Posted by SLS on May 17, 2000, at 14:24:06
In reply to Re: Amineptine substitute?, posted by PeterJ on May 16, 2000, at 18:58:50
Thanks Peter.
> 1. It's not too clear what the difference between
> releasers and uptake inhibitors is clinically.
> Amphetamine does both.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.
> Cocaine inhibits DA uptake but does not cause release. Both have very similar behavioral effects.
Cocaine putatively promotes the release of dopamine in the nucleus accumbens. I don't know what mechanisms are responsible for this, but I haven't encountered anything that involves actions at the synapse. Perhaps it accomplishes this through activation of afferent pathways in a way similar to opiates. I guess this might occur as the result of norepinephrine reuptake inhibition by cocaine in the amygdala or hippocampus.
> The mechanism of amineptine depend on
> which lab you believe. I've seen a studies that
> say it increases DA release and others that say
> it only inhibits uptake. I'm inclined to think
> it is an uptake inhibitor only, based on its
> large tricylic structure.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.
> BTW, the dopamine transporter acts like a shuttle
> that goes back and forth across the cell membrane.
> When it crosses it can take a molecule of
> dopamine with it. (Imagine one of those clotheslines
> strung btween two buildings with a pulley. The
> dopamine transporter is like a basket on the line.)
> It can shuttle dopamine into or out of the cell,
> depending on the situation.
> If you give amphetamine, it binds to the shuttle
> on the outside of the cell. The shuttle then
> crosses over to the inside face of the membrane,
> taking the amphetamine with it. The amphetamine
> is released inside. Then some dopamine binds to the
> now empty transporter and it is shuttled to the outside
> of the cell.
> A pure uptake inhibitor will bind to
> the tranporter when it is on the outside surface of the
> cell and put it in such a conformation that it is stuck
> there and cannot cross back over. Thus it cannot shuttle
> dopamine into the cell.
Much thanks! I did not know this.
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. :-)
> 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.
> 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).
> 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.
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.
> 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?
Thanks again.
Sincerely,
Scott
poster:SLS
thread:33419
URL: http://www.dr-bob.org/babble/20000517/msgs/33781.html