Posted by zeugma on February 26, 2006, at 16:10:34
In reply to Re: provigil discussion » zeugma, posted by SLS on February 26, 2006, at 14:38:46
Here, modafinil seems to act as an amplifier. By itself, though, it does not elicit 5-HT increase. I noticed some other work by these same authors suggesting otherwise, but at concentrations too high to be relevant to those in clinical use.>>
I believe you're referring to this:
Doses of modafinil administered to rats are much higher than those administered to other species, including mice:
So possibly the effect on 5-HT observed by Fuxe et al. is therapeutically relevant to humans, in isolation.
What really puzzles me is that modafinil has absolutely no REM-suppressant or anticataleptic effect. This in itself is surprising, since most drugs that work through the alpha-1 adrenoceptor (directly or not) are REM-suppressant and anticataleptic, and I am recovering from my usual Sunday series of REM-distorted sleep episodes that were not a problem when I was on methylphenidate (meaning I could nap on methylphenidate and not experience a sleep-onset REM period that causes immediate, unpleasant waking). Buspirone, too, through stimulation of post-synaptic 5-HT1A receptors or alpha-2 adrenoceptors, blocks REM, making it useful as a quick REM suppressant (but I am trying to stay awake today, so fell asleep involuntarily- but last week I was able to nap during the afternoon after taking buspirone). So I was especially interested in the following passage of the reference you cited:
<<
It has been hypothesized that activation of 5-HT neurons contributes to the function of ascending arousal systems projecting to the forebrain (O'Hearn and Molliver, 1984; McQuade and Sharp, 1995, 1997; Portas et al., 1998). Within the brainstem, serotonergic inputs to REM-sleep active areas in the pedunculopontine tegmental and laterodorsal tegmental nucleus (Honda and Semba, 1994; Vertes and Kocsis, 1994) would tend to suppress REM sleep (Thakkar et al., 1998; Monti and Monti, 2000; Portas et al., 2000). Consistent with this model, in vitro data have shown that 5-HT and 5-HT1A agonists inhibit neurons in those regions (Luebke et al., 1992; Leonard and Llinas, 1994). Furthermore, microinjections of 5-HT into the laterodorsal tegmental nucleus in behaving (unanesthetized) cats and rats have been shown to produce a dose-dependent suppression of REM sleep (Sanford et al., 1994; Horner et al., 1997). In addition, there is direct evidence that suppression of 5-HT neuronal activity in the DRN increases REM sleep (Portas et al., 1996). Thus, direct activation of 5-HT neurons by hcrts could promote wakefulness or suppress sleep states through these and other brainstem and forebrain projections. >>The statement elsewhere in the article that the hypocretin ACTIVATED GABAA signalling in the dorsal raphe is consistent with the fact that both modafinil and clonazepam induce sleep onset REM for me:
<<In the present study, we have found that high concentrations of hcrts can have an indirect inhibitory effect on 5-HT cells by exciting GABAergic interneurons in the DRN area. It remains to be determined how hcrts interact with other transmitters in regulating the GABAergic inputs to the 5-HT cells. Nevertheless, the present results show that the influence of hcrts in the DRN is more complex than simply the direct excitation of 5-HT neurons.>>
Most narcoleptics lack hypocretin in their CSF, but nonetheless they still experience the hypocretinergic effects (increased waking, and aggravation of cataplexy/REM). In fact one physician even speculated (under the sway of earlier thorists who maintained that modafinil worked directly on alpha-1 receptors) that modafinil must be a mixed agonist/antagonist at alpha-1 receptors, since it induced cataplexy and sleep onset REM in his patient.
I would guess that it is hypocretin that is responsible for much of modafinil's effects, from reading the article you cited.
I suppose hypocretin's activation of GABAergic interneurons in the DRN might also be responsible for why modafinil is not especially epileptigenic.
By the way, Karel Fuxe is one of the most illustrious names in neuropharmacology.
-z
poster:zeugma
thread:612884
URL: http://www.dr-bob.org/babble/20060219/msgs/613525.html