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.
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> 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.
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> > It is similar to nomifensine? (which was also looked at for ADHD).
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> > Did you find that nomifensine had a positive effect on cognition?
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> 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.
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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?
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> > 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.
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> Thanks for the link. I'll have to check it out.
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> > I wonder if D4 ligands have been looked at in depression.
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> 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.
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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
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poster:zeugma
thread:611154
URL: http://www.dr-bob.org/babble/20060219/msgs/612259.html