Posted by SLS on August 8, 2000, at 17:44:18
In reply to Re: Adrafinil: John, Scott, posted by AndrewB on August 7, 2000, at 11:39:47
Hi Andrew.
> I don't know if Naphazoline crosses the blood brain barrier.I believe naphazoline enters the brain through the eye, as the eye lies on the brain side of the blood-brain barrier.
> On a related note, I am very interested in the idea of an alphal1 andrenergic agonist being able to be centrally selective in its actions (vs. having both central and periphereal action) as is claimed (hah, hah!) for adrafinil.
I tried looking for such a drug a few months back, but came up empty. I really didn't invest that much energy into it. I guess naphazoline is the closest thing to it, and is probably why Dr. Goldstein has come to rely on it.
By the way, what URLs are available for Dr. Goldstein? My guess is that you utilize more than one resource. His ideas to use different drugs (substances) as biological probes are exciting and in accord with my own. I've suggested this type of algorithm in the past, but didn't know that anyone had actually put them into practice. Have you thought to contact him?
> Reboxetine's effect of severely limiting my athletic stamina and the sexual side effects, I believe are due to periphereal alpha1 agonism. So I would think a centrally acting alpha1 agonist would be great for a lot of people, myself included.
What mechanisms are proposed for why NE alpha-1 agonism affects your athletic performance? What exactly do you experience? Are you sure it is not related to sympathetic/cardiac effects?
> Glutamate opens the calcium channels. Compare this to the calcium channel blocking action of nimodipine. Too much calcium within the cell somehow leads to neuron death. I forgot the speicifics. Anyway, such glutamate induced neuron death is being recognized as a leading factor in a lot mental maladies and other conditions. For example, the greater part of the brain damage caused by a stroke is not due to hypoxia, rather glutamate toxicity.
I am too anergic to do the homework, but aren't there other substances (peptides?) released by the traumatized tissue that is responsible for much of the neuronal damage? Ornithine something-or-other. Years ago, I read of a strategy intended to prevent the secretion of or inactivate these substances. It was critical to intervene within hours of the event. This did not involve increasing cerebral blood flow via CA-channel blockade. Aside from L-type CA-channel blockade, what other properties does nimodipine possess?
> It is Memantine's glutamate limiting actions, as an NMDA receptor antagonist, that enables it to be effective in the treatment of dementia, neuropathic pain, Alzheimers, Huntington's disease, Amyotrophic Lateral Sclerosis and glaucoma. The miracles of modern medicine!
What are some of the main functions and pathways involved with NMDA receptors?
> Now Scott, let me ask you, how do you think lamotrigine's glutamate lowering action translates into its effectiveness as a mood stabilizer.By inhibiting the release of glutamate, lamotrigine (Lamictal) allows the glutamate/GABA balance to shift in favor of GABA. GABA receptors and neurons are responsible for preventing the overactivity of excitatory pathways. One of Depakote's properties is to increase GABA activity. Neurontin (gabapentin), an anolog of GABA, was thought to increase the synthesis of GABA. (The NMDA explanation you describe may be a more viable explanation). Tiagabine (Gabitril), another anticonvulsant proposed as a mood stabilizer, potentiates GABA neurotransmission by acting as a GABA uptake inhibitor. Topiramate (Topomax) may act more like lamotrigine in that it probably inhibits glutamate activity by inhibiting the NMDA receptor.
As for mood stabilization per se, I don't know enough to report specifics. As for anti-manic potential, I have come across some abstracts detailing the role of GABA pathways in reducing the activity of DA neurons in the nucleus accumbens in a manner antagonistic of glutamatergic input.
> Have you ever considered taking a mood stabilizer?
So far, lamotrigine is the only one that consistently produces some relief from depression. However, it does not seem particularly effective as an antimanic drug for me as it did not prevent a Nardil discontinuation-induced mixed state that I experienced a year ago. My guess is that the antidepressant properties of lamotrigine are distinct from its mood stabilization properties and may involve dopaminergic phenomena. One of the early studies reported some pro-dopaminergic activity.
I think lithium may be helpful in the future, but I hate the affect-flattening effect and passivity it produces. Depakote makes me feel moderately worse in the long-run, although it can produce an improvement initially and acutely. Neurontin affects me in a similar manner, but really whacks me out within a week or two. I have discovered this past week that the exacerbation of depression and the cognitive disturbances it produces is time-dependant and not dosage-dependant. A few months ago, it left me in a worsened state for at least three weeks after discontinuation. I am a bit frightened by Neurontin.
> I'm not sure why reboxetine pooped out. The timing of it though clears selegiline of any association with it. Actually, I quickly built up a tolerance to Naphazoline (the alpha1 agonist)
I didn't know that you had gleaned a positive effect from naphazoline. What did it do for you and how long did it last?
> and this tolerance seems also to have crossed over and effected reboxetine's ability to act on these receptors. But, hey, I wouldn't lay money down on that being what really happened.
Receptor dynamics can be permanently changed by drug exposure, particularly if it is repeated and intermittant.
I would like to comment on a description JohnL recently offered. He sait that it took adrafinil longer to produce an adequate response once he discontinued it and later restarted it.
> One final note, Dr. Goldstein lists neurontin as an (indirect) NMDA antagonist.
Topiramate (Topomax) is thought to be a direct-acting antagonist of the NMDA receptor. This is in addition to its GABAergic potentiation properties. I hope I eventually get around to learning more about glutamate, NMDA, and sigma receptors - to name a few. I wish I had more of my wits to be able to. I also wish I were closer to a medical school library.
> Best wishes to the both of you
As always, the sentiments are reciprocal.
Take care.
- Scott
poster:SLS
thread:42223
URL: http://www.dr-bob.org/babble/20000729/msgs/42381.html