Posted by PeterJ on May 17, 2000, at 17:40:38
In reply to Re: Amineptine substitute?, posted by SLS on May 17, 2000, at 14:24:06
> Amphetamine is considered to be a much more potent releaser of dopamine and norepinephrine than it is a reuptake inhibitor. From what I've read, it seems that it is its releasing effect that is given most of the credit for its clinical and biological activity.I wouldn't argue with that, except to say that the way it causes release--by binding to the dopamine shuttle and moving into the cell--inherently blocks uptake at the same time. So it's not a simple matter to separate the two effects. For example, in a cell already releasing larger amounts of dopamine it might act mainly by inhibiting uptake, but in a cell not releasing dopamine to start with its greateest effect would be release.
> How is the release of neurotransmitter effected by a drug acting at the synapse differentiated from that which may be a result of pharmacological activity elsewhere. Perhaps some studies do not use a paradigm that would accomplish this effectively.
In a whole brain study, enchanced release and reuptake inhibition are very hard to distinguish. They both result in more dopamine outside the cell. The best way to determine the actual moleculer effect is to study binding to the transporter in in vitro systems, such as cloned cells expressing the transporter gene.
> I read that amphetamine promotes the release of norepinephrine via vesicular release.
>
> Does any of this happen at DA terminals?
> Does amphetamine also promote the release of norepinephrine via NE transporter?
>
> I'm having you do my homework. :-)This reference should be helpful:
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10193907&dopt=Abstract
> > 2. Mazindol has been studied in a PET study of
> > human subjects. The study intended to explore
> > its use as a treatment for cocaine addiction.
> > Typical doses of mazindol only
> > bound a very small percent of DA receptors. It
> > was felt that doses high enough to inhibit
> > DA receptors would have excessive side effects.
> > Mazindol seems to be about 20X more potent
> > at inhibiting NE uptake.
>
> Any chance you could point me in the direction of some of this info? I find this quite disappointing.http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9676890&dopt=Abstract
The one ray of hope is that the study was done in cocaine addicts, and they may have elevated levels of the dopamine transporter. Perhaps in non-addicts mazindol would look better.
> > It has been reported to relieve
> > depression in a few cases, but that may
> > be due to its NE effects as much as its DA
> > effects.
>
> I imagine all of these investigations studied mazindol as monotherapy. I would like to consider it as an adjunct to things like amisulpride or an MAO inhibitor. DA agonists and amphetamines are also usually ineffective at treating depression monotherapeutically, but are often good augmenting agents to antidepressants (I hope).It's worth a try. Just be cautious of its NE effects re hypertension, anxiety etc.
>
> > 7. Initial enhancement by many substances of
> > dopamine activity often results in only short-
> > lived benefits. Dr. Baron Shopsin, who
> > studied several dopamine drugs clinically in the
> > 70s and 80s found this to be their achilles heel.
>
> Do you mean "enhancement" of an antidepressant effect during ongoing antidepressant therapy? This seems to have been my experience with Dexedrine and Parlodel.I meant enchancement over baseline DA activity, i.e. as monotherapy. Adjunctive use has a better record as you know, although even there, the more specfic DA effects may often fade with time.
> Baron Shopsin was my doctor for almost four years. I did some work for him as a research assistant. He was quite fond of pemoline as an augmenting agent, particularly with Parnate. He also liked to use Pirebedil, then known as ET-495. Dr. Shopsin was a disciple of Nathan Klein. He had a keen mind and was ahead of his time. He was one of the first to conclude that schizo-affective disorder was a discreet illness, and wrote a book about it (of which he was quite proud). He was also the first investigator to recognize that Wellbutrin carried less liability to induce mania. Unfortunately, he moved his practice out to the Old Brickyard.By "Old Brickyard" do you mean Indianapolis? Or is this a metaphor with which I am unfamiliar?
Pemoline is an excellent DA releasing drug. Very selective. No effect on NE, thus no concern about hypertension w/ MAOIs. Unfortunately fewer doctors are prescribing it since the FDA sent out a "Dear Doctor" letter warning of liver toxicity. The thing is, liver toxicity from pemoline is very rare in adults. For children with ADHD it can be problematic.
> > 9. Direct DA agonists like piribidel, bromocriptine,
> > pramipexole, etc., may also help.
>
> I am trying to decide which of these I would like to use. Pergolide is also a candidate. Any thoughts?I'm not sure which would be best, but a direct agonist is worth trying.
One more thought: DA is also taken up by the NE transporter (i.e. on nearby NE terminals) so blocking the NE transporter may enhance the effects of DA release/uptake inhibition in some areas.
Peter
poster:PeterJ
thread:33419
URL: http://www.dr-bob.org/babble/20000517/msgs/33806.html