Posted by SLS on February 26, 2006, at 9:11:37
In reply to Re: provigil discussion » SLS, posted by mike99 on February 25, 2006, at 13:51:04
> Do you have any thoughts then on how provigil stimulates the cardiovascular system,
Not really. Again, I would refer you to structures in the hypothalamus and reticular formation that contain orexinergic (hypocretin) and glutamatergic neurons. The hypothalamus most certainly serves to regulate vital bodily functions.
Regarding modafinil and dopamine, at least one mechanism by which limbic areas rich in DA neurons are stimulated is via the glutamate-releasing properties of modafinil in the thalamus. The GABA-glutamate balance is shifted towards glutamate, thus stimulating (disinhibiting) the nucleus accumbens, a reward center located in the limbic system. I don't believe modafinil affects directly any DA receptor or transporter.
My first guess is that beta blockers would help to mitigate any tachycardia or perhaps even anxiety. The beta blocker probably would not act to antagonize the pharmacology of modafinil, but, rather, to simply compensate for it downstream. Losartan might be an ideal drug as it would also help mitigate the increase in blood pressure seen with modafinil. It would help reduce the effects of the excess plasma NE that modafinil is capable of producing. It should accomplish this by preventing the stimulation of peripheral NE alpha-1 receptors by endogenous NE.
The problem with some of the older studies of modafinil is that they focused almost exclusively on the effects it had on aminergic neurotransmission, particularly NE and DA. Unfortunately, some of the investigators jumped to conclusions prematurely regarding the mechanisms of involvement of these neurotransmitters. Just because a particular pathway must be intact for a drug to produce changes downstream doesn't mean that this pathway is directly affected by the test drug. However, this was the basis by which the original research inferred a direct effect for modafinil on NE receptors.
Modafinil was originally pronounced to be a central alpha-1 adrenergic agonist. No more.
The package label and PDR entries for modafil were written after the NE receptor theories were debunked. The mechanisms by which modafinil produces wakefulness are not well understood, but probably do involve hypocretin. By contrast, the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.Sorry for the redundancies.
- Scott
poster:SLS
thread:612884
URL: http://www.dr-bob.org/babble/20060219/msgs/613408.html