did you find that nomifensine had a positive effect on cognition?
>
> I was hoping that it would be. Unfortunately, mazindol might not be the potent DA reuptake inhibitor it was first thought to be. Nomifensine was indeed a DA reuptake inhibitor along with being a potent NE reuptake inhibitor. For some people with TRD, it was a powerful antidepressant with few side effects that has been the only thing that ever worked for them. I can't speak to its potential as an ADD drug. I never saw it used to treat it. However, it cleared-up my cognitive impairments for the time I responded to it. For me, an almost instantaneous improvement in cognitive function always accompanies a true antidepressant response.
>
I have experienced that with atomoxetine most strikingly (immediate clearing up of my cognitive processes), and to a lesser degree with nortriptyline. Modafinil exerted an immediate slowing of my cognitive processes, which feels almost anticholinergic.Modafinil also causes a dry mouth that feels like I am overdosing on atropine. I hope it's not some complicated interaction with nortriptyline. But there are no cardiac effects from the combination of modafinil and nortriptyline whatsoever.> > > What are your thoughts on sibutramine?
>
> > Ken Gillman, who operates a site called http://psychotropical.com/, speaks highly of this as an AD, at least when I used to visit his site.
>
> Thanks for the link. I'll have to check it out.
>
> >
>
> > I wonder if D4 ligands have been looked at in depression.
>
> I don't know. The only thing that comes to mind is sulpiride (but not amisulpride), which acts as a ligand to D4. It is an antagonist. Ropinirole seems to ring a bell also, but would be an agonist. If you come up with anything on ropinerole, please post what you find.
>
Apomorphine is a much stronger agonist for the D4 receptor than ropinerole.Quinpirole is also a potent D4 agonist but I do not know if it is commercially available. Apomorphine apparently has been found to prevent depression in Parkinson's. but I imagine it is virtually impossible to get off-label.Sulpiride is a D4 antagonist, but clozapine is much more potent. Interestingly, sulpiride has been looked at in the treatment of narcolepsy- as an anticataplectic that does not suppress REM. D2/D3 antagonism is the mechanism attributed to this effect, so clozapine (even if it were not prone to hematoxicity) would not be effective for this purpose.
-z
>
This is the end of the thread.
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